Design and synthesis of novel tetrahydrofuran cyclic urea derivatives as androgen receptor antagonists
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Design and synthesis of novel tetrahydrofuran cyclic urea derivatives as androgen receptor antagonists MURALIKRISHNA YARAGANIa, PRASAD YADLAPALLIb, SRIRAM RAGHAVANc, NIRAIKULAM AYYADURAId, SARAVANAN CHINNUSAMYe,* , VENKATA BASAVESWARA RAO MANDAVAf and RAJASEKHARA PRASAD KOTTAPALLIa,* a Department
of Chemistry, Koneru Lakshmaiah Education Foundation, Guntur, Andhra Pradesh 522 502, India b GVK Biosciences Pvt. Ltd, Hyderabad, Telangana 500 076, India c CAS in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu 600 020, India d Department of Biochemistry and Biotechnology, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India e Department of Chemistry, Center for Advanced Organic Materials (Sona-AROMA), Sona College of Technology, Salem, Tamil Nadu 636 005, India f Department of Chemistry, Krishna University, Krishna, Andhra Pradesh 521 001, India E-mail: [email protected]; [email protected] MS received 3 December 2019; revised 27 May 2020; accepted 24 July 2020
Abstract. In order to improve the antiproliferative activity of androgen receptor (AR) antagonists, which used clinically for the treatment of prostate cancer that is a major cause of male death in worldwide, we report the design and synthesis of a series of tetrahydrofuran cyclic urea-based non-steroidal small molecule AR antagonists and exhibit potent AR antagonistic activity. These molecules with higher stereochemical aspects have been achieved by changing the hydantoin analogue antiandrogens to 4-(2-oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2-(trifluoromethyl)benzonitrile analogues. Here, the thio-hydantoin pharmacophore of the recently reported antagonists is replaced by tetrahydrofuran cyclic urea. The antiproliferative properties of these molecules have been evaluated against androgen-dependent (LNCaP) cell line. Among the reported molecules, 4-(2-oxohexahydro-1H-furo[3,4-d]imidazol-1-yl)-2-(trifluoromethyl)benzonitrile (AR04) showed significantly improved in vitro activity, IC50 = 3.926 lM. Molecular structure-activity relationship studies confirm that the oxetane analogue AR04 is distinct from other synthesized AR antagonists. These results have suggested that AR04 exhibiting their potential as a lead compound for the alternative treatment of prostate cancer. Keywords. Prostate cancer; tetrahydrofuran cyclic urea; androgen receptor antagonist; oxetane; hydantoin.
1. Introduction Prostate cancer (PC) is considered as one of the leading causes of all cancer deaths in most developed countries.1 And it is one of the most common cancer among men in the USA and the second most dangerous cause of male death worldwide, after lung cancer.2–4 Even though several treatment methods exist for PC, including castration, chemotherapy and
radiation therapy, androgen deprivation is one of the main approaches to treat it at the various stages of its development, which falls unde
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