Bioorganic Chemistry 90 (2019) 103073

Contents lists available at ScienceDirect

Bioorganic Chemistry

journal homepage: www.elsevier.com/locate/bioorg

Minireview The stilbene derivatives, nucleosides, and nucleosides modified by stilbene T derivatives Hanna Krawczyk

Department of Organic Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

ARTICLE INFO ABSTRACT

Keywords: In this short review, including 187 references, the issues of biological activity of stilbene derivatives and nu- Nucleoside cleosides and the biological and medicinal potential of fusion of these two classes are discussed. The stilbenes, Derivative of stilbene especially the stilbenoids, and nucleosides are both biologically active. Hybrids formed from binding of these Stilbene compounds have not yet been broadly studied. However, those that have been investigated exhibit desirable Nucleoside hybrids medicinal properties. The review is divided in such parts: I. Derivative of stilbene (biomedical investigations, biological activities in cells, enzymes and hazard), parts II. naturally occurred nucleoside and its derivatives: uridine, thymidine and 5-methyluridine, cytidine, adenosine, guanosine and part III. hybrid molecules- drugs and hybrid molecules- nucleoside - stilbene and its derivative.

1. Introduction studies (phase 1b, a clinical trial in relapsed/refractory acute myeloid leukemia) show that OXi4503 (combretastatin A1 diphosphate, CA1P, 6 Nanomedicine is a challenge and a chance for mankind, but its Fig. 1) is more potent than other clinically evaluated vascular-dis- development requires new highly efficient tools. Nanoplatforms that rupting agents [16]. In conclusion, the stilbene compounds have been can simultaneously accommodate multiple biofunctional species (e.g. proven to possess potent anticancer, antiinflammatory and antioxidant therapeutic agents and diagnostic factors) and concurrently transport activities. The nucleosides and their analogs also exhibit biological them into the host cells are such novel devices. Integration of two or properties. For example, adenosine (7, Fig. 1) is used in diseases of the more different therapeutic mechanisms in one nanosystem can poten- heart, and its derivatives, dCF (2′-deoxycoformycin) [17,18], 2CdA (2- tially produce synergistic effects and offer better treatment outcomes chloro-2′- deoxyadenosine) [19,20] and F-ara-A (9-beta-D-2-arabinosil [1]. -2-fluoroadenine) [21] (8, 9, 10, Fig. 1) are used in the treatment of Nanoplatforms are variously organized. They may be small-mole- malignant blood tumors. Although resveratrol in combination with cule drugs, physically embedded into the macrocycles or nanoparticles nucleoside analogs [22,23] exhibits potent synergistic inhibitory ac- (NPs) or conjugated to the carriers via chemically labile linkages [2-4]. tivity against human immunodeficiency Virus (HIV-1), the chemical Stilbenes a family of secondary metabolites derived via phenylpropa- combinations of the nucleoside (in the purine ring) and stilbene have noid pathway or via the polyketide pathway [5], either of which con- been poorly documented so far. By combining the nucleoside with the sists of a trans or cis-ethene double bond substituted with a phenyl on stilbene derivatives, different molecular hybrids can be obtained. In this both carbon atoms of the double bond. Naturally occurring nucleosides manuscript, a short review is presented of the reactivity of stilbene modified by stilben (1, Fig. 1)- derivatives may constitute one of the derivatives and nucleosides with purine and pyrimidine ring and hy- components of such a system. Several reports have shown that certain brids of the either. derivatives of hydroxystilbenes significantly extend the lifespan of se- lected biological species such as yeast (Saccharomyces cerevisiae), worm 2. Stilbene derivatives (Caenorhabditis elegans) and fish (Nothobranchius furzeri) [6-8]. It was reported that resveratrol (2, RSV, Fig. 1), belonging to the same class of Stilbene derivatives are usually thermally and chemically stable, compounds, synergistically enhanced the anti-HIV-1 activity of the and exhibit absorption and fluorescence properties that are convenient nucleoside analogs zidovudine, zalcitabine, and didanosine (3, 4, 5 for monitoring by relevant optical techniques [24,25]. They play an Fig. 1) [9]. Derivatives of methoxy stilbenes, such as combretastatins, important role in the area of photophysical [26], photochemical [27], also exhibit antimiotic and antivascular properties [10-15]. Preclinical biophysical [28], and biomedical investigations [29]. Stilbenes and

E-mail address: [email protected]. https://doi.org/10.1016/j.bioorg.2019.103073 Received 29 January 2019; Received in revised form 23 April 2019; Accepted 15 June 2019 Available online 17 June 2019 0045-2068/ © 2019 Published by Elsevier Inc. H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Fig. 1. The derivatives of stilben (1, 2, 6), of adenosine (7) and biological active derivatives of nucleoside (3–5, 8–10). their derivatives, stilbenoids, form a multidisciplinary field that com- environment, improve the adaptive capacity of the nervous and im- bines many important branches of chemistry, biology, physics and mune systems, show antitumor, cardioprotective and lipid-lowering medicine. This field is under active investigation now. activities, inhibit lipid peroxidation. The most known and tested stil- benes are: resveratrol (2), derivatives of naturally occurring com- bretastatin A1, OXi4503 (6) and pterostilbene (E-3,5-dimethoxy-4′- 2.1. Naturally occurring stilbenes hydroxystilbene).

Presently, more representatives of stilbenoids are known - a group of natural, biologically active substances, according to the chemical 2.2. Stilbenes- biomedical investigations structure belonging to the group of polyphenolic compounds - phe- nylpropanoids. Representatives of this group of compounds can be Several papers concern interaction of stilbene derivatives with DNA. detected in such classes of plants as gymnosperms, angiosperms, A run of stilbene–DNA conjugates with different substituents in the bryophytes, and pteridophytes. Their main sources are fruits such as distal aromatic ring of the stilben was explored [30]. Stilbenes were grapes, blueberries, peanuts, cocoa. The history of their detection is linked with DNA in position 5′ of nucleoside. Aminomethylstilben (11) associated with the discovery of the protective functions of plants in and trimethoxystilben derivative (12)(Fig. 2) were investigated to be response to the action of external stimuli. Studies revealed pronounced the fidelity- and affinity-enhancing modulators of DNA duplex stability. antioxidant properties. The mechanism of development of many dis- The phosphoramidite of the trimethoxystilbene was used in automatic eases is associated with the processes of oxidation of free radicals. They DNA synthesis, simplified the generation of DNA chips which improved can be interrupted by the effect of antioxidants. Possible mechanisms of fidelity. antioxidant action of stilbenoids and their effect on diseases caused by Lewis et al described [31] the structure and properties of 18 hairpin- excessive amounts of free radicals have been studied. Stilbenoids in- forming bis(oligonucleotide) conjugates connected with stilbene die- crease the tone and stability of the body to stress factors of the ther linkers. It was demonstrated that conjugates possessing bis(2-

2 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

(Mabs) were generated against the trans-4-N,N-dimethylamino-4′-ni- trostilben (14, Fig. 3.). Stilbene moiety was bound in a planar con- formation. Rotation around the excited-state C]C bond and the styryl- anilino CeC bond was investigated to be restricted by interactions be- tween the ligand and the definite antibody residues. Recently it was demonstrated that resveratrol and pterostilbene completely block HIV-1 infection at a low micromolar dose in resting CD4 T cells, primarily at the reverse transcription step [35]. However, resveratrol alone does not inhibit HIV-1 infection of activated T cells, but it does synergize with nucleoside reverse transcriptase inhibitors in these cells to inhibit reverse transcription.

2.3. Stilbenes- biological activities in cells Fig. 2. Aminomethylstilben (11) and trimethoxystilben derivative (12). Stilbenoids possess a wide range of properties, which allow con- hydroxyethyl) stilbene 4,4′-diether linkers created the most stable DNA sidering these compounds as potentially important drugs with a broad hairpins. It was shown that hairpins with two T-A base pairs or four therapeutic field [36,37]. Trans-resveratrol (2) may be used as a cancer noncanonical G-G base pairs were stable at room temperature and in- chemo-preventive agent showing antioxidant activity and causing up- creasing the length of the hydroxyalkyl groups resulted in a decrease in regulation of NO production [38,39]. There were investigations that hairpin thermal stability. In turn diethylstilbestrol (13, DES, Fig. 3.) resveratrol therapy may prevent the hypertensive response and the was shown by 32P-post-labeling analysis to bind covalently to DNA in relaxation response to acetylcholine [40]. The resveratrol also exhibits vivo and in vitro [32]. Influence of DES dose, the age of the animal, and cardioprotective effects, and anticancer properties. It is known for its organ specificity on adduct formation in hamsters was examined. Cu- ability to suppress the proliferation of a wide variety of tumor cells, mene hydroperoxide was required as a cofactor in the covalent binding including lymphoid and myeloid cancers, multiple myeloma, cancers of of DES to DNA catalyzed by hamster liver microsomes. It was concluded the breast, prostate, stomach, colon, pancreas, and thyroid melanoma, that stilbene–DNA adduction could occur only under oxidative stress head and neck squamous cell carcinoma, ovarian carcinoma, and cer- conditions. Stilbenes also are reported to inhibit DNA synthesis and vical carcinoma [41]. In turn, Valle et al. propose that the anticancer duplication and lymphocyte proliferation during immunosuppressive mechanisms of RSV could reside in targeting cancer cell metabolism, therapies [33]. promoting mitochondrial electron transport chain overload and, ulti- An interesting investigation of stilbenes has been carried out in the mately, increasing ROS production [42]. These investigations of oxygen intracellular delivery of synthetic nucleic acids [28], especially the way consumption, ATP levels, Western blotting and other molecular biology to deliver short, double-stranded RNA to living cells. They are of in- techniques were carried out to characterize the metabolic signature of terest because of the potential to engage the RNA interference ma- RSV in SW620 colon cancer cells. The cytotoxic effects of resveratrol chinery and to regulate mRNA expression. Chemical modification with were associated with an increase in oxygen consumption supported by stilbenes of the termini of hybridized RNA strands enabled the display mitochondrial biogenesis and increased fatty acid oxidation. This par- of small organic moieties on the outer surface of the micelle corona. It tial reversion of the Warburg effect (the observation that cancer cells was found that some of these modifications can have a tremendous tend to favor metabolism via aerobic glycolysis rather than the much impact on cellular internalization efficiencies. The display of hydro- more efficient oxidative phosphorylation pathway) was followed by phobic stilbene units dramatically increased cell uptake into HeLa cells hyperpolarization of mitochondrial membrane and reactive oxygen without the need for toxic transfection reagents. species production, leading to an increased apoptosis. Therefore, the It is worth noting that a complex of donor–acceptor-substituted authors postulated that the anticancer mechanisms of RSV could reside stilbene with antibodies has been prepared [34], Monoclonal antibodies in targeting cancer cell metabolism, promoting mitochondrial electron

Fig. 3. Structures of: diethylstilbestrol (13), E-4-N, N-dimethylamino-4′-nitrostilben (14), CA4P (15), OXi4503 (16), fosbretabulin (17), pterostilbene (18), oxyRSV (19), DHS (20) and pinosylvin (21).

3 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073 transport chain over load and, ultimately, increasing ROS production. antiinflammatory activities as they inhibit the arachidonic acid Resveratrol is a compound with potent pharmacological effects as- pathway leading to the formation of prostaglandins that activate car- sociated with its antioxidant properties. In the brain, resveratrol pro- cinogenesis and stimulate cancer cell growth by inhibiting the hydro- duces protective responses against cerebral ischemia (a neurological peroxidase activity of cyclooxygenase [58]. Stilbenes slow the pro- condition in which energetics and oxidative stress are disregulated), gression of carcinogenesis in a dose-dependent manner thus inhibits the decreases infarct volume and improves neurological function [43]. development of preneoplastic lesions. Combretastatins (for example CA1P, 6 Fig. 1, and 15, Fig. 3) are po- In the study described in the reference [59], the effect of several tential new vascular disrupting agents (VDAs) and vascular targeting resveratrol structural analogues on AMP-activated protein kinase agents (VTAs) and show a remarkable ability to inhibit gastric tumor (AMPK) activity in HepG2 cells was investigated, and combretastatin A- metastasis and enhanced antitumor immune reactivity [10]. Ovarian 4 (CA-4) was identified as an activator of AMPK detection byits cancer is called a “silent killer”, and its late diagnosis reduces the phosphorylation. It was shown that cryptococcal production of both overall cure rate. Compound 15 exhibits higher cytotoxicity in ovarian PGE2 and PGF2α could be inhibited by resveratrol, among other cancer cell lines (OVCAR3, EC50 = 3.45(nM); OVK18, compounds [60]. These polyphenolic molecules acted as inhibitors of EC50 = 1.99(nM)) [44]. lipoxygenase enzymes. Aranda et al. [61] observed that the unspecific OXi4503 (16, Fig. 3) is the diphosphate prodrug of the stilbenoid peroxygenases (UPOs) from the basidiomycetes Agrocybe aegerita combretastatin A1 with vascular disrupting and antineoplastic activities (AaeUPO), Coprinopsis cinerea (rCciUPO) and Marasmius rotula [14,45-47]. Upon administration, combretastatin A1 diphosphate (MroUPO) were able to catalyze the regioselective hydroxylation of E- (CA1P) is dephosphorylated to afford the active metabolite com- stilbene to 4,4′-dihydroxy-E-stilbene (DHS, 20, Fig. 3), and resveratrol bretastatin A1 (CA1), which promotes rapid microtubule depolymer- analogue, whose preventive effects on cancer invasion and metastasis ization; endothelial cell mitotic arrest and apoptosis, destruction of the have been shown. The above oxyfunctionalizations by fungal UPOs tumor vasculature, disruption of tumor blood flow and tumor cell ne- represent a novel and simple alternative to chemical synthesis for the crosis may ensue [10-16]. The vascular effects of OXi4503 and CA4P production of DHS, RSV and oxyresveratrol. It was reported in com- were assessed in the implanted MDA-MB-231 adenocarcinoma and the putational study of cyclooxygenase (prostaglandin-endoperoxide syn- MHEC5-T hemangio-endothelioma in severe combined im- thase) inhibition selectivity of stilbenoid inhibitors [62]. Pharmaceu- munodeficiency mice. Oxi4503 induced the shutdown of tumor blood tical inhibition of COX can provide relief from the symptoms of vessels in a dose-dependent pattern with an ED50 at 3 mg/kg and CA4P inflammation and pain [63]. Worth mentioning about pinosylvin (E- at 43 mg/kg [48]. 3,5-dihydroxystilbene) which is a pre-infectious stilbenoid toxin (i.e. The corresponding disodium phosphate prodrug of CA-4 (fos- synthesized prior to infection), contrary to phytoalexins which are bretabulin, 17, Fig. 3) is currently at an advanced stage of clinical de- synthesized during infection [64]. Pinosylvin (21, Fig. 3). biosynthe- velopment, having recently entered phase II studies in combination sized with malonyl-CoA as its direct precursors. Correlation between with carboplatin or paclitaxel in patients with anaplastic thyroid cancer lysine malonylation and pinosylvin biosynthesis remains unknown. Xu and phase Ib and phase II trial of pazopanib +/− fosbretabulin in et.al [65] can find that the malonyl-CoA-driven lysine malonylation advanced recurrent ovarian cancer [49]. plays an important role in the interaction between the engineered It is worth noting that these compounds contain numerous methoxy pathway of pinosylvin synthesis and Escherichia coli chassis cell. Over- groups in the framework. These compounds may provide an effective supply of malonyl-CoA leads to an increase in malonylation level of means to treat refractory organ-infiltrating leukemias and are poten- global proteome as well as the enzymes in the artificial pathway, tially important for optimizing the therapeutic combination of vascular thereby decreasing the yield of pinosylvin. The modification of the targeting agents with radiotherapy. Moreover, only the Z-isomer of the enzymes in the biosynthetic pathway to adjust their acylation level stilbenoid exhibits the biological activity, whereas the E-isomer does successfully improved the yield of pinosylvin. The effect of protein not [50]. Another active stilbene is pterostilbene (4-[(E)-2-(3,5-di- acylation on the biosynthetic pathway, found during these investiga- methoxyphenyl)ethenyl]phenol, 18, Fig. 3) which possesses lipid and tions, helps optimization of synthetic scaffolds and provides new stra- glucose lowering effects used in the treatment of resistant hematology tegies in metabolic engineering and synthetic biology at the protein malignancies, exhibits antioxidant capacity, and demonstrates con- post-translational level. centration-dependent anticancer activity [51-54]. When the interaction of a series of stilbenes, based on combretastatin A-4 with tubulin, was 2.5. Stilbenes- hazard investigated [55], it was found that the substitution of small alkyl substituents for the 4′-MeO group of combretastatin A-4 and the loss of Diethylstilbestrol (13, Fig. 3) is a synthetically obtained stilben. the 3′-OH group did not show a major effect on the interaction with Originally it was given to pregnant women to prevent miscarriages and tubulin. premature births. In later years, studies have shown that it does not have a positive effect on pregnancy. In addition, the daughters of 2.4. Stilbenes- biochemical effect women who took stilbestrol are 40 times more susceptible to cervical or vagina cancer. Their sons may have testicular cysts and abnormal The mechanism of action of stilbene derivatives is inhibition of the structure testicle [66,67]. It has also been found that the stilbene de- cellular events associated with tumor initiation, promotion, and pro- rivative 4,4′-diaminostilbene-2,2′-disulfonic acid, (an intermediate in gression. These compounds induce quinone reductase enzyme that the manufacture of fluorescent whitening agents) is reducing sexual plays a role in detoxifying carcinogens thus acts as an antimutagen function: activity and performance, interest, satisfaction, and physio- [56]. Stilbenes contained in various foods are associated with health logical competence in man [68]. Unfortunately, there are not many beneficial effects [57]. The study of several natural stilbene were tested studies on the danger of using stilbene derivatives. for their potential to regulate the activity of lipoxygenase and cy- clooxygenase in vitro. The most potent inhibitor of 5-lipoxygenase was 3. Naturally occurring nucleoside pterostilbene (18, Fig. 3) (IC50 = 9.32 μM). Also, pterostilbene (IC50 = 11.70 and 27.04 μM for cyclooxygenase-1 and cyclooxygenase- Nucleoside is a building block of nucleic acids, consisting of D-ribose 2, respectively) and oxyresveratrol (19, Fig. 3) (IC50 = 18.49; 2.79 and or 2-deoxy-D-ribose bonded to heterocyclic aromatic amine base by a 14.71 μM for 5-lipoxygenase, cyclooxygenase-1, and cyclooxygenase-2, β–N-glycosidic bond. The most important naturally occurring diazines respectively) were capable to inhibit catalytic activity of all three tested are the pyrimidine bases uracil thymine, and cytosine their crate nu- enzymes. In summary, these results indicated that stilbenes have cleoside uridine (22, Fig. 4) thymidine (23, Fig. 4), (5-methyluridine,

4 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Fig. 4. Structures of: uridine (22), thymidine (23), 5-methyluridine (24), cytidine (25) and guanosine (26). ribothymidine 24, Fig. 4) and cytidine (25, Fig. 4) respectively. Purines significantly elevated concentration of modified nucleosides inthe (adenine and guanine) together with pyrimidine bases (adenosine (7, urine. Observation of the amount of 28 and 29 in patients with ma- Fig. 1) and guanosine (26, Fig. 4) also constituents of DNA and RNA are lignant tumors may be useful in determining the effectiveness of consequently, of fundamental importance in life processes. As a result, therapy and the degree of development of the disease. 5-iodo-2′-deox- several pyrimidines and purines nucleoside analogs have been devel- yuridine is applied in inflammation of the cornea [70-73]. It can be oped as antiviral agents [69] or different drugs [70-73]. Summarizing successfully keratitis can be treated caused by herpes viruses, and more, the synthesis of modified nucleosides has an important impact on importantly, corneal infections caused by viruses from HSV groups human health since many antiviral and antitumoral agents belong to (Herpes Simplex virus). Investigations have shown that increasing anti- this type of compounds. viral activity of 30 can be obtained by irradiation of the cornea visible light after previous, local use of 5-iodo-2′-deoxyuridine. Epithelial cells 3.1. Uridine and its derivatives that have been attacked by the herpes virus may be treated with a low concentration of iodouridine. It is postulated that the mechanism by One of the five standard nucleosides is uridine, which is found in which virus replication is limited consists in the phosphorylation of RNA and not DNA. Uridine helps cells operate and regulate enzymes iodouridine to monophosphate or iodouridine triphosphate. This pro- within the brain and plays a vital role in brain tissue vitality. It is one of cess inhibits accordingly thymidine phosphorylation or inhibits the use the best nootropics for increasing synaptic plasticity by making it easier of thymidine triphosphate DNA biosynthesis. Administration of 30 for for your neurons to form new connections as well as greater encoding 14 days to patients with keratitis resulted in the reconstruction of the and storage of memories [74]. The derivatives of uridine such as 5- corneal epithelium. The main purpose of using iodouridine as an an- fluoro-2′-deoxyuridine [75-77] (27, Fig. 5), pseudouridine [78-80] (28, ticancer drug is its action to reveal cancer cells, which causes an in- Fig. 5), dihydrouridine [79] (29, Fig. 5), 5-iodo-2′-deoxyuridine [70] creased concentration of 30 on cancer cells per unit of time. Iodouridine (30, iodouridine, Fig. 5), 5-trifluoromethyl-2′-deoxyuridine [81-83] treatment was given to 24 patients with advanced bone cancer-sar- (31, trifluridine, Fig. 5) and (E)-5-(2-bromvinyl)-2′- deoxyuridine [84] comas. A combination of iodouridine and the intravenous infusion was (32, Brivudine, Fig. 5) are used in clinical medicine. used besides hypofractionated radiotherapy. The results showed less Their action results in inhibition of the growth of tumor cells and systemic toxicity in relation to the previously used bromo of uridine viruses. 5-fluor-2′- deoxyuridine is considered one of the most suc- [84]. cessful agents in the treatment of colorectal cancer and oesophageal 5-trifluoromethyl-2′-deoxyuridine is used in the treatment of herpes cancer [76]. It is also used in the treatment of basal cell carcinoma, infections, especially those of the eye. However, it is not a cure for the where it is administered locally, and intra-arterial administration is infection, only for the treatment of an inflammatory focus. It can ac- used in the treatment of liver cancer [85]. 5-fluorouracil is considered celerate wound healing and reduce the risk of complications such as to be a phase-specific drug, which works in a specific phase ofthecell loss of vision. It is also effective in the treatment of corneal epithelial cycle. It is active in the S phase, where it acts on cells responsible for the inflammation when there is no clinical response from the patient after synthesis of deoxyribonucleic acid (DNA). In contrast to other cytostatic administration of iodouridine or there is hypersensitivity to iodour- drugs from the antimetabolite group, this drug does not have a sta- idine. Studies have shown that 31 was also effective in patients resistant tionary phase in the curve of the dose-response of the cellular response. to other antiviral drugs. It is a component of the Viroptic (in the United In the body, 5-fluorouracil is converted to compound 27. This reaction States) drug appearing in the form of drops. After installation of the is catalyzed by the enzyme thymidine phosphorylase. The compound in drug into the human eye, trifluridine penetrates inside the knob, where this form is active against cancer cells. It works by blocking the con- it is transformed into a triphosphate trifluorometylourydyny. In this version of 2-deoxyuridine monophosphate to monophosphate thymi- form, it is an inhibitor competing with thymidine triphosphate for DNA dine due to which the synthesis of DNA is blocked [86]. Pseudouridine polymerase. Once embedded in the virus genome it is damaged and its and dihydrouridine [78-80] are used as an accurate tumor marker for activity reduced [81-83]. 5-trifluoromethyl-2′-deoxyuridine is part ofa clinical diagnosis of thyroid cancer. These low molecular weight che- combination drug (TAS-102) used as a third- or fourth-line treatment of micals are excreted in human urine. Their concentration is dependent metastatic colorectal cancer after chemotherapy and targeted ther- on the degree of RNA degradation in the human body, so any dis- apeutics have failed [87]. turbances in RNA result in changes in the concentration of these com- Finally, (E)-5-(2-bromvinyl)-2′-deoxyuridine (Brivudine) is an anti- pounds. Studies have shown that people with thyroid cancer have a viral drug used in the treatment of Herpes zoster [84]. It proved to be

Fig. 5. Structures of: 5-fluoro-2′-deoxyuridine (27), pseudouridine (28), dihydrouridine (29), 5-iodo-2′-deoxyuridine (30), 5-trifluoromethyl-2′-deoxyuridine (31) and (E)-5-(2-bromvinyl)-2′- deoxyuridine (32).

5 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073 much more effective in the treatment of common Herpes simplex virus the level of modified nucleosides, including 5-methyluridine, in urine than iodouridine. occurs in patients with leukemia, lymphoma, lung cancer, esophagus The drug acts by incorporating into viral DNA and blocking the cancer, breast cancer, kidney cancer, liver cancer, bladder cancer and action of DNA polymerase, inhibiting viral replication. In the form of colon cancer. Therefore, the results of the examination confirmed the triphosphate, it is recognized as a strong inhibitor of the replication of usefulness of using of modified nucleosides as tumor markers [98]. Herpes zoster and Varicella virus [88]. Drug activity can be observed only Molecularly imprinted polymers (MIPs) are used in pharmaceutical during active virus replication. Therefore, 32 cannot be used as a pre- sciences. They are used in the processes of isolation and concentration ventive drug. After its use, a reduction in acute pain, acceleration of of analytes, as selective adsorbents in chromatographic columns and in wound healing and prevention of scarring can be noticed. columns for solid phase extraction (SPE). Polymers with molecular trace are cheap in synthesis, and are characterized by high selectivity as well as mechanical, thermal and chemical resistance. Due to these 3.2. Thymidine and 5-methyluridine and its derivatives features, they can be a new generation of materials used for the con- struction of diagnostic tests. A study with the molecular trace of 5- Thymidine (23 Fig. 4) is an essential nucleoside for the construction methyluridine was carried out, in which the ability and suitability of of DNA. The critical stage of thymidine synthesis appears to be the the polymer (5-methyluridine-2′,3′-(4-vinylbenzyl) boronate 5-MeU-tri- methylation of deoxyuridine monophosphate at the 5- position with the B, 36, Fig. 6) for the adsorption of natural nucleosides were evaluated, assistance of the enzyme thymidylate synthetase and methylene adduct and it has been proven that the molecular trace polymer can be used for of tetrahydrofolic acid as a coenzyme. During this reaction, a molecule the direct extraction of tumor markers from urine [99]. of dihydrofolic acid is formed. For the process to be reversible, dihy- In recent years, there has been a development in the design of drugs drofolic acid must be hydrogenated to the tetrahydrofolic form. The that affect the expression of genes by directly binding to nucleic acids. enzyme dihydrofolate reductase catalyzes this transformation. At this One group of potential drugs manifesting such features may be anti- point methotrexate [89], a drug for leukemia, becomes involved. Be- sense oligonucleotides. Those are complementary fragments of nucleic cause of the similarity to dihydrofolic acid, methotrexate inhibits di- acids that, by hybridization, form complexes with target mRNA or DNA hydrofolate reductase, thus inhibiting the biosynthesis of thymidine, sequences inhibiting gene expression [100]. Antisense technology is and thereby reduces its content within cells. The drug containing the widely used in vitro and in vivo as a tool to study the regulation me- thymidine skeleton is Edoxudine (5-Ethyl-2′-deoxyuridine, 33, Fig. 6), chanisms in biological processes and as a potential therapeutic agent in which is used against herpes simplex virus [90]. the treatment of cancer, viral infections, and genetic disorders. One of 5-Methyluridine (24, Fig. 4), is an endogenous methylated nucleo- the modified nucleosides that can potentially be used in antisense side found in human fluids. In cells, 5-methyluridine is present in tRNA, therapy is bridged with 2′-O, 4′-C-ethyleneoxy-5-methyluridine (EoNA- formed during its post-transcriptional modification by the methylation T, 37, Fig. 6). After being built into oligonucleotides it was noticed that of uridine [91]. Ribothymidine (T) is found in the TΨC tRNA loop, those containing EoNA-T better stabilized single-strand RNA duplexes which is responsible for the attachment of tRNA to the ribosome. 5- (ssRNA) and double-stranded DNA triplexes (dsDNA), compared to methyluridine forms Hoogsteen inverted pairs with adenosine at posi- natural or modified oligonucleotides seven-membered bridged of5- tion 58 and stabilizes the loop structure. Nucleoside analogs, including methyluridine. Moreover, the increased resistance to nuclease de- 24, are used as antiviral drugs. [92] Most of them, after entering the gradation was observed throughout the experiment [101]. cell, are phosphorylated by kinases to mono- or triphosphates that in- 5-Methyluridine (xm5U) and their 2-tioanalogs (xm5s2U) are a bio- hibit viral replication. The anti-HIV nucleoside analogs include 5-me- logically relevant class of modified nucleosides. Incorporation of 5- thyluridine derivatives: Zidovudine (AZT, azidothymidine, Retrovir®, methyluridine/2-thiouridine (38, Fig. 6) into the oligonucleotide se- 3) [93] and Stavudine (d4T, Zerit®, [94] 34, Fig. 6), while the drug used quence facilitates using the resulting molecules for model the research in hepatitis B is Telbivudine (Tyzeka®, [95] 35, Fig. 6). The use of on the structural requirements of tRNA interaction with partners in oligonucleotides containing 5-methyluridine derivatives is being stu- complex bioprocesses. Therefore, an efficient and simple synthesis of5- died in genetic diagnosis, gene therapy and in biosensors and DNA methyluridine and 2-thiomethyluridine derivatives is an important microarrays [96]. element of this research [102]. The most modified nucleosides are found in tRNA. Upon completion of translation, RNA is catabolized and releases nucleosides. Modified nucleosides cannot be used in de novo RNA synthesis, so they are re- 3.3. Cytidine and its derivatives moved from the cells as end products of metabolism and then enter the urine with blood. An increase in the content of modified nucleosides in Cytidine, (25, Fig. 4) a pyrimidine nucleoside, is a precursor for the urine may suggest an increase in the rate of metabolic transfor- uridine. Both cytidine and uridine are utilized in RNA synthesis. Cyti- mation of tRNA in tumor tissues [97]. It was shown that the increase in dine is a pyrimidine that besides being incorporated into nucleic acids,

Fig. 6. Structures of: Edoxudine (33), Stavudine (34), Telbivudine (35), 5-methyluridine-2′,3′-(4-vinylbenzyl) boronate (36), 2′-O,4′-C-ethyleneoxy-5-methyluridine (37) and 2-thiouridine analogs (38).

6 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Fig. 7. Structures of: 5-azacytidine (39), 5-aza-2′-deoxycytidine (40), zebularine (41), cytarabine (42), gemcitabine (43), fluorescent triazole- cytidines derivative (44) and modified 2′-deoxycytidine bearing a 5-(dimethylamino)naphthalene-1-sulfonyl moiety (45). can serve as a substrate for the salvage pathway of pyrimidine nu- this compound is based on the competitive inhibition of RNA poly- cleotide synthesis. It is a precursor of cytidine triphosphate (CTP) merase and DNA activity, because it competes with the natural sub- needed in the phosphatidylcholine (PC) and phosphatidylethanolamine strate (respectively cytidine-5′-triphosphate and 2′-deoxycytidine-5′- (PE) biosynthetic pathways. These variations probably reflect the spe- triphosphate) in the active center of these enzymes. In addition, the cies differences in cytidine deaminase, an enzyme that converts cytidine incorporation of cytarabine into the DNA disrupts its spatial structure, into uridine in the body. The transport of cytidine into the brain ex- which further complicates the course of replication. Cytarabine is a tracellular fluid, and then into neurons and glia, is an essential pre- specific drug and is particularly active in the S phase of the cellcycle requisite for cytidine to be utilized in the brain [103]. The nucleoside [111]. analogs, including cytidine analogs, are often used in cancer che- Gemcitabine (2′,2′-difluoro-2′-deoxycytidine 43, Fig. 7) is used motherapy. They belong to an important group of drugs, which are primarily in leukemia therapies. It should be emphasized that this drug antimetabolites. The mechanism of action of these compounds lies was the only one of the nucleoside analogs, that has been used in the primarily in the incorporation of the proper metabolite and disruption treatment of solid tumors. In combination with other drugs (eg. cis- of its functions [103-116]. platin, 5-fluorouracil) it is part of the treatment of pancreatic cancer, The oldest antineoplastic agents that are DNMT1 inhibitors are 5- lung cancer, ovarian cancer and breast cancer [112]. Like cytarabine, azacytidine (Vidaza®, 39, Fig. 7) and 5-aza-2′-deoxycytidine (Da- gemcitabine is a prodrug that is phosphorylated in cells to active me- cogen®, 40, Fig. 7). Like other nucleoside analogs, these compounds are tabolites - gemcitabine-5′-diphosphate and gemcitabine-5′-tripho- gradually phosphorylated to mono-, di- and triphosphates after entering sphate. The cytotoxic effect of gemcitabine is based on the inhibition of the cell [104]. The resulting 5-azacitidine-5′-triphosphate becomes a DNA synthesis through two mechanisms. The first one is gemcitabine- substrate for RNA synthesis and 5-aza-2′-deoxycytidine-5′-triphosphate 5′-diphosphate, which is an inhibitor of nucleotide reductase. Inhibiting for DNA synthesis. After reduction catalyzed by ribonucleosidotripho- the activity of this enzyme reduces the overall concentration of deox- sphate reductase, phosphorylated 5-azacytidine can also become a yribonucleotides - substrates for DNA synthesis. The second mechanism substrate for DNA synthesis. Compounds 39 and 40 are used primarily is based on the competitive inhibition of DNA polymerase activity by in the treatment of blood cancers, and especially in the treatment of gemcitabine-5′-triphosphate. Gemcitabine is also a phase-specific drug myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and with the strongest effect on cells in the S phase of the cell cycle [112]. chronic myeloid leukemia (CML), myelomonocytic myocyte leukemia In recent years, growing interest has been observed in molecular (CMML). According to several clinical trials, MDS treatment based on 5- biology techniques, and especially in their use in medicine. The effect of azacytidine is relatively effective (the percentage of positive responses this is, among other things, the creation of a new branch of diagnostics - is estimated at about 60%) and is characterized by a relatively low risk molecular diagnostics. One of the main methods used in molecular di- of serious side effects [105,106]. agnostics is hybridization. The essence of this process is the ability of Like all other cytidine analogs, zebularine (41, Fig. 7) must be in- nucleic acids to create two or more stable stranded structures that are a corporated into DNA to reveal its cytotoxic properties. As with 5-aza- consequence of pairing of complementary base pairs. The tools used in nucleotides, the mechanism of methyltransferase inhibition is its hybridization are oligonucleotide molecular probes. These are short covalent binding to DNA and inhibits tumor growth both in vitro and in fragments of single-stranded DNA with a strictly defined sequence, vivo. The low electron density of position 5, due to the absence of the which is complementary to the sequence of the gene being sought. amino group in position 4, does not promote methylation. Blocking the Thanks to the appropriate labeling of probes, it is possible to identify reaction at this stage prevents the release of the enzyme [107,108]. and locate complementary sequences to them. One way of marking is Cytarabine (cytosine arabinoside, ara-C, (42, Fig. 7) is considered fluorescent labeling. For the synthesis of such probes, nucleotides with one of the most effective antileukemic drugs and is the main element in attached molecules capable of fluorescence (fluorophores) are used. An most treatment regimens of acute myeloid leukemia (AML). The drug is example of a fluorophore is the 2′-deoxycytidine derivative shown in also used in the treatment of non-Hodgkin's lymphomas and acute (44, Fig. 7) [113,114]. It is worth noting that none of the reagents used lymphocytic leukemia (ALL) [109]. Cytosine arabinoside is a prodrug for its synthesis (5-ethynylcytidine and phenyl azide) shows fluorescent that, when penetrated into a cell, is phosphorylated - the active meta- properties. Another example of a fluorescent nucleoside may be DNSC - a bolite is cytarabine-5′-triphosphate [110]. The mechanism of action of 2′-deoxycytidine derivative with the 5- (dimethylamino) naphthalene-

7 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Fig. 8. Structures of: cordycepin (46), 8-oxoG (47), Fapy-G (48), mercaptopurine (49), thioguanine (50), azathioprine (51) pemetrexed (52) and nelarabine (53).

1-sulfonyl moiety on the nitrogen atom at the 4-position of the pyr- and - due to its short half-life - one of the safest medicaments [126]. imidine ring [115,116]. This derivative can be used for direct detection Adenosine concentration control in the extracellular space has been of GGG (Guanine-Guanine-Guanine) sequence because, during hy- shown to counteract epilepsy [127]. This has been proven by studying bridization of an oligonucleotide containing DNSC with the target se- patients with epilepsy in which adenosine kinase (ADK) shows in- quence containing the GGG triad, a fluorescence enhancement is ob- creased expression. This results in the phosphorylation of adenosine to served. The structures are presented in (45, Fig. 7). 5′-AMP and the reduction of its amount in the extracellular space, which leads to astrogliosis and reduces symptoms of epilepsy. It is an- 3.4. Adenosine and its derivatives ticipated that antagonists of P2X7 recombinant interleukin 1β may be a drug for long-lasting and recurrent epilepsy. Adenosine (7, Fig. 1) is the main metabolite of all cells in the human Adenosine helps in the fight against neuronal and neurodegenera- body. It participates in key pathways, such as the synthesis of purine tive disorders such as schizophrenia, Alzheimer's disease, Parkinson's nucleic acid bases, amino acid metabolism or cellular metabolic reg- disease, Huntington's disease, or sclerosis [128]. ulation [117]. It is called a “local hormone” or “retaliatory metabolite,” A derivative of adenosine, cordycepin, (3′-deoxyadenosine, 46, because it plays an important role in stressful conditions, i.e. ischemia, Fig. 8) has been widely used as an antitumor compound, which has hypoxia, trauma, stress, convulsions, pain, and inflammation [118]. In been found to exert antiangiogenic, antimetastatic, and anti- such circumstances, the intracellular adenosine concentration increases proliferative effects, as well as to induce apoptosis [129]. The antitumor to the micromolar amount (under homeostatic conditions it is expressed effect of cordycepin is about regulation of signaling pathways related to at the nanomolar level), and is released into the extracellular en- tumor growth and metastasis. The cordycepin inhibits tumor growth via vironment, in order to inhibit metabolism in the neighboring cells. It is regulating tumor apoptosis, inducing cell cycle arrest and targeting assumed that this is a self-monitoring mechanism to minimize cell da- cancer stem cells. Cordycepin regulates tumor microenvironment via mage [119]. suppressing tumor metastasis-related pathways. Recently, research into The nucleoside has two equivalent regulatory roles in the central the use of adenosine derivatives for therapeutic purposes has been in- nervous system. It is a modulator of homeostasis (a function common to tensified [130-132]. all cell types) and a neuromodulator at the synapse level. Although these roles are often considered together, their mechanisms differ from 3.5. Guanosine and its derivatives each other [120,121]. Adenosine is directly related to the energy metabolism of cells as Guanosine (26, Fig. 4) is a precursor of nucleotides which are cru- ATP (adenosine-5′-triphosphate), ADP (adenosine-5′-diphosphate) and cial for functioning of cells: GMP, cGMP, GDP, and GTP. Purines, in AMP (adenosine-5′-monophosphate) [121]. 5′-AMP-activated protein particular, guanine (part of guanosine) and isoguanine (an isomer of kinase (AMPK) is a pivotal energy sensor that alleviates or delays the guanine), form supramolecular tetra- or pentameric structures [133]. process of fibrogenesis. Fibrosis is a process characterized by excessive Guanine tetramers are of a special biological significance, because they extracellular matrix (ECM) accumulation after inflammatory injury, are present in telomeres, where they act as telomerase inhibitors [134]. which is also a crucial cause of aging [122]. 5′-AMP-activated protein In addition, they have a biological function in the dimerization of the kinase (AMPK) is also universally distributed in various cells and or- HIV and localized RNA genome (site-specific) recombination of genetic gans. It is a significant endogenous defensive molecule that responds to coding for immunoglobulins [135]. Guanine fragments rich in DNA are harmful stimuli, such as cerebral ischemia, cerebral hemorrhage, and, an easy target for free radicals, because this compound has the lowest neurodegenerative diseases (NDD) [123]. The main pathway for the oxidative potential among nitrogenous bases that build nucleic acids formation of adenosine is its release from AMP. This process is cata- [136]. The accumulation of guanine oxidation products limits the lyzed by 5′-nucleotidase (inside the cell) or by ecto-5′-nucleotidase ability of telomere to regenerate [137]. DNA glycosidases, which re- (outside the cell). Adenosine can also be derived from the S-adenosyl move some guanine oxidation products, hydantoin derivatives, play a homocysteine (SAH) hydrolysis reaction, formed from S-adeno- significant role in preserving the protective properties of guanine tet- sylmethionine [124]. Adenosine has been tested on several animal ramers in telomere [138]. models, and it has been found to reduce the symptoms of ischemic heart Reactive oxygen species (ROS) are the most abundant radicals in disease, brain injuries, seizures, pain, and inflammation [125]. cells. The imbalance between production and neutralization or removal Adenosine is also used as a drug in tachycardia with a wide range of of ROS causes oxidative stress resulting in damage of lipids, proteins, QRS and paroxysmal supraventricular tachycardias, as it is an effective and DNA [139]. Glutathione, glutathione peroxidase, superoxide

8 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073 dismutase and antioxidants provided in the diet (such as vitamins E, C, prodrug after oral administration [149]. After the administration by carotenoids) typically are responsible for elimination of free radical deacetylation and oxidation famciclovir (56, Fig. 9) is converted to oxides. Guanine oxidation at C8 causes formation 7,8-dihydro-8-ox- penciclovir (57, Fig. 9). The range of use is analogous to acyclovir, oguanine (8-oxoG, 47, Fig. 8) or an open-ring product imidazole − 2,6- although its efficacy in vitro against HBV has also been demonstrated diamino-4-hydroxy-formamidopyrimidine (Fapy-G, 48, Fig. 8). 8-oxoG [150]. is one of the best-characterized products of oxidation of nitrogenous Another drug is Valganciclovir (58, Fig. 9) which is a precursor of bases. It has been shown to be highly mutagenic in both in vitro and in ganciclovir for oral administration [151]. Ganciclovir (59, Fig. 9) is vivo (the majority of which are mutations related to the conversion of poorly absorbed from the gastrointestinal tract, so it is used in- guanine to thymine), but also the lack of blocking the synthesis of DNA, travenously. The scope of activity there is HSV, VZV, HZV and Cyto- and shows little or no cytotoxicity [140]. An agarose gel electrophoresis megaloviruses. It is, however, very toxic, and causes dangerous side ef- 1 assay demonstrated that DNA was damaged by O2 with less than 5 min fects [152]. Entecavir (60, Fig. 9) is a guanosine analog that has a of UVA irradiation. Additionally, 5 mM resveratrol dissolved in MeOH selective affinity for HBV [153]. Like the antiviral drugs, after entering could relieve the observed oxidation stress [141]. The authors proposed the cell, it is phosphorylated, and its action is based on competitive the mechanism that the phenol ring of resveratrol links with the free activity with dGTP and inhibition of DNA polymerases. In oral ad- 1 amino groups (NH) of guanine at the beginning of O2 attack, thereby ministration, it is absorbed well and easily penetrates the tissues. Im- protecting guanine. portantly, it does not affect the activity of cytochrome P450 and does Substances which are structurally like similar to guanine can be not show any interaction with substances metabolized by this enzyme. found in the following drugs: mercaptopurine, thioguanine and aza- Drugs used in AIDS and HIV infection act on the reverse tran- thioprine (49, 50, 51, Fig. 8). Mercaptopurine is a drug used in acute scriptase DNA (otherwise known as DNA dependent RNA polymerase) myelogenous leukemia and lymphoblastic and is relatively non-toxic whose presence is characteristic for the retrovirus family. For the most (compared to others chemotherapeutics). Its derivative, thioguanine, part, those are 2′,3′-dideoxyinosine (didanosine, ddI, 5, Fig. 1) drugs has similar characteristics and uses. that, due to the absence of the γ'-hydroxyl group, inhibit the structure of In turn, another derivative, azathioprine, is an immunosuppressive the DNA chain. These medicines include: didanosine, which is quickly drug. Its active metabolite, which inhibits purine synthesis, is methyl- absorbed from the digestive tract, but is unstable in an acidic en- thioinosine monophosphate (the mercaptopurine nucleotide), whereas vironment -it is given in tablets containing a special buffer or delayed the DNA or RNA are built-in deoxythioguanosine or thioguanosine capsules release [154]. Another drug is abacavir (61, Fig. 9) [155]. This triphosphates [142]. Pemetrexed (52, Fig. 8) belongs to the group of medicine converts into the active metabolite - carbovir 5′ - triphosphate folic acid antagonists [143]. It is an inhibitor of thymidylate synthase, (62, Fig. 9), which is dGTP analogue. It can be used in combination and also inhibits the activity of other enzymes involved in folate me- with many other anti-AIDS drugs. After oral administration, it is ab- tabolism. Inside cells, it undergoes polyglutamation to a compound that sorbed quickly and to a large extent. is 60 times more active. It found application in the treatment of breast [143], lung [144]or colon cancer [145]. Nelarabine (53, Fig. 8) is a prodrug that in the body is first de- 4. Hybrid molecules- drugs methylated to 9-β-D-arabinofuranosylguanine and then phosphorylated to the trinucleotide. It acts as a factor that builds into the DNA and Over the years, the paradigm of “one disease, one gene, one mole- inhibits its synthesis. This drug is used to treat leukemias and lym- cular target, one drug” was used in drug chemistry. It was noted that phomas associated with T lymphocytes (in which the nelarabine me- drugs that selectively block a single target were not very effective in tabolite accumulates extensively) [146,147]. complex diseases such as cancer or diabetes. The development of sys- Guanine derivatives are also used in antiviral therapy. Aciclovir (54, tems biology and increased knowledge about the molecular complexity Fig. 9) works on herpes viruses (HSV-1, HSV-β), chickenpox, zoster (VZV) of diseases has led to work on designing multi-purpose drugs, the drugs and Epstein-Barr virus [148]. It is considered a relatively safe drug, but that affect many elements of the human body, activating or blocking unsuitable for topical use with acyclovir-resistant HSV infections and in the molecular target. The molecular target may be macromolecules the treatment of AISMS and CMV infections. Valaciclovir (55, Fig. 9) is (enzymes), structures composed of macromolecules or structures con- included in prodrugs - during hepatic metabolism it is transformed for sisting of medium-sized molecules that exhibit a higher order organi- aciclovir and 1-valine. It has similar characteristics to aciclovir but zation, e.g. biological membranes [156]. There are three possible differs in its absorption - almost the entire dose is absorbed fromthe pharmacological approaches to creating a new drug (Fig. 10) [157]. Traditionally, doctors treat patients by giving them “cocktails” of

Fig. 9. Structures of: aciclovir (54), valaciclovir (55), famciclovir (56), penciclovir (57), valganciclovir (58), ganciclovir (59), entecavir (60), abacavir (61), and carbovir (62).

9 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

1. drug coctail 2. multicomponent drug 3. multiple ligand

2 tablets 1 tablet 1 tablet 2 agents 2 agents 1 active agent

Fig. 10. Three main clinical scenarios: 1- drug cocktail, 2- multicomponent drug,3- multiple ligand, for multitarget therapy (the figure prepared based on Ref. [157]). drugs. Most often the “cocktail” is given in the form of two or more multiple ligands are the molecules that are obtained because of individual tablets (scenario 1) [157-159]. Recently, multicomponent “merged” compounds. Because of the imposition of similar elements drugs have been used in which two or more medications are in one belonging to both molecules, one therapeutically active compound is tablet. In the case of such a drug, dosing is easier, which promotes the obtained. This is achieved when both compounds have many common treatment of patients (scenario 2)[157]. An alternative strategy is to structural elements such as a hydroxyl group or a heterocyclic ring create a single chemical entity (multiple ligands) that is able to re- [164]. cognize many molecular targets simultaneously (scenario 3) [157]. Most medicinal products can be compared to multiple ligands. In ad- 4.1. Hybrids of stilbenes and nucleosides dition to their therapeutic effect, they usually have one or more side effects. However, the goal in the design of multiple ligands are activities It is known that resveratrol and pterostilbene in combination with that have a positive effect on therapy [160-162]. In the case of multi- nucleoside analogues [35] exhibit potent synergistic inhibitory activity functional drugs, there is less risk of interactions between different against human immunodeficiency Virus (HIV-1) infection and these drugs than in the case of “cocktails” of drugs or multicomponent drugs. components are served in the form of “cocktails”. Resveratrol has only In addition, taking one medicine is easier for the patient and caring for moderate activity against HIV. After addition of hydroxy stilbene to the patient is easier for the medical staff. Furthermore, the risk of taking treatments with lysates containing nucleoside analogs, e.g. zidovudine, a dose other than recommended is reduced, and research shows that the didanosine, and zalcitabine, there is a significant increase in anti-HIV number of side effects is reduced as well. activity. The addition of stilbene increased the antiviral activity 10 One can imagine preparation of hybrid molecules with a dual mode times [165]. Resveratrol interacts also with two DNA sequences con- of action to create efficient new drugs. On this account, hybrid mole- taining AATT/TTAA segments [166]. The mode of interaction has been cules are defined as chemical entities with two or more structural do- studied using absorption, steady-state fluorescence, and Circular Di- mains having different biological functions and dual activity, indicating chroism (CD) spectroscopic techniques. The CD studies depicted the that a hybrid molecule acts as two distinct pharmacophores. In this structural changes in DNA upon resveratrol binding. Fluorescence data case, a single molecule should be synthesized by combining two se- showed a stoichiometry of 1:1 for d(CGAATTCG)2-resveratrol complex lectively acting molecules. The combination of elements can be carried and 1:4 for d(CGTTAACG)2-resveratrol complex. The next example of out in three ways, using a “link, fusion or merger ” of both molecules biologicallyactive“cocktails”, is the use of stilbene derivatives for the with each other (Fig. 11) [163]. Ligands vary greatly in the degree of production of medicaments for the treatment of solid tumors, e.g. the merger of the frameworks (and the underlying pharmacophores) of melanoma or stomach carcinoma. There are disclosed combinations of the selective ligands used as the starting points. the stilbene derivatives with DNA-intercalating substances: adenosine Conjugates are multiple ligands in which the molecular frameworks, triphosphate, uridine triphosphate, guanosine triphosphate, cytidine which contain the underlying pharmacophore elements for each target, triphosphate and thymidine triphosphate [167]. There has also been are well separated by a distinct linker group that is not found in either investigated the effect of a cytidine analog, 5-azacytidine, which is of the selective ligands. If the ligand structures are directly connected known to block DNA methylation, on resveratrol biosynthesis and stil- and the connector is not seen either overlap of structures, can be said bene synthase (STS) gene expression in Vitis amurensis cultured cells. The about fusion ligands. The most common and most sought-after type of results demonstrate that 5-azacytidine is able to increase resveratrol production in Vitis amurensis cultured cells through a mechanism that involves the induction of STS gene expression [168]. A “cocktail” of resveratrol was investigated, which is known as an inhibitor of ribo- nucleotide reductase (RR), a key enzyme of DNA synthesis, with cy- tarabine. In growth inhibition, apoptosis, and clonogenic assays, re- sveratrol acted synergistically with ara-C in HL-60 cells [169]. The stilbenes are a group of compounds known to bind to DNA [170-173]. Stilbene-DNA conjugates form very stable bridged hairpins [174].A very interesting study was presented by Richert et al., [175] in which six different stilbene carboxylic acids were conjugated on-support to protected DNA with a 5′-aminopropanol residue. The effect of the modifications on duplex stability in the obtained compounds wasde- termined via UV-melting curves. Currently, only one relationship can be found in the literature that has been created as result of the com- Fig. 11. The methods of combining the skeletons of selectively acting mole- bination of uridine and a stilbene derivative (hybrid molecule) 3′- cules: linking, fusing and merging (the figure prepared based on ref.[163]). phosphate - (4-hydroxy tamoxifen) uridine (UpHT, 63, Fig. 12) is used

10 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Fig. 12. Structures of: UpHT (63), tamoxifen (64), 4-hydroxytamoxifen (65) and ABT-072 (66).

Scheme 1. Scheme of reactions nucleosides: uridine (22), 5-methyluridine (24), cytidine (25), adenosine (7), and guanosine (26) with stilbene derivatives (67, 68).

as a prodrug in therapy of breast cancer [176]. Tamoxifen (T, 64, regarded as “fused”. Fig. 12) acts as an antiestrogen and is one of the most commonly used Krawczyk et al. [179-183] studied stilbene derivatives that are hormonal drugs in the prevention and treatment of breast cancer. The “fused” with nucleosides such as uridine, 5-methyluridine, adenosine, administration may lead to an increased risk of endometrial cancer. To cytidine and guanosine (67–78, Scheme 1). It is worth noticing that the minimize side effects, UpHT has been synthesized. It has a greater hy- obtained stilbene modified nucleoside can also be used as monomers in drophilicity than the parent drug, which may improve pharmacokinetic the stereo control synthesis of RNA analogs or in supramolecular as- properties [176]. In the human body, under the influence of RNase-1, it sembly. is broken down into 4-hydroxytamoxifen (HT, 65, Fig. 12). Studies have Modifications on the exocyclic amino guanosine group are anin- shown that UpHT has antiproliferative effects, which results in sup- teresting example of fusing. The modification of the exocyclic amino pression of MCF-7 cancer cells after using UpHT in the treatment of group deoxyguanosine changes the reactivity of this substance in the breast cancer. ABT-072 (66, Fig. 12), a non-nucleoside HCV NS5B process of oxidation by reactive oxygen and nitrogen (Reactive polymerase inhibitor [177,178], is another connection of a stilbene Oxygen/Nitrogen Species - ROS, RNS). This is particularly true for N2- derivative with dihydrouracil analogs. In this compound, the frame- phenyl-oxyguanosine (79, Fig. 13), which is in embedded double- works are actually touching each other, and these ligands can be stranded DNA. It reduces the degradation, resulting from the oxidation

11 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Fig. 13. Structures of deoxyguanosine (79) and guanosine derivatives (80), (81) and (82) modified in N2 position.

of even these bases of guanine compounds, that are distant from the References fragments containing modified guanine systems [184]. The guanosine derivatives modified in this position are therefore interesting objects of [1] X. Dai, C. Tan, Combination of microRNA therapeutics with small-molecule an- research due to possible antioxidative and anticancer activity. The ticancer drugs: Mechanism of action and co-delivery nanocarriers, Adv. Drug. Delivery. Rev. 81 (2015) 184–197. substance 79 was also a research object as a selective Herpes simpex [2] Y. Hu, N.N. Zhao, B.R. Yu, F.S. Liu, F.J. Xu, Versatile types of polysaccharide-based 2 virus thymidine kinase inhibitor [185]. The derivatives of C -triazoly- supramolecular polycation/pDNA nanoplexes for gene delivery, Nanoscale 6 linosines (80, 81, Fig. 13), described as showing activity against Cyto- (2014) 7560–7569. [3] Y. Zhao, B.R. Yu, H. Hu, Y. Hu, N.N. Zhao, F. Xu, New low molecular weight megalovirus and a Vesicular stomatitis virus [186] also have antiviral polycation-based nanoparticles for effective codelivery of pDNA and Drug, ACS significance. In turn, the group of guanosine derivatives containing a p- Appl. Mater Interf. 6 (2014) 17911–17919. methoxybenzyl group at the N2 (82, Fig. 13) position [187] is an ex- [4] B. Yang, X. Dong, Q. Lei, R. Zhuo, J. Feng, X. Zhang, Host-guest interaction-based ample of connection that exhibits a strong activity of translation in- self-engineering of nano-sized vesicles for co-delivery of genes and anticancer drugs, ACS Appl. Mater Interf. 7 (2015) 22084–22094. hibitors in Ascaris suum nematode. [5] A.S. Dubrovina, K.V. Kiselev, Regulation of stilbene biosynthesis in plants, Planta 246 (2017) 597–623. [6] K.T. Howitz, K.J. Bitterman, H.Y. Cohen, D.W. Lamming, S. Lavu, J.G. Wood, R.E. Zipkin, P. Chung, A. Kisielewski, L.-L. Zhang, B. Scherer, D.A. Sinclair, Small 5. Conclusions molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan, Nature 425 (2003) 191–196. The chemistry of stilbenes has been extensively investigated for [7] T.M. Bass, D. Weinkove, K. Houthoofd, D. Gems, L. Partridge, Effects of resveratrol on lifespan in drosophila melanogaster and caenorhabditis elegans, Mech. Ageing. decades. Unique features of this class of compounds have long been a Dev. 128 (10) (2007) 546–552. matter of great interest. Especially, during recent years, the accumu- [8] S. Valdesalic, A. Cellerino, Extremely short lifespan in the annual fish lation of relevant results has been observed: 1) stilbene derivatives have Nothobranchius furzeri, Proc. R. Soc. Lond. B Biol. Sci. 270 (2003) S189–S191. [9] L.X. Wang, A. Heredia, H. Song, Z. Zhang, B. Yu, C. Davis, R. Redfield, Resveratrol been used as molecular probes and labels for investigation of dynamic glucuronides as the metabolites of resveratrol in humans: characterization, properties of proteins and biomembranes; 2) stilbenoids are naturally synthesis, and anti-HIV activity, J. Pharm. Sci. (2004) 2448–2457. present in plants and make an important contribution to biochemical [10] H.-L. Lin, S.-H. Chiou, C.-W. Wu, W.-B. Lin, L.-H. Chen, Y.-P. Yang, M.-L. Tsai, Y.- and physiological processes in plants. They have also been used as H. Uen, J.-P. Liou, C.-W. Chi, Combretastatin A4-induced differential cytotoxicity and reduced metastatic ability by inhibition of AKT function in human gastric drugs and antitumor agents. The most active stilbenes are trans-re- cancer cells, J. Pharmacol. Exp. Ther. 323 (2007) 365–373. sveratrol, combretastatins or pterostilbene. The second class of the [11] R.M. Horsman, A.B. Bohn, M. Busk, Vascular targeting therapy: potential benefit presented compounds is nucleosides and their analogs, which also ex- depends on tumor and host related effects, Exp. Oncol. 32 (2010) 143–148. [12] S. Senan, E.F. Smit, Design of clinical trials of radiation combined with anti- hibit biological properties. Nucleoside are building blocks of nucleic angiogenic therapy, Oncol. 12 (2007) 465–477. acids. For example, adenosine is used in heart diseases. Its derivatives, [13] J.A. Lee, N.M. Biel, R.T. Kozikowski, D.W. Siemann, B.S. Sorg, In vivo spectral and dCF (2′-deoxycoformycin), 2CdA (2-chloro-2′- deoxyadenosine), and F- fluorescence microscopy comparison of microvascular function after treatment with OXi4503, Sunitinib and their combination in Caki-2 tumors, Biomed. Opt. ara-A (9-beta-D-2-arabinosil -2-fluoroadenine) are used in the treat- Exp. 5 (6) (2014) 1965–1979. ment of malignant blood tumors. Resveratrol in combination with nu- [14] M.R. Stratford, L.K. Folkes, Quantitative determination of the anticancer prodrug cleoside analogs exhibits synergistic inhibitory activity against human combretastatin A1 phosphate (OXi4503, CA1P), the active CA1 and its glucur- onide metabolites in human urine and of CA1 in plasma by HPLC with mass immunodeficiency Virus (HIV-1). By combining the nucleoside withthe spectrometric detection, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 898 stilbene derivatives, different molecular hybrids were obtained. They (2012) 1–6. could be used to recognize many molecular targets simultaneously. For [15] J. Cummings, M. Zweifel, N. Smith, P. Ross, J. Peters, G. Rustin, P. Price, M.R. Middleton, T. Ward, C. Dive, Evaluation of cell death mechanisms induced by example, modifications on the exocyclic amino guanosine group arean the vascular disrupting agent OXi4503 during a phase I clinical trial, Br. J. Cancer interesting instance of fusing. The substance 79 was also a research 106 (11) (2012) 1766–1771. object as a selective Herpes simplex virus thymidine kinase inhibitor. [16] Oxigene company web site wwwoxigenecom. The derivatives of C2-triazolylinosines were described as showing ac- [17] R.O. Dillman, A new chemotherapeutic agent: deoxycoformycin (pentostatin), Sem. Hematol. 31 (1994) 16–27. tivity against Cytomegalovirus. In turn, the group of guanosine deriva- [18] N. Niitsu, Y. Honma, Leuk. Lymphoma 34 (1999) 261–271. tives containing a p-methoxybenzyl group at the N2 position is an ex- [19] T. Robak, Purine nucleoside analogues in the treatment of myleoid leukemias, ample of a connection that exhibits a strong activity of translation Leuk. Lymphoma 44 (2003) 391–409. [20] A. Delannoy, 2-chloro-2'-deoxyadenosine: clinical applications in hematology, inhibitors in Ascaris suum nematode. It seems that the combination of Blood Rev. 10 (1996) 148–166. nucleosides and stilbene derivatives has a large medical potential. The [21] J.C. Akins, D.H. Peters, A. Markham, Fludarabine an update of its pharmacology discussed literature seems to provide the basis for the assumption that and use in the treatment of haematological malignancies, Drugs 53 (1997) 1005–1037. such combinations may contribute to the discovery of new drugs with a [22] A. Heredia, C. Davis, R. Redfield, Synergistic inhibition of HIV-1 in activated and variety of activities. resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol, J. Acq. Immun. Def. Synd 25 (3) (2000) 246–255. [23] B. Trinite, D.N. Levy, Potent inhibition of HIV-1 replication in resting CD4 T cells Acknowledgement by resveratrol and pterostilbene, Antimicrob. Agents. Ch. 61 (9) (2017) e00408–17/1 e00408-17/16. This work was supported by Faculty of Chemistry Warsaw [24] R. Wei, L. Tong, Y. You, X. Liu, Faming Zhuanli Shenqing (2018) CN 108047369 A 20180518; R. V. Doddamani, R. G. Tasaganva, S. R. University of Technology.

12 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Inamdar, M. Y. Kariduraganavar, Synthesis of chromophores and polyimides with adenocarcinoma-derived colon cancer cells, Biochem. Pharmacol. 84 (2012) a green chemistry approach for second-order nonlinear optical applications. 612–624. Polymers for Advanced Technologies, 29 (2018) 2091–2102. [51] M. Tolomeo, S. Grimaudo, A. Di Cristina, M. Roberti, et al., Pterostilbene and 3' [25] G. Likhtenshtein, Stilbenes Applications in Chemistry, Life Sciences and Materials -hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR- Science, Wiley-VCH Verlag Gmbh & Co Kgaa Weinheim, 2010. ABL-expressing leukemia cells, Int. J. Biochem. & Cell Biol. 37 (2005) 1709–1726. [26] C.-Y. Tsai, Y.-M. Liao, W.-Ch Liao, W.-J. Lin, P. Perumal, H.-H. Hu, Sh-Y. Lin, Ch- [52] P. Ferrer, M. Asensi, R. Segarra, A. Ortega, M. Benlloch, E. Obrador, M.T. Varea, H. Chang, S.-Y. Cai, T.-M. Sun, et al., Magnetically Controllable Random Lasers, G. Asensio, L. Jordá, J.M. Estrela, Association between pterostilbene and quercetin Adv. Mater. Technol. 2 (12) (2017) 101002/admt201700170. inhibits metastatic activity of B16 melanoma, Neoplasia 7 (2005) 37–47. [27] X. Qin, G. Ding, Y. Gong, C. Jing, G. Peng, S. Liu, L. Niu, S. Zhang, Z. Luo, H. Li, [53] C.M. Remsberg, J.A. Yanez, Y. Ohgami, K.R. Vega-Villa, A.M. Rimando, F. Gao, et al., Stilbene-benzophenone dyads for free radical initiating poly- N.M. Davies, Pharmacometrics of pterostilbene: preclinical pharmacokinetics and merization of methyl methacrylate under visible light irradiation, Dyes Pigments metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity, 132 (2016) 27–40. Phytother. Res. 22 (2008) 169–179. [28] G.I. Likhtenshtein, Stilbene molecular probes as potential materials for bioengi- [54] N. Suh, S. Paul, X. Hao, B. Simi, H. Xiao, A.M. Rimando, B.S. Reddy, Pterostilbene, neering: real time analysis of antioxidants and nitric oxide Immunoassay in an active constituent of blueberries, suppresses aberrant crypt foci formation in Solution and Biomembranes Fluidity, Adv. Mater. Res. 699 (2013) 718–723. the azoxymethane-induced colon carcinogenesis model in rats, Clin. Cancer Res. [29] A. Roloff, D.A. Nelles, M.P. Thompson, G.W. Yeo, N.C. Gianneschi, Self- 13 (2007) 350–355. Transfecting micellar RNA: modulating nanoparticle cell interactions via high [55] J.A. Woods, J.A. Hadfield, G.R. Pettit, B.W. Fox, A.T. McGown, The interaction density display of small molecule ligands on micelle coronas, Bioconjugate Chem. with tubulin of a series of stilbenes based on combretastatin A-4, Brit. J. Canc. 71 29 (1) (2018) 126–135. (1995) 705–711. [30] Z. Dogan, R. Paulini, J.A.R. Stuetz, S.R.C. Narayanan, 5‘-Tethered stilbene deri- [56] D. Ronchetti, F. Impagnatiello, M. Guzzetta, L. Gasparini, M. Borgatti, et al., vatives as fidelity- and affinity-enhancing modulators of DNA duplex stability, J. Modulation of iNOS expression by a nitric oxide-releasing derivative of the natural Am. Chem. Soc. 126 (2004) 4762–4763. antioxidant ferulic acid in activated RAW 2647 macrophages, Eur. J. Pharmacol. [31] F.D. Lewis, Y. Wu, X. Liu, Synthesis, structure, and photochemistry of ex- 532 (2006) 162–169. ceptionally stable synthetic dna hairpins with stilbene diether linkers, J. Am. [57] Z. Kutil, M. Kvasnicova, V. Temml, D. Schuster, P. Marsik, E.F. Cusimamani, J.- Chem. Soc. 124 (2002) 12165–12173. D. Lou, T. Vanek, P. Landa, Effect of dietary stilbenes on 5-lipoxygenaseand cy- [32] H.K. Bhat, X. Han, A. Gladek, J.G. Liehr, Regulation of the formation of the major clooxygenases activities in vitro, Int. J. Food Proper. 18 (2015) 1471–1477. diethylstilbestrol-DNA adduct and some evidence of its structure, Carcinogenesis [58] J. Dai, R.J. Mumper, Plant phenolics: extraction, analysis and their antioxidant 15 (1994) 2137–2142. and anticancer properties, Molecules 15 (2010) 7313–7352. [33] B. Uttara, A.V. Singh, P. Zamboni, R.T. Mahajan, Oxidative stress and neurode- [59] F. Zhang, C. Sun, J. Wu, C. He, X. Ge, W. Huang, Y. Zou, X. Chen, W. Qi, Q. Zhai, generative diseases: a review of upstream and downstream antioxidant therapeutic Combretastatin A-4 activates AMP-activated protein kinase and improves glucose options, Curr. Neuropharmacol. 7 (2009) 65–74. metabolism in db/db mice, Pharmacol. Res. 57 (2008) 318–323. [34] F. Tian, E.W. Debler, D.P. Millar, A.A. Deniz, I.A. Wilson, P.G. Schultz, The effects [60] Y.-M. Yang, X.-X. Wang, J.-Z. Chen, S.-J. Wang, H. Hu, H.-Q. Wang, Resveratrol of antibodies on stilbene excited-state energetics, Angew. Chem. Int. Ed. 45 (2006) attenuates adenosine diphosphate-induced platelet activation by reducing protein 7763–7765; kinase C activity, Am. J. Chin. Med. 36 (2008) 603–613. H. Meier, Blue fluorescent exciplexes consisting of trans-stilbene and antibodies, [61] C. Aranda, R. Ullrich, J. Kiebist, K. Scheibner, J.C. del Rio, M. Hofrichter, Angew. Chem. Int. Ed. 40 (2001) 1851–1853. A.T. Martinez, A. Gutierrez, Selective synthesis of the resveratrol analogue 4,4′- [35] Ch.N. Chan, B. Trinité, D.N. Levy, Potent inhibition of HIV-1 replication in resting dihydroxy-trans-stilbene and stilbenoids modification by fungal peroxygenases, CD4 T cells by resveratrol and pterostilbene, Antimicrobial Agents Chemotherapy Catal. Sci. Technol. 8 (9) (2018) 2394–2401. 61 (9) (2017) e00408–e417. [62] B. Hosseini, S. Seyed, A.M. Chippindale, H. Irannejad, A crystallographic and [36] G. Xiong, Z. Zhiyue, Ch Dawei, Q. Mingxi, W. Feng, C. Dongmei, S. Yi, Y. Mingshi, theoretical study of an (E)-2-hydroxyiminoethanone derivative: prediction of cy- Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the clooxygenase inhibition selectivity of stilbenoids by MM-PBSA and the role of treatment of drug-resistant tumors, Asian. J. Pharm. Sci. (2018), https://doi.org/ atomic charge, J. Biomol. Struct. Dyn. (2018) 1–12, https://doi.org/10.1080/ 10.1016/ j.ajps. 2018.03.002. 07391102.2018.1462256. [37] L. Jian, M. Xiaoqing, Ch. Tongkai, Q. Defang, Z. Ying, Preparation and char- [63] C. Litalien, P. Beaulieu, From Receptors to Effectors Molecular Mechanisms of acterization of pelletized solid dispersion of resveratrol with mesoporous silica Drug Actions. (2011) Chap. 117. microparticles to improve dissolution by fluid-bed coating techniques, Asian. J [64] H. Hovelstad, I. Leirset, K. Oyaas, A. Fiksdahl, Screening analyses of pinosylvin Pharm. Sci. 11 (4) (2016) 528–535. stilbenes, resin acids and lignans in norwegian conifers, Molecules 11 (2006) [38] C.E. Harper, B.B. Patel, J. Wang, A. Arabshahi, I.A. Eltoum, C.A. Lamartiniere, 103–114. Resveratrol suppresses prostate cancer progression in transgenic mice, [65] J.-Y. Xu, Y. Xu, X. Chu, M. Tan, B.-C. Ye, Protein acylation affects the artificial Carcinogenesis 28 (2007) 1946–1953. biosynthetic pathway for pinosylvin production in engineered E coli, ACS Chem. [39] G. Tozer, C. Kanthou, B.C. Baguley, Disrupting tumour blood vessels, Nat. Rev. Biol. 13 (5) (2018) 1200–1208. Cancer 5 (2005) 423–435. [66] A.L. Herbst, H. Ulfelder, D.C. Poskanzer, L.D. Longo, Adenocarcinoma of the va- [40] C. Silan, The effects of chronic resveratrol treatment on vascular responsiveness of gina Association of maternal stilbestrol therapy with tumor appearance in young streptozotocin-induced diabetic rats, Biol Pharmaceut. Bull. 31 (2008) 897–902. women1971, Am. J. Obstet. Gynecol. 181 (6) (1999) 1574–1575. [41] B.B. Aggarwal, A. Bhardwaj, R.S. Aggarwal, N.P. Seeram, S. Shishodia, Y. Takada, [67] E. Adam, D.G. Decker, A.L. Herbst, K.L. Noller, B.C. Tilley, D.E. Townsend, Vaginal Role of resveratrol in prevention and therapy of cancer: preclinical and clinical and cervical cancers and other abnormalities associated with exposure in utero to studies, Anticancer Res. 24 (2004) 2783–2840. diethylstilbestrol and related synthetic hormones, Cancer Res. 37 (1977) [42] M.D. Blanquer-Rosselló, R. Hernández-López, P. Roca, J. Oliver, A. Valle, 1249–1251. Resveratrol induces mitochondrial respiration and apoptosis in SW620 colon [68] E.A. Whelan, B. Grajewski, D.K. Wild, T.M. Schnorr, R. Alderfer, Evaluation of cancer cells, Biochim. Biophys. Acta 1861 (2) (2017) 431–440. reproductive function among men occupationally exposed to a stilbene derivative: [43] N. Pineda-Ramirez, G.F. Gutierrez Aguilar, M. Espinoza-Rojo, P. Aguilera, Current II. perceived libido and potency, Am. J. Ind. Med. 29 (1996) 59–65. evidence for AMPK activation involvement on resveratrol-induced neuroprotec- [69] W.E. Diederich, H. Steuber, Therapy of Viral Infections, Vol.15 of Topics in tion in cerebral ischemia, Nutr. Neurosci. 21 (4) (2018) 229–247. Medicinal Chemistry, Springer, 2015, p. 6 ISBN 9783662467596. [44] T. Doura, K. Takahashi, Y. Ogra, N. Suzuki, Combretastatin A4-β-Galactosyl [70] W.H. Prusoff, A review of some acpects of 5-iododeoxyuridine and azauridine, Conjugates for Ovarian Cancer Prodrug Monotherapy, ACS Med. Chem. Lett. 8 Cancer Res. 23 (1963) 1246–1259. (2017) 211–214. [71] T.J. Kinsella, et al., A chase I study of intravenous iododeoxyuridine as a clinical [45] J.A. Lee, N.M. Biel, R.T. Kozikowski, D.W. Siemann, B.S. Sorg, In vivo spectral and radiosensitizer, Int. J. Radiat. Oncol. 11 (1985) 1941–1946. fluorescence microscopy comparison of microvascular function after treatment [72] I. Serra, T.D. Bavaro, A. Cecchini, S. Daly, A.M. Albertini, M. Terreni, D. Ubiali, A with OXi4503, Sunitinib and their combination in Caki-2 tumors, Biomed. Opt. comparison between immobilized pyrimidine nucleoside phosphorylase from Exp. 5 (2014) 1965–1979. Bacillus subtilis and thymidine phosphorylase from Escherichia coli in the [46] T. Fifis, L. Nguyen, C.L. Malcontenti-Wilson, S. Chan, P.L. Nunes Costa, synthesis of 5-substituted pyrimidine 2′-deoxyribonucleosides, J. Mol. Catal. B- J. Daruwalla, M. Nikfarjam, V. Muralidharan, M. Waltham, E.W. Thompson, Enzym. 95 (2013) 16–21. C. Christophi, Treatment with the vascular disruptive agent OXi4503 induces an [73] D.J.M. Purifoy, The range of anti-herpesvirus agents, Rev. Contemporary immediate and widespread epithelial to mesenchymal transition in the surviving Pharmacother. 7 (2) (1996) 63–73. tumor, Cancer Med. 2 (2013) 595–610. [74] P.J. Kamphuis, H. Gerardus, M. Groenendijk, A. Bongers, PCT Int Appl WO (2008) [47] J. Cummings, M. Zweifel, N. Smith, P. Ross, J. Peters, G. Rustin, P. Price, 2009002166. M.R. Middleton, T. Ward, C. Dive, Evaluation of cell death mechanisms induced by [75] M. Taverna-Porro, L.A. Bouvier, C.A. Pereira, J.M. Montserrat, A.M. Iribarren, the vascular disrupting agent OXi4503 during a phase I clinical trial, Br. J. Cancer Chemoenzymatic preparation of nucleosides from furanoses, Tetrahedron Lett. 49 106 (2012) 1766–1771. (2008) 2642–2645. [48] J. Hua, Y. Sheng, K.G. Pinney, C.M. Garner, R.R. Kane, J.A. Prezioso, G.R. Pettit, [76] D.H. Ilson, Oesophageal cancer: new developments in systemic therapy, Cancer D.J. Chaplin, K. Edvardsen, OXi4503, a novel vascular targeting agent: effects on Treat. Rev. 29 (2003) 525–532. blood flow and antitumor activity in comparison to combretastatin A-4 phosphate, [77] A.F. Jorge, A. Avino, A.A.C.C. Pais, R. Eritja, C. Fabrega, DNA-based nanoscaffolds Anticancer Res. 23 (2B) (2003) 1433–1440. as vehicles for 5-fluoro-2'-deoxyuridine oligomers in colorectal cancer therapy, [49] Information about fosbretabulin on < https://clinicaltrialsgov/ct2/home > . Nanoscale 10 (15) (2018) 7238–7249. [50] L.M. Greene, N.M. O’Boyle, D.P. Nolan, M.J. Meegan, D.M. Zistere, The vascular [78] S. La, J.H. Cho, J. Kim, K. Kim, Capillary electropherotic profiling and pat tern targeting agent Combretastatin-A4 directly induces autophagy in recognition analysis of urinary nucleosides from thyroid cancer patients Anal,

13 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

Chim. Acta 486 (2003) 171–182. purine nucleoside analogues A new approach to antitumor and antiviral agents, J. [79] T. Hamma, A.R. Ferre-D’Amare, Pseudouridine synthases, Chem. Biol. 13 (2006) Med. Chem. 36 (1993) 635–653. 1125–1135. [112] < https://wwwdrugscom/monograph/gemcitabine-hydrochloridehtml > and re- [80] A. Seidel, S. Brunner, P. Seidel, G.I. Fritz, O. Herbarth, Modified nucleosides: an ferences cited there. accurate tumour marker for clinical diagnosis of cancer, early detection and [113] D.W. Dodd, K.N. Swanick, J.T. Price, A.L. Brazeau, M.J. Ferguson, N.D. Jones, therapy control, Brit. J. Cancer. 94 (11) (2006) 1726–1733. R.H.E. Hudson, Blue fluorescent deoxycytidine analogues: convergent synthesis, [81] K.R. Wilhelmus, Antiviral treatment and other therapeutic interventions for harpes solid-state and electronic structure, and solvatochromism, Org. Biomol. Chem. 11 simplex virus epithelial keratitis (Review), Cochrane Database Syst. Rev. 1 (2015) (2013) 5605–5614. CD002898101002/14651858. [114] H. Krishna, M.H. Caruthers, Alkynyl phosphonate DNA: a versatile “click”able [82] O.G. Sahin, Post-Varicella discifrom keratitis: Case Report, Open. J. Ophthalmol. 2 backbone for DNA-based biological applications, J. Am. Chem. Soc. 134 (2012) (2012) 83–84. 11618–11631. [83] O.H. Temmink, T. Emura, M. de Bruin, M. Fukushima, G. Peters, Therapeutic [115] K.T. Kim, H.W. Kim, D. Moon, Y.M. Rheeb, B.H. Kim, DNSC: a fluorescent, en- potential of the dual-targeted TAS-102 formulation in the treatment of gastro- vironmentally sensitive cytidine derivative for the direct detection of GGG triad intestinal malignancies, J. Cancer. Sci. 98 (2007) 779–789. sequences, Org. Biomol. Chem. 11 (2013) 5605–5614. [84] E. De Clercq, Discovery and development of BVDU (brivudin) as a therapeutic for [116] K. Chicas, R. H. E. Hudson. Fluorescent Analogues of Biomolecular Building the treatment of Herpes zoster, Biochem. Pharmacol. 68 (12) (2004) 2301–2315. Blocks, Ed Wilhelmsson M, TorY (2016) 174–207. [85] H. Baden, Continuous intra-arterial infusion of 5-fluor-2-deoxyuridine in primary [117] R.A. Cunh, Adenosine as a neuromodulator and as a homeostatic regulator in the and metastatic liver cancer, Ugeskrift for laeger 130 (17) (1968) 721–727. nervous system: different roles, different sources and different receptors, [86] K. Hata, M. Osaki, H. Kanasaki, K. Nakayama, R. Fujiwaki, H. Ito, K. Miyazaki, Neurochem. Int. 38 (2001) 107–125. Induction of thymidine phosphorylase expression by taxol does not enhance fur- [118] R. Siles, J.F. Ackley, M.B. Hadimani, J.J. Hall, B.E. Mugabe, R. Guddneppanavar, tulon sensitivity in a cisplatin-resistant human ovarian carcinoma cell line, K.A. Monk, J.-C. Chapuis, G.R. Pettit, D.J. Chaplin, K. Edvardsen, M.L. Trawick, Anticancer Res. 23 (2B) (2003) 1525–1531. C.M. Garner, K.G. Pinney, Combretastatin dinitrogen-substituted stilbene analo- [87] Y. Miyamoto, E. Oki, H. Saeki, Y. Maehara, H. Baba, Recent advances in systemic gues as tubulin-binding and vascular-disrupting agents, J. Nat. Prod. 71 (2008) chemotherapy for metastatic colorectal cancer, Gan to Kagaku Ryoho 43 (1) 313–320. (2016) 15–23. [119] A. de Mendonça, A.M. Sebastião, J.A. Ribeiro, Adenosine: does it have a neuro- [88] K. Hew, S.L. Dahlroth, S. Veerappan, L.X. Pan, T. Cornvik, P. Nordlund, Structure protective role after all? Brain Res. Brain Res. Rev. 33 (2000) 258–274. of the varicella zoster virus thymidylate synthase establishes functional and [120] D. Boison, Adenosine as a neuromodulator in neurological diseases, Curr. Opin. structural similarities as the humanenzyme and potentiates itself as a target of Pharmacol. 8 (1) (2008) 2–7, https://doi.org/10.1016/j.coph.2007.09.002. brivudine, PLoS One 10 (12) (2015) e0143947/1–e143947/16. [121] T. Porkka-Heiskanen, L. Alanko, A. Kalinchuk, D. Stenberg, Adenosine and sleep, [89] M. Kupczewska-Dobecka, Methotrexate – genotoxic and teratogenic for medical Sleep Med. Rev. 6 (4) (2002) 321–332. staff of oncology wards? Med Pr. 66 (2) (2015) 265–275. [122] S. Jiang, T. Li, T. Ji, Z. Yang, W. Yi, S. Di, Y. Sun, D. Wang, Y. Yang, AMPK [90] R. Hamuy, B. Berman, Topical antiviral agents for herpes simplex virus infections, orchestrates an elaborate cascade protecting tissue from fibrosis and aging, Ageing Drug. Today. 34 (12) (1998) 1013–1025. Res. Rev. 38 (2017) 18–27. [91] H. Hori, Methylated nucleosides in tRNA and tRNA methyltransferases, Front. [123] S. Jiang, T. Li, W. Yi, Z. Yang, D. Wang, Y. Yang, C. Gu, AMPK: Potential ther- Genet. 5 (144) (2014) 1–26. apeutic target for ischemic stroke, Theranostics 16 (2018) 4535–4551. [92] G. Ciaramella, PCT Int. Appl. (2017) WO 2017015457 A1 20170126. [124] T.V. Dunwiddie, S.A. Masino, The role and regulation of adenosine in the central [93] J. Fischer, C.R. Ganellin, Analogue-based Drug Discovery, John Wiley & Sons nervous system, Annu. Rev. Neurosci. 24 (2001) 31–55. (2006) 505. [125] T. Noji, A. Karasawa, H. Kusaka, Adenosine uptake inhibitors, Europ. J. Pharm. [94] N. Magula, M. Dedicoat, Cochrane Database, Syst. Rev. 1 (2015) CD007497 495 (2004) 1–16. 101002/14651858CD007497. [126] T. Porkka-Heiskanen, A.V. Kalinchuk, Adenosine, energy metabolism and sleep [95] C.L. Lai, N. Leung, E.K. Teo, Telbivudine Phase II Investigator Group, et al, A 1- homeostasis, Sleep Med. Rev. 15 (2011) 123–135. year trial of telbivudine, lamivudine, and the combination in patients with he- [127] M. Cieślak, A. Wojtczak, M. Komoszyński, Role of the purinergic signaling in patitis B e antigen-positive chronic hepatitis B, Gastroenterology 129 (2) (2005) epilepsy, Pharmacol. Rep. 69 (1) (2017) 130. 528–536. [128] S. Masino, D. Boison, Adenosine: A key link between metabolism and brain ac- [96] E. Werz, S. Korneev, M. Montilla-Martinez, R. Wagner, R. Hemmler, C. Walter, tivity New York, Springer, NY, 2013. J. Eisfeld, K. Gall, H. Rosemeyer, Specific DNA duplex formation at an artificial [129] Y. Jin, X. Meng, Z. Qiu, Y. Su, P. Yu, P. Qu, Antitumor and antimetastatic roles of lipid bilayer: towards a new DNA biosensor technology, Chem. Biodivers. 9 (2012) cordycepin, one bioactive compound of Cordyceps militaris, Saudi J. Biol. Sci. 25 272–281. (5) (2018) 991–995. [97] A. Seidel, S. Brunner, P. Seidel, G.I. Fritz, O. Herbarth, Modified nucleosides: an [130] M. Zaluski, K. Stanuch, T. Karcz, S. Hinz, G. Latacz, E. Szymańska, accurate tumour marker for clinical diagnosis of cancer, early detection and J. Schabikowski, A. Doroz-Plonka, J. Handzlik, A. Drabczynska, et al., Tricyclic therapy control, Br. J. Cancer 94 (2006) 1726–1733. xanthine derivatives containing a basic substituent: adenosine receptor affinity [98] Y. Zheng, H. Kong, J. Xiong, et al., Clinical significance and prognostic value of and drug-related properties, Med. Chem. Comm. (2018), https://doi.org/10.1039/ urinary nucleosides in breast cancer patients, Clin. Biochem. 38 (2005) 24–30. c8md00070k. [99] D. Jégourel, R. Delépée, et al., Molecularly imprinted polymer of 5-methyluridine [131] S.K. Lee, C.H.W. Park, PCT Int. Appl. (2018) WO 2018080127 A1 20180503. for solid-phase extraction of pyrimidine nucleoside cancer markers in urine, [132] H. Zhu, J. Wang, PCT Int. Appl. (2017) WO 2017157248 A1 20170921. Bioorgan Med. Chem. 16 (2008) 8932–8939. [133] F. Seela, N. Ramzaeva, H. Rosemeyer, Product Class 17: Purines, Sci. Synthesis [100] A. Alama, F. Barbieri, M. Cagnoli, G. Schettini, Org. Lett. 2013 3702–3705. Thieme 16 (2004) 945–1108. Antisense oligonucleotides as therapeutic agents. Pharmacol. Res., 3 1997 [134] A. Zahler, et al., Nature Inhibition of telomerase by G-quartet DNA structures, 171–178; V. K. Sharma, R. K. Sharma, S. K. Singh, Med.Chem.Commun., 5 2014 Nature 350 (1991) 718–720. 1454–1471. [135] G. Laughlan, et al., The high-resolution crystal structure of a parallel-stranded [101] Y. Hari, T. Morikawa, T. Osawa, S. Obika, Synthesis and properties of 2'-O,4'-C- guanine tetraplex, Science 265 (5171) (1994) 520–524. ethyleneoxy bridged 5-methyluridine, Org. Lett. (2013) 3702–3705. [136] J. Cadet, T. Douki, D. Gasparutto, J.L. Ravanat, Oxidative damage to DNA: for- [102] K. Bartosik, G. Leszczyńska, Synthesis of various substituted 5-methyluridines mation, measurement and biochemical features, Mutat. Res. 531 (1,2) (2003) (xm5U) and 2-thiouridines (xm5s2U) via nucleophilic substitution of 5-pivaloy- 5–23. loxymethyluridine/2-thiouridine, Tetrahedron Lett. 52 (2) (2006) 389–397. [137] P. Opresko, J. Fan, S. Danzy, D.M. Wilson, V.A. Bohr, Oxidative damage in telo- [103] M. Cansev, Uridine and cytidine in the brain: their transport and utilization, Brain meric DNA disrupts recognition by TRF1 and TRF2, Nucleic Acids. Res. 33 (4) Res. Rev. 52 (2) (2006) 389–397. (2005) 1230–1239. [104] K. Fabianowska-Majewska, B. Krawczyk, Mechanism of action of nucleoside [138] J. Zhou, M. Liu, A.M. Fleming, C.J. Burrows, S.S. Wallace, The NEIL glycosylases analogues, used in blood cancer therapy, Acta Haematologica Polonica 36 (2005) remove oxidized guanine lesions from telomeric and promoter quadruplex DNA 55–72. structures, Nucleic Acids. Res. 43 (8) (2015) 4039–4054. [105] L.R. Silverman, J.F. Holland, R.S. Weinberg, et al., Effects of treatment with 5- [139] S. Quideau, et al., Plant polyphenols: chemical properties, biological activities, azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodys- and synthesis, Angew. Chem. Int. Ed. 50 (2011) 586–621; plastic syndromes, Leukemia 7 (supl. 1) (1993) 21–29. J. Sirerol, et al., Role of natural stilbenes in the prevention of cancer, Oxid Med. [106] L.R. Silverman, J.F. Holland, E.P. Demakos, Azacitidine in myelodysplastic syn- Cell Longev (2016) 15 2016:3128951. dromes: CALGB studies 8421 and 8921, Ann. Hematol. 68 (1994) A12. [140] J. Brozmanová, A. Dudás, J.A. Henriques, Repair of oxidative DNA damage–an [107] L. Zhou, X. Cheng, B.A. Connolly, M.J. Dickman, P.J. Hurd, D.P. Hornby, important factor reducing cancer risk, Neoplasma 48 (2) (2001) 85–93. Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with [141] Q. Kong, X. Yin, J. Yu, X. Ren, Mechanistic processes of resveratrol in inhibiting DNA methyltransferases, J. Mol. Biol. 321 (2002) 591–599. the oxidative damage of guanine, as evidenced by UHPLC-MS2, J. Chromatogr. B [108] C. Avendano, J.C. Menendez, Medicinal Chemistry of Anticancer Drugs, Second 1093–1094 (2018) 174–182. ed., Elsevier, 2008, pp. 322–335. [142] S. Sahasranaman, D. Howard, S. Roy, Clinical pharmacology and pharmacoge- [109] J. Fischer, C.R. Ganellin, Analogue-based Drug Discovery, John Wiley & Sons, netics of thiopurines, Eur. J. Clin. Pharmacol. 64 (8) (2008) 753–767. 2006, p. 511. [143] M. Vandana, S.K. Sahoo, Reduced folate carrier independent internalization of [110] R.L. Momparler, Optimization of cytarabine (ARA-C) therapy for acute myeloid PEGylated pemetrexed: a potential nanomedicinal approach for breast cancer leukemia Exp, Hematol. Oncol. 2 (2013) 20, https://doi.org/10.1186/2162-3619- therapy, Mol. Pharmaceut. 9 (10) (2012) 2828–2843. 2-20. [144] Y. Cheng, H. Murakami, P.-C.H. Yang, J. He, K. Nakagawa, J.H. Kang, J.-H. Kim, [111] P.A. Bonnet, R.K. Robins, Modulation of leukocyte genetic expression by novel X. Wang, S. Enatsu, T. Puri, et al., Randomized phase II trial of gefitinib with and

14 H. Krawczyk Bioorganic Chemistry 90 (2019) 103073

without pemetrexed as first-line therapy in patients with advanced nonsquamous groove of DNA sequences with AATT and TTAA segments induces differential non-small-cell lung cancer with activating epidermal growth factor receptor mu- stability, J. Photoch. Photo.bio. B 170 (2017) 217–224. tations, J. Clin. Oncol. 34 (27) (2016) 3258–3266. [167] V. Wacheck, T. Szekeres, Use of stilbene derivatives for the production of medi- [145] S. Nannizzi, G.J. Veal, E.M.V. Giovannetti, S. Ricciardi, C.J. Ottley, M. Tacc, caments for the treatment of solid tumors, PCT Int. Appl. (2007) R. Danesi, Cellular and molecular mechanisms for the synergistic cytotoxicity WO 2007002973 A2 20070111. elicited by oxaliplatin and pemetrexed in colon cancer cell lines, Cancer Chemoth. [168] K.V. Kiselev, A.P. Tyunin, A.Y. Manyakhin, Y.N. Zhuravlev, Resveratrol content Pharm. 66 (3) (2010) 547–558. and expression patterns of stilbene synthase genes in Vitis amurensis cells treated [146] L.W. Buie, S.S. Epstein, C.M. Lindley, Nelarabine: a novel purine antimetabolite with 5-azacytidine plant cell, Tissue Organ Culture 105 (1) (2011) 65–72. antineoplastic agent, Clin. Ther. 29 (9) (2007) 1887–1899. [169] Z. Horvath, P. Saiko, Ch. Illmer, S. Madlener, T. Hoechtl, W. Bauer, T. Erker, [147] K. Burley, J. Wolf, E. Raffoux, D.I. Marks, Long-term survival following post-al- W. Jaeger, M. Fritzer-Szekeres, T. Szekeres, Synergistic action of resveratrol, an lograft relapse of T-cell acute lymphoblastic leukaemia: a novel approach using ingredient of wine, with Ara-C and tiazofurin in HL-60 human promyelocytic nelarabine and donor lymphocyte infusions, Bone Marrow Transplant. 53 (3) leukemia cells, Exp. Hematol. 33 (2005) 329–335. (2018) 344–346. [170] B. Festy, M. Daune, Hydroxystilbamidine nonintercalating drug as a probe of [148] E. de Clercq, H.J. Field, Antiviral prodrugs – the development of successful pro- nucleic acid conformation, Biochemistry 12 (1973) 4827–4834. drug strategies for antiviral chemotherapy, Brit. J. of Pharmacol. 147 (1) (2006) [171] B. Festy, J. Sturm, M. Daune, Interaction between hydroxystilbamidine and DNA: I 1–11. binding isotherms and thermodynamics of the association BBA-proteins, Proteom. [149] S.M. Gureyeva, A.M. Goy, A. Yu Kondratova, O.H. Oksamytna, The biopharma- 407 (1975) 24–42. ceutical studies of Valavir film-coated tablets 05 g, Visnik Farmatsii 4 (2015) [172] K. Fukuhara, N. Miyata, Resveratrol as a new type of DNA-cleaving agent, Bioorg. 37–40. Med. Chem. Lett. 8 (1998) 3187–3192. [150] M. Melegari, P.P. Scaglioni, J.R. Wands, Hepatitis B virus mutants associated with [173] T. Jaunet-Lahary, D.P. Vercauteren, F. Fleury, A.D. Laurent, Computational si- 3TC and famciclovir administration are replication defective, Hepatology 27 (2) mulations determining disulfonic stilbene derivative bioavailability within human (1998) 628–633. serum albumin, Phys. Chem. Chem. Phys. 20 (2018) 18020–18030. [151] M. Eriksson, J.J. Jokinen, S. Soederlund, P. Haemmaeinen, J. Lommi, [174] M.K. Herrlein, R.L. Letsinger, Remarkably stable base-stacked structure, Angew. K. Lemstroem, Low-dose valganciclovir prohylaxis is efficacious and safe in Chem. Int. Ed. Engl. 36 (1997) 599–601. Cytomegalovirus seropositive heart transplant recipients with anti-thymocyte glo- [175] Z. Dogan, R. Paulini, J.A. Rojas Stutz, S. Narayanan, C. Richert, 5'-Tethered stil- bulin, Transpl. Infects. Dis. 20 (3) (2018) n/a. bene derivatives as fidelity- and affinity-enhancing modulators of DNA duplex [152] V. Seidel, C. Feiterna-Sperling, J.-P. Siedentopf, J. Hofmann, W. Henrich, stability, J. Am. Chem. Soc. 126 (2004) 4762–4763. Ch. Buehrer, K. Weizsaecker, Intrauterine therapy of Cytomegalovirus infection [176] G.A. Ellis, N.A. McGrath, M.J. Palte, R.T. Raines, Ribonuclease-activated cancer with valganciclovir: review of the literature, Med. Microbiol. and Immun. 206 (5) prodrug, ACS Med. Chem. Lett. 3 (2012) 268–272. (2017) 347–354. [177] P. Donner, J.T. Randolph, P. Huang, R. Wagner, C. Maring, B.H. Lim, L. Colletti, [153] J. Wang, Y. Yu, G. Li, Ch. Shen, Z. Meng, J. Zheng, Y. Jia, S. Chen, X. Zhang, Y. Liu, R. Mondal, J. Beyer, G. Koev, K. Marsh, D. Beno, K. Longenecker, T. Pilot- M. Zhu, et al., J. Hepatol. 68 (1) (2018) 16–24. Matias, W. Kati, A. Molla, D. Kempf, High potency improvements to weak aryl [154] A. Pruvost, Measurement of intracellular didanosine and tenofovir phosphorylated uracil HCV polymerase inhibitor leads, Bioorg. Med. Chem. Lett. 23 (2013) metabolites and possible interaction of the two drugs in human immunodeficiency 4367–4369. virus-infected patients, Antimicrob. Agents. Ch. 4 (2005) 1907–1914. [178] J.T. Randolph, A.Ch. Krueger, P.L. Donner, J.K. Pratt, D. Liu, Ch.E. Motter, [155] B.M. Kane, HIV/AIDS Treatment Drugs, Infobase Publishing, 2008, p. 56. T.W. Rockway, M.D. Tufano, R. Wagner, H.B. Lim, et al., Synthesis and biological [156] F. Van Bambeke, D. Lambert, M-P. Mingeot-Leclercq, P. Tulkens, Antiinfective characterization of aryl uracil inhibitors of hepatitis C virus NS5B polymerase: therapy: Mechanisms of action In: Infectious Diseases, D Armstrong and J Cohen discovery of ABT-072, a trans-stilbene analog with good oral bioavailability, J. ed, Mosby, London, United Kingdom, section 7, chapter 1, (1999) pp 11–114. Med. Chem. 61 (2018) 1153–1163. [157] R. Morphy, Z. Rankovic, Designed multiple ligands an emerging drug discovery [179] P. Szczecinski, K. Kordowska, H. Krawczyk, Method for obtaining new stilbene praradigm, J. Med. Chem. 48 (2005) 6523–6543. derivatives of uridine with (E)-configuration. (2017) PL 225922 B1 20170630. [158] H. Takano, K. Sawada, N. Sato, A. Natoya, T. Tarumi, S. Hirayama, K. Koizumi, [180] E. Palak, J. Wrzosek, M. Poterała, H. Krawczyk, Synthesis of stilbenes derivative of T.A. Takahashi, S. Sekiguchi, T. Koike, Mobilization of peripheral blood progenitor 5-methyluridine, in: Z. Hubicki (Ed.) Science and Industry - spectroscopic methods cells following CHOP treatment combined with delayed granulocytecolony-sti- in practice, new challenges and opportunities, ISBN 978-83-945225-3-7 (2017) mulating factor administration in patients with non- Hodgkin’s lymphoma, Leuk. pp.206-211. Lymphoma 21 (1996) 473–478. [181] M. Pionkowska, P. Szczeciński, H. Krawczyk, Synthesis of stilbenes derivative of [159] B.A. Larder, S.D. Kemp, P.R. Harrigan, Potential mechanism for sustained anti- cytidine, in: Z. Hubicki (Ed.) Science and Industry - spectroscopic methods in retroviral effiacy of AZT-3TC combination therapy, Science 269 (1995) 696–699. practice, new challenges and opportunities, ISBN978-83-939465-5-6 (2015) pp. [160] E. Jenwitheesuk, J.A. Horst, K.L. Rivas, W.C. Van Voorhis, R. Samudrala, Novel 525-529. paradigms for drug discovery: computational multitarget screening, Trends. [182] J. Wrzosek, E. Palak, E. Jaśkowska, H. Krawczyk, Synthesis of stilbenes derivative Pharmacol. Sci. 29 (2008) 62–71. of adenosine, in: Z. Hubicki (Ed.) Science and Industry - spectroscopic methods in [161] N. Chufarova, K. Czarnecka, R. Skibinski, M. Cuchra, I. Majsterek, P. Szymanski, practice, new challenges and opportunities, ISBN 978-83-945225-3-7 (2017) pp. New tacrine-acridine hybrids as promising multifunctional drugs for potential 212-215. treatment of Alzheimer's disease, Archiv Pharm 351 (7) (2018) e1800050. [183] K. Pawłowska, H. Krawczyk, P. Szczeciński, Synthesis of methoxy and carbox- [162] S.J. Basha, P.D. Mohan, P. Yeggoni, Z.R. Babu, P.B. Kumar, A.D. Rao, et al., New ystilbenes derivative of guanosine, in: Z. Hubicki (Ed.) Science and Industry - flavone-cyanoacetamide hybrids with a combination of cholinergic, antioxidant, spectroscopic methods in practice, new challenges and opportunities, ISBN 978- modulation of β-amyloid aggregation, and neuroprotection properties as in- 83-945225-0-6 (2016) pp. 59-63. novative multifunctional therapeutic candidates for Alzheimer's disease and un- [184] K. Nakatani, Ch. Dohno, I. Saito, N2-Phenyldeoxyguanosine: modulation of the raveling their mechanism of action with acetylcholinesterase, Mol. Pharmaceut. chemical properties of deoxyguanosine toward one-electron oxidation in DNA, J. 15 (6) (2018) 2206–2223. Am. Chem. Soc. 124 (2002) 6802–6803. [163] R. Morphy, Z. Rankovic, The physicochemical challenges of designing multiple [185] F. Focher, C. Hildebrand, S. Freese, G. Ciarrocchi, T. Noonan, S. Sangalli, ligands, J. Med. Chem. 49 (2006) 4961–4970. N. Brown, S. Spadari, G. Wright, N2-phenyldeoxyguanosine: a novel selective in- [164] R. Morphy, Z. Rankovic, Designing multiple ligands - medicinal chemistry stra- hibitor of herpes simplex thymidine kinase, J. Med. Chem. 31 (1988) 1496–1500. tegies and challenges, Curr. Pharm. Des. 15 (6) (2009) 587–600. [186] K. Lakshman, A. Kumar, R. Balachandran, B.W. Day, G. Andrei, R. Snoeck, [165] A. Heredia, Ch.E. Davis, M.S. Reitz, N.M. Le, M.A. Wainberg, J.S. Foulke, L.- J. Balzarin, Synthesis and biological properties of C-2 triazolylinosine derivatives, X. Wang, R.R. Redfield, Targeting of the purine biosynthesis host cell pathway J. Org. Chem. 77 (2012) 5870–5883. enhances the activity of tenofovir against sensitive and drug-resistant HIV-1, J. [187] K. Piecyk, R.E. Davis, M. Jankowska-Anyszka, Synthesis of N2-modified 7-me- Infect. Dis. 208 (12) (2013) 2085–2094. thylguanosine 5’-monophosphates as nematode translation inhibitors, Bioorgan. [166] M.S. Nair, S. D'Mello, R. Pant, P.M. Poluri, Binding of resveratrol to the minor Med. Chem. 20 (2012) 4781–4789.

15