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Synthesis of New Cisplatin Derivatives from Bile Acids

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Synthesis of New Cisplatin Derivatives from Bile Acids molecules Article Synthesis of New Cisplatin Derivatives from Bile Acids Barbara Seroka 1,* , Zenon Łotowski 1,*, Agnieszka Hryniewicka 1 , Lucie Rárová 2, 3, 1 1, Rafal R. Sicinski *, Aneta M. Tomkiel and Jacek W. Morzycki y 1 Faculty of Chemistry, University of Białystok, K. Ciołkowskiego 1K, 15-245 Białystok, Poland; [email protected] (A.H.); [email protected] (A.M.T.); [email protected] (J.W.M.) 2 Laboratory of Growth Regulators, Faculty of Science, Palacký University, and Institute of Experimental Botany of the Czech Academy of Sciences, Šlechtitel ˚u27, CZ-78371 Olomouc, Czech Republic; [email protected] 3 Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland * Correspondence: [email protected] (B.S.); [email protected] (Z.Ł.); [email protected] (R.R.S.) Dedicated to Professor Hector F. DeLuca (University of Wisconsin Madison, USA) on the occasion of his y 90th birthday. Academic Editor: Rafal R. Sicinski Received: 15 November 2019; Accepted: 2 February 2020; Published: 4 February 2020 Abstract: A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity. Keywords: bile acids; lithocholic acid; deoxycholic acid; hyodeoxycholic acid; cholic acid; steroidal diamines; platinum(II) complexes 1. Introduction Cisplatin is one of the most effective chemotherapeutic agents used in the treatment of many human cancers [1]. Unfortunately, its therapeutic use is limited due to harmful side effects, in particular nephrotoxicity [2,3]. Although many anticancer platinum complexes have been developed so far [4], there is still a need to find more active and more selective drugs. Combining of two bioactive molecules as a way to improve the biological properties of the starting compounds is a common practice in medical chemistry [5]. In addition, a natural compound that is designed to form a hybrid molecule together with cisplatin should be a good transporter for transferring the drug to cancer cells. Binding biomolecules to drugs always causes a drastic change in the structure of the carrier as well as in the structure of the pharmacologically active compound. We recently used this idea to design steroid-based cisplatin derivatives according to the general formula shown in Figure1[6,7]. As a result of our previous work, steroidal cisplatin analogs were obtained: two series of cholestane-based Pt(II) complexes derived from cholesterol (1–4) and a complex 5 (Figure2) synthesized from 16-dehydropregnenolone acetate [6]. However, the most promising was cisplatin derivative 6 based on lithocholic acid (LCA) [7]. Although the complex 6 showed only moderate cytotoxicity (IC50 28 µM) in the initial test against the HeLa cervical cancer cell line, it proved to be non-toxic to normal fibroblasts. This selectivity opens the way for modification of this complex to be more active while maintaining a lack of toxicity to healthy cells. Molecules 2020, 25, 655; doi:10.3390/molecules25030655 www.mdpi.com/journal/molecules Molecules 2020,, 25,, 655x FOR PEER REVIEW 2 of 15 Molecules 2020, 25, x FOR PEER REVIEW 2 of 15 Figure 1. General model of steroid-based cisplatin derivatives (n = 1 or 2). Figure 1. General model of steroid-based cisplatin derivatives (n = 11 or or 2). 2). Figure 2. Steroid-based cisplatin derivatives [[6,7].6,7]. Figure 2. Steroid-based cisplatin derivatives [6,7]. The biological functions of bile acidsacids dependdepend onon theirtheir chemicalchemical naturenature andand polaritypolarity [[8].8]. Both The biological functions of bile acids depend on their chemical nature and polarity [8]. Both LCA and deoxycholic acid (DCA) are hydrophobic but show didifferentfferent toxicitytoxicity [[9].9]. Bajaj et al. [[10]10] LCA and deoxycholic acid (DCA) are hydrophobic but show different toxicity [9]. Bajaj et al. [10] have reported that DCA having two hydroxyl groupsgroups shows weak interactions with cell membranes have reported that DCA having two hydroxyl groups shows weak interactions with cell membranes compared toto highlyhighly hydrophobic hydrophobic LCA. LCA. The The hydration hydration barrier barrier between between cell membranescell membranes and DCAand DCA does compared to highly hydrophobic LCA. The hydration barrier between cell membranes and DCA notdoes favor not thefavor interactions the interactions that cause that poor cause uptake poor in mammalianuptake in mammalian cells. In contrast, cells. moreIn contrast, hydrophobic more does not favor the interactions that cause poor uptake in mammalian cells. In contrast, more LCAhydrophobic can easily LCA penetrate can easily cell membranes.penetrate cell In membranes. addition, the In varied addition, activity the varied of DCA activity and LCA of DCA may alsoand hydrophobic LCA can easily penetrate cell membranes. In addition, the varied activity of DCA and resultLCA may from theiralso diresultfferent from binding their to different cellular receptorsbinding [to11 –cellular13]. Lithocholic receptors acid [11–13]. exhibits Lithocholic high antitumor acid LCA may also result from their different binding to cellular receptors [11–13]. Lithocholic acid activityexhibits [14high,15 ],antitumor is involved activity in human [14,15], and animalis involved carcinogenesis in human [ 16and], can animal selectively carcinogenesis kill neuroblastoma [16], can exhibits high antitumor activity [14,15], is involved in human and animal carcinogenesis [16], can cellselectively lines [17 kill], and neuroblastoma selectively induces cell lines apoptosis [17], and in prostateselectively [18 ]induces and colon apoptosi cancers cellsin prostate [19]. LCA [18] elicits and selectively kill neuroblastoma cell lines [17], and selectively induces apoptosis in prostate [18] and apoptosiscolon cancer by activationcells [19]. bothLCA extrinsicelicits apoptosis and intrinsic by activation pathways both without extrinsic entering and to intrinsic cancer cells. pathways It has colon cancer cells [19]. LCA elicits apoptosis by activation both extrinsic and intrinsic pathways beenwithout suggested entering that to cancer target cells. of cancerous It has been tissue sugge is moststed likelythat target localized of cancerous at the surface tissue ofis themost plasma likely without entering to cancer cells. It has been suggested that target of cancerous tissue is most likely membranelocalized at and the issurface either activatedof the plasma or deactivated membrane by an LCAd is ineither order activated to elicit apoptosisor deactivated [18]. by LCA in localized at the surface of the plasma membrane and is either activated or deactivated by LCA in orderBile to elicit acids apoptosis directly activate [18]. various intracellular ligand-activated nuclear receptors, such as the order to elicit apoptosis [18]. farnesoidBile acids X receptor directly (FXR), activate pregnane various X receptor intracellular (PXR), ligand-activated and vitamin D receptor nuclear (VDR),receptors, and such cell surface as the Bile acids directly activate various intracellular ligand-activated nuclear receptors, such as the Gfarnesoid protein-coupled X receptor receptors (FXR), pregnane (GPCRs), suchX receptor as the G(PXR), protein-coupled and vitamin bile D receptor acid receptor (VDR), (TGR5 and andcell farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), and cell Gpbar-1).surface G FXRprotein-coupled and PXR are receptors highly expressed (GPCRs), insuch tissues as the that G are protein-coupled exposed to bile bile acids, acid including receptor surface G protein-coupled receptors (GPCRs), such as the G protein-coupled bile acid receptor the(TGR5 liver and and Gpbar-1). the intestine, FXR and whereas PXR are VDR highly is widely expressed expressed in tissues in mostthat are tissues. exposed TGR5 to bile is highlyacids, (TGR5 and Gpbar-1). FXR and PXR are highly expressed in tissues that are exposed to bile acids, expressedincluding the along liver the and intestinal the intestine, tract, with whereas the highest VDR expressionis widely expressed found in thein most ileum tissues. and colon. TGR5 It is including the liver and the intestine, whereas VDR is widely expressed in most tissues. TGR5 is alsohighly expressed expressed in along nontraditional the intestinal bile tract, acid targetwith th organse highest including expression white found and brownin the ileum adipose, and spleen, colon. highly expressed along the intestinal tract, with the highest expression found in the ileum and colon. kidney,It is also pancreas, expressed lung, in macrophages,nontraditional andbile the acid central target nervous organs systemincluding [20 ].white Moreover, and brown some receptorsadipose, It is also expressed in nontraditional bile acid target organs including white and brown adipose, foundspleen, to kidney, be overexpressed pancreas, lung, in cancer macrophages, cell lines, e.g.,and GPCRsthe central are overexpressednervous system in [20]. lung, Moreover, prostate, breast, some spleen, kidney, pancreas, lung, macrophages, and the central nervous system [20]. Moreover, some andreceptors neuroblastomas. found to be Thisoverexpressed fact is exploited in cancer in targeting cell lines, drugs e.g., toGPCRs cancerous are overexpressed tissues and the in tumor lung, receptors found to be overexpressed
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