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Current Enzyme Inhibition

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ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

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Research Article

Synthesis, Characterization and Evaluation of 5α, 6β-Dihalo Androsterone Derivatives as 5α-Reductase Inhibitors

Author(s): Akansha Sharma, Priyanka Rana, Poonam Arora, Tanzeer Kaur and Neelima Dhingra*

Volume 18, Issue 3, 2022

Published on: 30 September, 2022

Page: [180 - 193] Pages: 14

DOI: 10.2174/1573408018666220525123827

Price: $65

Abstract

Background and Objective: Testosterone under the influence of 5α-reductase enzyme gets converted to dihydrotestosterone and high levels are found to be causative for androgen dependent diseases like benign prostatic hyperplasia. Thus, 5α-reductase has been recognised as an important target for discovering new drugs against Benign Prostatic Hyperplasia and Prostate Cancer.

Methods: In the present study, a series of 5α, 6β-Dichloro-17-Oxoandrostan-3β-yl esters (7a-7f) were synthesized and characterized by analytical and spectroscopic methods. The compounds were evaluated for their 5α-reductase inhibitory activity in-vivo by their effect on serum androgen levels.

Results: The target compounds (7a-7f) showed increased anti-androgenic activity as compared to finasteride and control, which implies that the target compounds are effective in inhibiting 5α-reductase. Particularly, compound 7b showing highest inhibitory activity and noteworthy D-Score was further sorted by performing solubility and dissolution studies. Results of these studies, when compared with finasteride, showed increased solubility and dissolution of target compound 7b.

Conclusion: These results demonstrated that enhancement of activity by the presence of electronegative group at position 3 of the steroidal nucleus makes 7b a lead compound for further exploration and optimal formulation.

Keywords: 5α-Reductase, testosterone, benign prostatic hyperplasia, finasteride, docking, solubility, intrinsic dissolution.

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[1]
Tiwari A, Krishna NS, Nanda K, Chugh A. Benign prostatic hyperplasia: An insight into current investigational medical therapies. Expert Opin Investig Drugs 2005; 14(11): 1359-72.
[http://dx.doi.org/10.1517/13543784.14.11.1359] [PMID: 16255676]
[2]
Wang YR, Xu Y, Jiang ZZ, Zhang LY, Wang T. Triptolide reduces prostate size and androgen level on testosterone-induced benign pros-tatic hyperplasia in Sprague Dawley rats. Chin J Nat Med 2017; 15(5): 341-6.
[http://dx.doi.org/10.1016/S1875-5364(17)30054-7] [PMID: 28558869]
[3]
Ziada A, Rosenblum M, Crawford ED. Benign prostatic hyperplasia: An overview. Urology 1999; 53(3) (Suppl. 3a): 1-6.
[http://dx.doi.org/10.1016/S0090-4295(98)00532-9] [PMID: 10094094]
[4]
Zhang W, Zhang X, Li H. et al. Prevalence of Lower Urinary Tract Symptoms suggestive of Benign Prostatic Hyperplasia (LUTS/BPH) in China: Results from the China health and retirement longitudinal study. BMJ Open 2019; 9(6): e022792.
[http://dx.doi.org/10.1136/bmjopen-2018-022792] [PMID: 31221864]
[5]
Irer B, Toylu A, Aslan G, Celebi I, Yorukoglu K, Atabey N. Increased expression of NKX3.1 in benign prostatic hyperplasia. Urology 2009; 73(5): 1140-4.
[http://dx.doi.org/10.1016/j.urology.2008.02.039] [PMID: 18597829]
[6]
Lee SH, Kim JC, Lee JY. et al. Effects of components of metabolic syndrome on sexual function in Korean BPH/LUTS patients. J Sex Med 2009; 6(8): 2292-8.
[http://dx.doi.org/10.1111/j.1743-6109.2009.01325.x] [PMID: 19493291]
[7]
Nickel JC. Inflammation and benign prostatic hyperplasia. Urol Clin North Am 2008; 35(1): 109-15. [vii.]
[http://dx.doi.org/10.1016/j.ucl.2007.09.012] [PMID: 18061029]
[8]
Roehrborn CG, McConnell JD, Saltzman B. et al. PLESS Study Group.. Storage (irritative) and voiding (obstructive) symptoms as predic-tors of benign prostatic hyperplasia progression and related outcomes. Eur Urol 2002; 42(1): 1-6.
[http://dx.doi.org/10.1016/S0302-2838(02)00210-5] [PMID: 12121721]
[9]
Hutchison A, Farmer R, Chapple C. et al. Characteristics of patients presenting with LUTS/BPH in six European countries. Eur Urol 2006; 50(3): 555-61.
[http://dx.doi.org/10.1016/j.eururo.2006.05.001] [PMID: 16782265]
[10]
Thomas D, Chughtai B, Kini M, Te A. Emerging drugs for the treatment of benign prostatic hyperplasia. Expert Opin Emerg Drugs 2017; 22(3): 201-12.
[http://dx.doi.org/10.1080/14728214.2017.1369953] [PMID: 28829208]
[11]
Ventura S. Oliver Vl, White CW, Xie JH, Haynes JM, Exintaris B. Novel drug targets for the pharmacotherapy of Benign Prostatic Hyper-plasia (BPH). Br J Pharmacol 2011; 163(5): 891-907.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01332.x] [PMID: 21410684]
[12]
Novara G, Galfano A, Gardi M, Ficarra V, Boccon-Gibod L, Artibani W. Critical review of guidelines for BPH diagnosis and treatment strategy. Eur Urol Suppl 2006; 5(4): 418-29.
[13]
Larson TR. Rationale and assessment of minimally invasive approaches to benign prostatic hyperplasia therapy. Urology 2002; 59(2) (Suppl. 1): 12-6.
[http://dx.doi.org/10.1016/S0090-4295(01)01557-6] [PMID: 11832309]
[14]
Kuntz RM. Current role of lasers in the treatment of Benign Prostatic Hyperplasia (BPH). Eur Urol 2006; 49(6): 961-9.
[http://dx.doi.org/10.1016/j.eururo.2006.03.028] [PMID: 16632179]
[15]
Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol 2012; 61(5): 917-25.
[http://dx.doi.org/10.1016/j.eururo.2012.01.013] [PMID: 22297243]
[16]
Axcrona K, Aaltomaa S, da Silva CM. et al. Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: Degarelix vs goserelin plus bicalutamide. BJU Int 2012; 110(11): 1721-8.
[http://dx.doi.org/10.1111/j.1464-410X.2012.11107.x] [PMID: 22500884]
[17]
Lowe FC, Ku JC. Phytotherapy in treatment of benign prostatic hyperplasia: a critical review. Urology 1996; 48(1): 12-20.
[http://dx.doi.org/10.1016/S0090-4295(96)00077-5] [PMID: 8693632]
[18]
Gerber GS. Phytotherapy for benign prostatic hyperplasia. Curr Urol Rep 2002; 3(4): 285-91.
[http://dx.doi.org/10.1007/s11934-002-0050-3] [PMID: 12149159]
[19]
Fukuda Y, Fukuta Y, Higashino R. et al. Hormonal effects of Z-350, possessing steroid 5α-reductase inhibitory and α1-adrenoceptor antagonistic actions, in the rat. Jpn J Pharmacol 2001; 86(3): 323-8.
[http://dx.doi.org/10.1254/jjp.86.323] [PMID: 11488433]
[20]
Smith AB, Carson CC. Finasteride in the treatment of patients with benign prostatic hyperplasia: a review. Ther Clin Risk Manag 2009; 5(3): 535-45.
[PMID: 19707263]
[21]
Jarman M, Smith HJ, Nicholls PJ, Simons C. Inhibitors of enzymes of androgen biosynthesis: cytochrome P450(17) α and 5 α-steroid reductase. Nat Prod Rep 1998; 15(5): 495-512.
[http://dx.doi.org/10.1039/a815495y] [PMID: 9807812]
[22]
Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M. Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders. Curr Pharm Des 2011; 17(2): 151-67.
[http://dx.doi.org/10.2174/138161211795049589] [PMID: 21361868]
[23]
Bruchovsky N, Sadar MD, Akakura K, Goldenberg SL, Matsuoka K, Rennie PS. Characterization of 5α-reductase gene expression in stroma and epithelium of human prostate. J Steroid Biochem Mol Biol 1996; 59(5-6): 397-404.
[http://dx.doi.org/10.1016/S0960-0760(96)00125-2] [PMID: 9010345]
[24]
Occhiato EG, Guarna A, Danza G, Serio M. Selective non-steroidal inhibitors of 5 α-reductase type 1. J Steroid Biochem Mol Biol 2004; 88(1): 1-16.
[http://dx.doi.org/10.1016/j.jsbmb.2003.10.004] [PMID: 15026079]
[25]
Aggarwal S, Mahapatra MK, Kumar R. et al. Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors. Bioorg Med Chem 2016; 24(4): 779-88.
[http://dx.doi.org/10.1016/j.bmc.2015.12.048] [PMID: 26780831]
[26]
Martínez MD, Edelsztein VC, Durán FJ, Di Chenna PH, Burton G. Synthesis of 6-azaprogesterone and 19-hydroxy-6-azasteroids. Steroids 2013; 78(1): 34-7.
[http://dx.doi.org/10.1016/j.steroids.2012.10.012] [PMID: 23127817]
[27]
Li X, Chen C, Singh SM, Labire F. The enzyme and inhibitors of 4-ene-3-oxosteroid 5α-oxidoreductase. Steroids 1995; 60(6): 430-41.
[http://dx.doi.org/10.1016/0039-128X(95)00021-H] [PMID: 7676475]
[28]
Cabeza M, Heuze I, Bratoeff E, Murillo E, Ramirez E, Lira A. New progesterone esters as 5α-reductase inhibitors. Chem Pharm Bull (Tokyo) 2001; 49(9): 1081-4.
[http://dx.doi.org/10.1248/cpb.49.1081] [PMID: 11558590]
[29]
Cabeza M, Gutiérrez E, Miranda R. et al. Androgenic and anti-androgenic effects of progesterone derivatives with different halogens as substituents at the C-6 position. Steroids 1999; 64(6): 413-21.
[http://dx.doi.org/10.1016/S0039-128X(99)00018-5] [PMID: 10433178]
[30]
Cabeza M, Quiroz A, Bratoeff E, Murillo ME, Ramírez E, Flores G. Synthesis and pharmacological evaluation of 4-halo progesterone derivatives as antiandrogen. Chem Pharm Bull (Tokyo) 1999; 47(9): 1232-6.
[http://dx.doi.org/10.1248/cpb.47.1232] [PMID: 10517005]
[31]
Garrido M, Bratoeff E, Bonilla D, Soriano J, Heuze Y, Cabeza M. New steroidal lactones as 5α-reductase inhibitors and antagonists for the androgen receptor. J Steroid Biochem Mol Biol 2011; 127(3-5): 367-73.
[http://dx.doi.org/10.1016/j.jsbmb.2011.07.001] [PMID: 21782943]
[32]
Dhingra N, Bhardwaj TR, Mehta N, Mukhopadhyay T, Kumar A, Kumar M. Synthesis, antiproliferative, acute toxicity and assessment of antiandrogenic activities of some newly synthesized steroidal lactams. Eur J Med Chem 2010; 45(6): 2229-36.
[http://dx.doi.org/10.1016/j.ejmech.2010.01.064] [PMID: 20171759]
[33]
Rassaie MJ, Kumari LG, Pandey PK, Gupta N, Kochupillai N, Grover PK. A highly specific heterologous enzyme-linked immunosorbent assay for measuring testosterone in plasma using antibody-coated immunoassay plates or polypropylene tubes. Steroids 1992; 57(6): 288-94.
[http://dx.doi.org/10.1016/0039-128X(92)90062-E] [PMID: 1440699]
[34]
Silva NS, Gonçalves LK, Duarte JL. et al. Computational analysis of physicochemical, pharmacokinetic and toxicological properties of deoxyhypusine synthase inhibitors with antimalarial activity. Comput Mol Biosci 2014; 4(04): 47.
[http://dx.doi.org/10.4236/cmb.2014.44006]
[35]
Segall AI, Vitale MF, Perez VL, Palacios ML, Pizzorno MT. A stability-indicating HPLC method to determine finasteride in a tablet formu-lation. J Liq Chromatogr Relat Technol 2002; 25(20): 3167-76.
[http://dx.doi.org/10.1081/JLC-120016216]
[36]
Suzuki R, Satoh H, Ohtani H, Hori S, Sawada Y. Saturable binding of finasteride to steroid 5α-reductase as determinant of nonlinear pharmacokinetics. Drug Metab Pharmacokinet 2010; 25(2): 208-13.
[http://dx.doi.org/10.2133/dmpk.25.208] [PMID: 20460827]
[37]
Smith MB, March J. Advanced Organic Chemistry. (5th ed.), New York: Jhon Wiley and Sons 2001.
[38]
Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J. Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 α-hydroxylase/C17-20-lyase) and 5 α-reductase types 1 and 2. J Med Chem 2000; 43(22): 4266-77.
[http://dx.doi.org/10.1021/jm001008m] [PMID: 11063622]

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