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Synthesis and Biological Evaluation of Bicalutamide Analogues for the Potential Treatment of Prostate Cancer

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Synthesis and Biological Evaluation of Bicalutamide Analogues for the Potential Treatment of Prostate Cancer molecules Article Synthesis and Biological Evaluation of Bicalutamide Analogues for the Potential Treatment of Prostate Cancer Sahar B. Kandil * , Christopher McGuigan and Andrew D. Westwell School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, UK; [email protected] (C.M.); [email protected] (A.D.W.) * Correspondence: [email protected]; Tel.: +44-02920-875800 Abstract: The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of 15 bicalutamide analogues (sulfide, deshydroxy, sulfone, and O-acetylated) were prepared and their antiproliferative activity evaluated against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). Bicalutamide and enzalutamide were used as positive controls. Seven of these compounds displayed remarkable enhancement in anticancer activity across the four PC cell lines. The deshydroxy analogue (16) was the most active compound with IC50 = 6.59–10.86 µM. Molecular modeling offers a plausible explanation of the higher activity of the sulfide analogues compared to their sulfone counterparts. Keywords: androgen receptor (AR); prostate cancer (PC); sulfone; diarylpropionamide; bicalutamide 1. Introduction The androgen receptor (AR) has essential anabolic and reproductive roles in men and women. Additionally, AR signaling plays a crucial function in tumorigenesis and Citation: Kandil, S.B.; McGuigan, C.; metastasis of different cancer types, including prostate, bladder, kidney, lung, breast, and Westwell, A.D. Synthesis and Biological Evaluation of Bicalutamide liver [1–3]. AR is a member of the nuclear receptor family and consists of three main Analogues for the Potential Treatment functional domains: a variable N-terminal domain, a highly conserved DNA-binding of Prostate Cancer. Molecules 2021, 26, domain (DBD), and a conserved ligand-binding domain (LBD) [4]. Binding of testos- 56. https://dx.doi.org/10.3390/ terone and dihydrotestosterone (DHT) to the LBD induces AR conformational changes molecules26010056 then translocation into the nucleus to interact with DNA and modulate prostate-specific antigen (PSA) levels [5]. AR antagonists (antiandrogens) inhibit these processes and are Academic Editor: Nicola Micale used for the treatment of advanced prostate cancer (PC) [6,7]. A variety of nonsteroidal Received: 4 December 2020 antiandrogens (NSAA) are approved for the treatment of PC. The first generation NSAAs Accepted: 22 December 2020 include flutamide, hydroxyflutamide, and bicalutamide (Figure1). However, these antian- Published: 24 December 2020 drogens eventually fail to inhibit the AR upon long-term treatment, switching from being AR antagonists to AR agonists with the development of castration-resistant prostate cancer Publisher’s Note: MDPI stays neu- (CRPC), an aggressive form of the disease with poor prognosis. Similarly, resistance to the tral with regard to jurisdictional claims more recent second-generation antiandrogens (enzalutamide, apalutamide) is developing in published maps and institutional in PC patients via the upregulation of AR expression [8]. More recently, darolutamide affiliations. (ODM-201) has been recently approved and clinically used in patients with nonmetastatic CRPC [9]. New AR antagonists are continuously needed to improve the efficacy of the clinically used compounds. Copyright: © 2020 by the authors. Li- In this paper, we present the design and synthesis of a series of new bicalutamide censee MDPI, Basel, Switzerland. This analogues, building on our previous work [10–13] to offer new therapeutic options for article is an open access article distributed combating the resistance observed in the clinical use of AR antagonists. under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). Molecules 2021, 26, 56. https://dx.doi.org/10.3390/molecules26010056 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 56 2 of 14 Molecules 2021, 26, x FOR PEER REVIEW 2 of 14 Molecules 2021, 26, x FOR PEER REVIEW 2 of 14 Figure 1. Chemical structures of the nonsteroidal antiandrogens (NSAA); flutamide, hy- FigureFigure 1.1. Chemical structures structures of of the the nonsteroidal nonsteroidal antiandrogens antiandrogens (NSAA); (NSAA); flutamide, flutamide, hy- hydroxyflu- droxyflutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, and darolutamide. tamide,droxyflutamide, nilutamide, nilutamide, bicalutamide, bicalutamide, enzalutamide, enzalutamide, apalutamide, apalutamide and darolutamide., and darolutamide. 2.2. Results ResultsResults and andand Discussion DiscussionDiscussion Generally,Generally, minor minor chemicalchemical chemical changeschanges changes inin in thethe the chemicalchemical chemical structurestructure structure ofof nonstnonst of nonsteroidaleroidaleroidal ARAR ARlig-lig- andsligandsands cancan can resultresult result inin in majormajor major pharmacologicalpharmacological pharmacological outcomeoutcome outcomesss [14[14 [14,,15].15].,15]. Previously,Previously, Previously, wewe we published published ex- ex- tensivetensivetensive SARSARSAR studies studiesstudies on onon bicalutamide bicalutamidebicalutamide analogues analoguesanalogues [10– 13[10[10].– Introduction–1313].]. IIntroductionntroduction of fluorinated ofof fluorinatedfluorinated groups groupsintogroups the into chemicalinto thethe chemicalchemical structure structurestructure of molecules ofof moleculesmolecules provides provides aprovides combination aa combinationcombination of electrostatic, ofof electroelectro stericstaticstatic and,, stericlipophilicsteric andand impactslipophiliclipophilic on impactsimpacts the physicochemical onon thethe physicochemicalphysicochemical properties and propertiesproperties biological andand activities biologicalbiological [16 activit–activit18]. iesies [16[16––1818Here]].. we are exploring the impact of additional chemical structure modifications HereonHere the wewe antiproliferative areare exploringexploring thethe activity impactimpact in ofof prostate additionaladditional cancer chemicalchemical cell lines. structurestructure The modificationsmodifications three main areas onon thethe of antiproliferativemodificationantiproliferative are activity activity ring A in ,in ring prostate prostateB, and cancer cancer linker cell cell arealines. lines.C The Theas three illustratedthree main main areas inareas Figure of of modification modification2. Fifteen arebicalutamideare ringring AA,, ringring derivatives BB,, andand linkerlinker were areaarea prepared CC asas illustratedillustrated and their inantiproliferativein FigureFigure 2.2. FifteenFifteen activity bicalutamidebicalutamide was evaluated deriv-deriv- ativesinatives vitro werewereagainst preparedprepared four different andand theirtheir human antiproliferativeantiproliferative prostate cancer activityactivity cell lines waswas (22Rv1, evaluatedevaluated DU-145, inin vitrovitro LNCaP, againstagainst and fourVCap).four differentdifferent humanhuman prostateprostate cancercancer cellcell lineslines (22Rv1,(22Rv1, DUDU--145,145, LNCaPLNCaP,, andand VCap).VCap). Figure 2. Chemical structure of bicalutamide and the areas of structural modifications, ring (A), ring FigureFigure 2. 2. Chemical Chemical structure structure of of bicalutamide bicalutamide and and the the areas areas of of str structuraluctural modifications, modifications, ring ring A A, ,ring ring B(BB, ,),and and and the the the linker linker linker area area area CC (. .C ). 2.1. Sulfide Analogues of Bicalutamide 2.1.2.1. SulfideSulfide AnaloguesAnalogues ofof BicalutamideBicalutamide Phenylacrylamides (4 and 5) were prepared by reacting the corresponding aniline (1 PhenylacrylamidesPhenylacrylamides ((44 andand 55)) werewere preparedprepared byby reactingreacting thethe correspondingcorresponding anilineaniline ((11 or 22)) with with methacryloyl methacryloyl chloride chloride ( (3)) in in dimethylacetamide dimethylacetamide (DMA) [1 [199]. Phenylacrylamides Phenylacrylamides (or4, 2 5)) with were methacryloyl epoxidized bychloride hydrogen (3) in peroxidedimethylacetamide and trifluoroacetic (DMA) [1 anhydride9]. Phenylacrylamides (TFAA) in (4, 5) were epoxidized by hydrogen peroxide and trifluoroacetic anhydride (TFAA) in di- dichloromethane(4, 5) were epoxidi tozed give by ( 6hydrogenand 7)[20 peroxide]. Subsequently, and trifluoroacetic the epoxides anhydride were reacted (TFAA) with in the di- chloromethanechloromethane toto givegive ((66 andand 77)) [[2020].]. SubsequentlySubsequently,, thethe epoxidesepoxides werewere reactedreacted withwith thethe aromaticaromatic thiolsthiols ((88 andand 99)) toto affordafford thethe sulfidesulfide derivativesderivatives ((1010––1122)) asas racemicracemic mixtures,mixtures, asas outlinedoutlined inin SchemeScheme 1.1. Molecules 2021, 26, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/molecules Molecules 2021, 26, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/molecules Molecules 2021, 26, 56 3 of 14 aromatic thiols (8 and 9) to afford the sulfide derivatives (10–12) as racemic mixtures, as Molecules 2021, 26, x FOR PEER REVIEWoutlined in Scheme1. 3 of 14 Scheme 1. ReagentsReagents and and conditions, ( ii)) DMA, DMA, rt, rt, 3 3 h h;; ( ii))H H2OO22, ,TFAA, TFAA, DCM, DCM, rt, rt, 24 24 h; h; ( (iiiiii)) NaH, NaH, THF, THF, RT, RT, 24 h. TheThe sulfide sulfide bicalutamidebicalutamide derivativesderivatives
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