pharmaceuticals Article Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties Kseniya Kovaleva 1 , Olga Yarovaya 1,2,* , Konstantin Ponomarev 1 , Sergey Cheresiz 2 , Amirhossein Azimirad 2, Irina Chernyshova 2, Alexandra Zakharenko 3, Vasily Konev 4, Tatiana Khlebnikova 4, Evgenii Mozhaytsev 1, Evgenii Suslov 1 , Dmitry Nilov 5 , Vytas Švedas 5,6 , Andrey Pokrovsky 2, Olga Lavrik 2,3 and Nariman Salakhutdinov 1 1 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia; [email protected] (K.K.); [email protected] (K.P.); [email protected] (E.M.); [email protected] (E.S.); [email protected] (N.S.) 2 V. Zelman Institute for the Medicine and Psychology, Novosibirsk State University, Pirogova St. 1, 630090 Novosibirsk, Russia; [email protected] (S.C.); [email protected] (A.A.); [email protected] (I.C.); [email protected] (A.P.); [email protected] (O.L.) 3 Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia; Citation: Kovaleva, K.; Yarovaya, O.; [email protected] 4 Ponomarev, K.; Cheresiz, S.; Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 5, Azimirad, A.; Chernyshova, I.; 630090 Novosibirsk, Russia; [email protected] (V.K.); [email protected] (T.K.) 5 Zakharenko, A.; Konev, V.; Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Lenin Hills 1, Bldg. 40, 119991 Moscow, Russia; [email protected] (D.N.); [email protected] (V.Š.) Khlebnikova, T.; Mozhaytsev, E.; et al. 6 Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, Bldg. 73, Design, Synthesis, and Molecular 119991 Moscow, Russia Docking Study of New Tyrosyl-DNA * Correspondence: [email protected] Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids Abstract: In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and and Adamantane Moieties. thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their in- Pharmaceuticals 2021, 14, 422. https://doi.org/10.3390/ph14050422 hibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotox- Academic Editors: Mary Meegan and icity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the Niamh M O’Boyle adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 Received: 26 March 2021 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Accepted: 23 April 2021 Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate. Published: 1 May 2021 Keywords: tyrosil-DNA-phosphodiesterase 1; adamantane; resin acid; TDP1 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction DNA in living organisms is constantly exposed to a variety of physical and chem- ical stresses, and damage occurs as a result. Bulk DNA damage is caused by UV light and environmental mutagens, and X-rays cause DNA double-strand breaks. Defects in Copyright: © 2021 by the authors. the repair of DNA damage are implicated in a variety of diseases, many of which are Licensee MDPI, Basel, Switzerland. typified by neurological dysfunction and/or increased genetic instability and cancer [1]. This article is an open access article Traditional cancer chemotherapy is aimed at damaging the DNA of malignant cells, and distributed under the terms and the results depend on the effectiveness of their repair systems. Recently, compounds that conditions of the Creative Commons act as DNA repair inhibitors have been considered as potential drugs [2,3]. The enzyme Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ tyrosil-DNA-phosphodiesterase 1 (TDP1) is one of the promising ones [4]. This enzyme 4.0/). is an important supplementary target for anticancer therapies based on topoisomerase Pharmaceuticals 2021, 14, 422. https://doi.org/10.3390/ph14050422 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 422 2 of 17 Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 18 inhibitors 1 (TOP1), since it plays a key role in the removal of TOP1-DNA adducts stabilized byTOP1 TOP1 inhibitors inhibitors such such as ascamptothecine camptothecine [5] [ 5and] and its its clinical clinical derivatives derivatives [6]. [6 ].TDP1 TDP1 is isalso also capablecapable of hydrolysing apurinic sites, sites, and and thus thus leading leading to to their their repair. repair. This This may may be be the the keykey activity needed for the repair repair of of DNA DNA da damagemage caused caused by by antitumour antitumour alkylating alkylating drugs drugs suchsuch asas temozolomidetemozolomide (TMZ), as as well as ionising radiation radiation [7]. [7]. Thus, Thus, the the inhibition inhibition of of TDP1TDP1 activity may significantly significantly enhance enhance the the th therapeuticerapeutic effect effect of of some some anticancer anticancer agents. agents. SCAN1SCAN1 is a natural mutant of of TDP1 TDP1 where where His4 His49393 is is replaced replaced with with Arg493 Arg493 in in the the binding binding pocketpocket [[8].8]. The mutation changes the the geometry geometry of of the the enzyme enzyme active active site, site, and and the the enzyme enzyme remainsremains covalently bound to to DNA. DNA. This This mutation mutation leads leads to to a a severe severe neurodegenerative neurodegenerative diseasedisease spinocerebellar ataxia syndrome syndrome with with axonal axonal neuropathy neuropathy (SCAN1). (SCAN1). It It is is currently currently suggestedsuggested that the pathology is is caused caused by by the the accumulation accumulation of of the the SCAN1-DNA SCAN1-DNA covalent covalent cleavagecleavage complexes [9]. [9]. It Itis isassumed assumed that that nerve nerve cells cells especially especially suffer suffer from from the accumu- the accu- mulationlation of such of such adducts adducts due due to their to their nonprolife nonproliferativerative nature nature leading leading to the to progressive the progressive ac- accumulationcumulation of ofunrepaired unrepaired DNA DNA lesions lesions [10]. [10 ].Therefore, Therefore, suppression suppression of of SCAN1 SCAN1 activity activity couldcould potentially improve the the SCAN1 SCAN1 patients patients’’ condition condition and and prevent prevent the the progression progression of of thethe disease.disease. The search for for inhibitors inhibitors of of ke keyy DNA DNA repair repair enzymes enzymes is is a apromising promising area area of of medicalmedical chemistry, as it represents one one of of the the ways ways to to design design effective effective therapies therapies for for cancer, cancer, asas wellwell asas cardiovascularcardiovascular and neurodegenerative diseases. diseases. Recently, Recently, a anumber number of of TDP1 TDP1 inhibitorinhibitor structural classes have have been been studie studied,d, including including pyrimidine pyrimidine nucleosides nucleosides [11], [11 ],fu- fu- ramidineramidine [12[12],], compoundscompounds with with benzopentathiepine benzopentathiepine moiety moiety [13 [13],], indenoisoquinolines indenoisoquinolines [14 ], and[14],5-arylidenethioxothiazolidinones and 5-arylidenethioxothiazolidinones [15] (Figure[15] (Figure1). 1). Figure 1. StructuresFigure 1. Structures of known of TDP1 known inhibitors. TDP1 inhibitors. Hybrid molecules created from from different different pharmacophores pharmacophores of of natural natural and and synthetic synthetic equivalentsequivalents are successfully us useded in in pharmaceutical pharmaceutical practice practice [16]. [16]. New New hybrid hybrid compounds compounds havehave been synthesised synthesised starting starting from from the the ph pharmacophoricarmacophoric natural natural compounds compounds with withinhib- in- hibitoryitory properties properties against against TDP1. TDP1. These These include include phenolic phenolic usnic usnic acid acidderivatives derivatives A [17], A [177-], 7-hydroxycoumarinshydroxycoumarins B [18], B [18 and], and 4-arylcoumarins 4-arylcoumarins C [19], C [19 derivatives], derivatives of deoxycholic of deoxycholic acid acid D D[[20]20 and] and adamantanecarboxylic adamantanecarboxylic acid acid monoterpene monoterpene esters esters E [21] E [21 (Figure] (Figure 2). 2). Our group previously obtained a set of ureas and thioureas based on the natural terpenoid dehydroabietylamine [22]. These compounds are able to inhibit TDP1 in the submicromolar range. They also lack toxicity against different cell lines in concentra- tions up to 100 µM. For the first time, we have shown that dehydroabietylamine TDP1 inhibitors in combination with TMZ demonstrate a better cytotoxic effect on glioblas- toma cells than TMZ alone, taken at the same concentration. Compound 1 (Figure3), which has a fragment of resin acid and adamantane, was an efficient inhibitor of TDP1 activity in vitro, and enhanced the cytotoxic effect of TMZ