Effect of Pregnenolone Derivatives on the Selective Inhibition of 5α-Reductase 2 Activity

Author(s): Marisa Cabeza*, Lucero Bautista, Eugene Bratoeff, Juan Soriano, Yvonne Heuze

Journal Name: Current Enzyme Inhibition

Volume 15 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Benign prostatic hyperplasia and prostate cancer are androgen-dependent diseases, and dihydrotestosterone (DHT), a 5α-reduced metabolite of testosterone (T), has been implicated as a causative factor in the progression of these diseases. The 5α-reductase enzyme (5α-R) converts T to DHT, which is responsible for increasing cell proliferation, and hence inhibition of this enzyme could lead to potential treatments for these afflictions.

Objective: This study focused on evaluating the biological activity of three series of pregnenolone derivatives as inhibitors of 5α-R and as antiandrogens on androgen-dependent glands.

Methods: To determine the biological activity of these compounds, we evaluated the effect of each one on suppressing the activity of both types of isozymes of 5α-R (1 and 2) by 50% (IC50). Using animal studies, we assessed the effect of these derivatives on the weight of the prostate, seminal vesicles, and diameter of the flank organs of castrated hamsters previously dosed with 1 mg/Kg T.

Results: In vitro experiments showed that derivatives 1f, 2b, and 3d were very effective inhibitors of the activity of 5α-R2, showing IC50 values of 21.8, 20, and 15 nM, respectively. Derivatives 2b and 3b showed a lower inhibition effect on 5α-R1.

The data also indicated that derivatives 2b, 1f, 3b, and 3d were very active in reducing prostate weight in the hamster model of benign prostatic hyperplasia.

Discussion: Pharmacological experiments showed that pregnenolone derivatives possess an antiandrogenic effect because of the inhibition of DHT production in androgen-dependent glands.

Conclusion: The pregnenolone derivatives studied suppressed type 2 5α-reductase activity and because of this, the weight and dimension of androgen-dependent organs were decreased.

Keywords: Electronegativity effect, flank organ test, pregnenolone derivatives, prostate, seminal vesicles, specificity by 5α- reductase 2, structure-activity improvement, type 2 5α-reductase.

[1]
Thomas, L.N.; Lazier, C.B.; Gupta, R.; Norman, R.W.; Troyer, D.A.; O’Brien, S.P.; Rittmaster, R.S. Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate, 2005, 63(3), 231-239.
[http://dx.doi.org/10.1002/pros.20188] [PMID: 15538746]
[2]
Brandt, M.; Levy, M.A. 3 β-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase from bovine adrenals: Mechanism of inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the dehydrogenase. Biochemistry, 1989, 28(1), 140-148.
[http://dx.doi.org/10.1021/bi00427a021] [PMID: 2706240]
[3]
Cabeza, M.; Sánchez-Márquez, A.; Garrido, M.; Silva, A.; Bratoeff, E. Recent advances in drug design and drug discovery for androgen- dependent diseases. Curr. Med. Chem., 2016, 23(8), 792-815.
[http://dx.doi.org/10.2174/0929867323666160210125642] [PMID: 26861003]
[4]
Aggarwal, S.; Thareja, S.; Bhardwaj, T.R.; Kumar, M. Self-organizing molecular field analysis on pregnane derivatives as human steroidal 5α-reductase inhibitors. Steroids, 2010, 75(6), 411-418.
[http://dx.doi.org/10.1016/j.steroids.2010.02.005] [PMID: 20170668]
[5]
Levy, M.A.; Brandt, M.; Greway, A.T. Mechanistic studies with solubilized rat liver steroid 5 α-reductase: Elucidation of the kinetic mechanism. Biochemistry, 1990, 29(11), 2808-2815.
[http://dx.doi.org/10.1021/bi00463a025] [PMID: 2140700]
[6]
Russell, D.W.; Wilson, J.D. Steroid 5 alpha-reductase: Two genes/two enzymes. Annu. Rev. Biochem., 1994, 63(1), 25-61.
[http://dx.doi.org/10.1146/annurev.bi.63.070194.000325] [PMID: 7979239]
[7]
Uemura, M.; Tamura, K.; Chung, S.; Honma, S.; Okuyama, A.; Nakamura, Y.; Nakagawa, H. Novel 5 α-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci., 2008, 99(1), 81-86.
[PMID: 17986282]
[8]
Ogishima, T.; Mitani, F.; Suematsu, M. Cytochrome P-450(17alpha) in β-cells of rat pancreas and its local steroidogenesis. J. Steroid Biochem. Mol. Biol., 2008, 111(1-2), 80-86.
[http://dx.doi.org/10.1016/j.jsbmb.2008.04.008] [PMID: 18556192]
[9]
Bruchovsky, N.; Wilson, J.D. The conversion of testosterone to 5-α-androstan-17-β-ol-3-one by rat prostate in vivo and in vitro. J. Biol. Chem., 1968, 243(8), 2012-2021.
[PMID: 4384673]
[10]
Silva-Ortiz, A.V.; Bratoeff, E.; Ramírez-Apan, T.; Heuze, Y.; Soriano, J.; Moreno, I.; Bravo, M.; Bautista, L.; Cabeza, M. Synthesis of new derivatives of 21-imidazolyl-16-dehydropregneno-lone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells. Bioorg. Med. Chem., 2017, 25(5), 1600-1607.
[http://dx.doi.org/10.1016/j.bmc.2017.01.018] [PMID: 28174065]
[11]
Ramírez, E.; Cabeza, M.; Heuze, I.; Gutiérrez, E.; Bratoeff, E.; Membrillo, M.; Lira, A. Synthesis and pharmacological evaluation of new 16-methyl pregnane derivatives. Chem. Pharm. Bull. (Tokyo), 2002, 50(1), 15-20.
[http://dx.doi.org/10.1248/cpb.50.15] [PMID: 11824579]
[12]
Cabeza, M.; Bratoeff, E.; Flores, E.; Ramírez, E.; Calleros, J.; Montes, D.; Quiroz, A.; Heuze, I. 5 α-reductase inhibitory and antiandrogenic activities of novel steroids in hamster seminal vesicles. Chem. Pharm. Bull. (Tokyo), 2002, 50(11), 1447-1452.
[http://dx.doi.org/10.1248/cpb.50.1447] [PMID: 12419908]
[13]
Flores, E.; Bratoeff, E.; Cabeza, M.; Ramírez, E.; Quiroz, A.; Heuze, I. Steroid 5alpha-reductase inhibitors. Mini Rev. Med. Chem., 2003, 3(3), 225-237.
[http://dx.doi.org/10.2174/1389557033488196] [PMID: 12570838]
[14]
Cabeza, M.; Flores, E.; Heuze, I.; Sánchez, M.; Bratoeff, E.; Ramírez, E.; Francolugo, V.A. Novel 17 substituted pregnadiene derivatives as 5 α-reductase inhibitors and their binding affinity for the androgen receptor. Chem. Pharm. Bull. (Tokyo), 2004, 52(5), 535-539.
[http://dx.doi.org/10.1248/cpb.52.535] [PMID: 15133203]
[15]
Pérez-Ornelas, V.; Cabeza, M.; Bratoeff, E.; Heuze, I.; Sánchez, M.; Ramírez, E.; Naranjo-Rodríguez, E. New 5α-reductase inhibitors: In vitro and in vivo effects. Steroids, 2005, 70(3), 217-224.
[http://dx.doi.org/10.1016/j.steroids.2004.11.008] [PMID: 15763601]
[16]
Bratoeff, E.; Cabeza, M.; Pérez-Ornelas, V.; Recillas, S.; Heuze, I. In vivo and in vitro effect of novel 4,16-pregnadiene-6,20-dione derivatives, as 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol., 2008, 111(3-5), 275-281.
[http://dx.doi.org/10.1016/j.jsbmb.2008.06.014] [PMID: 18644453]
[17]
Bratoeff, E.; García, P.; Heuze, Y.; Soriano, J.; Mejía, A.; Labastida, A.M.; Valencia, N.; Cabeza, M. Molecular interactions of progesterone derivatives with 5 α-reductase types 1 and 2 and androgen receptors. Steroids, 2010, 75(7), 499-505.
[http://dx.doi.org/10.1016/j.steroids.2010.03.006] [PMID: 20359488]
[18]
Cabeza, M.; Bratoeff, E.; Heuze, I.; Rojas, A.; Terán, N.; Ochoa, M.; Ramírez-Apan, T.; Ramírez, E.; Pérez, V.; Gracia, I. New progesterone derivatives as inhibitors of 5α-reductase enzyme and prostate cancer cell growth. J. Enzyme Inhib. Med. Chem., 2006, 21(4), 371-378.
[http://dx.doi.org/10.1080/14756360600748474] [PMID: 17059168]
[19]
Garrido, M.; González-Arenas, A.; Camacho-Arroyo, I.; Cabeza, M.; Alcaráz, B.; Bratoeff, E. Effect of new hybrids based on 5,16-pregnadiene scaffold linked to an anti-inflammatory drug on the growth of a human astrocytoma cell line (U373). Eur. J. Med. Chem., 2015, 93(0), 135-141.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.048] [PMID: 25666913]
[20]
Chávez-Riveros, A.; Cruz Noriega, A.; Ramírez Apan, M.T.; Miranda, L.D.; Bratoeff, E. Synthesis and cytotoxic effect of pregnenolone derivatives with one or two α,β-unsaturated carbonyls and an ester moiety at C-21 or C-3. Steroids, 2018, 131, 37-45.
[http://dx.doi.org/10.1016/j.steroids.2018.01.004] [PMID: 29360536]
[21]
Hochberg, R.B. Biological esterification of steroids. Endocr. Rev., 1998, 19(3), 331-348.
[PMID: 9626557]
[22]
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), 367-373.
[http://dx.doi.org/10.1016/j.jsbmb.2011.07.001] [PMID: 21782943]
[23]
Ellsworth, K.; Azzolina, B.; Baginsky, W.; Bull, H.; Chang, B.; Cimis, G.; Mitra, S.; Toney, J.; Bakshi, R.K.; Rasmusson, G.R.; Tolman, R.L.; Harris, G.S. MK386: A potent, selective inhibitor of the human type 1 5α-reductase. J. Steroid Biochem. Mol. Biol., 1996, 58(4), 377-384.
[http://dx.doi.org/10.1016/0960-0760(96)00050-7] [PMID: 8903421]
[24]
Silva-Ortiz, A.V.; Bratoeff, E.; Ramírez-Apan, T.; Heuze, Y.; Sánchez, A.; Soriano, J.; Cabeza, M. Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1. Bioorganic & Medicinal Chemistry., 2015, 23(24), 7535-7542.
[25]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72(1-2), 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[26]
Arellano, Y.; Bratoeff, E.; Segura, T.; Mendoza, M.E.; Sánchez-Márquez, A.; Medina, Y.; Heuze, Y.; Soriano, J.; Cabeza, M. Novel dehydroepiandrosterone benzimidazolyl derivatives as 5α-reductase isozymes inhibitors. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 908-914.
[http://dx.doi.org/10.3109/14756366.2015.1070843] [PMID: 26394987]
[27]
Arellano, Y.; Bratoeff, E.; Garrido, M.; Soriano, J.; Heuze, Y.; Cabeza, M. New ester derivatives of dehydroepiandrosterone as 5α-reductase inhibitors. Steroids, 2011, 76(12), 1241-1246.
[http://dx.doi.org/10.1016/j.steroids.2011.05.015] [PMID: 21729714]
[28]
Bratoeff, E.; Cabeza, M.; Flores, E.; Ramirez, E.; Quiroz, A.; Heuze, I. Synthesis and pharmacological evaluation of new steroidal 5 α-reductase inhibitors. Proc. West. Pharmacol. Soc., 2002, 45, 187-190.
[PMID: 12434577]
[29]
Takayasu, S.; Adachi, K. The intranuclear binding of 17 beta-hydroxy-5 α-androstan-3-one and testosterone by hamster sebaceous glands. Endocrinology, 1975, 96(2), 525-529.
[http://dx.doi.org/10.1210/endo-96-2-525] [PMID: 163188]
[30]
Cabeza, M.; Heuze, Y.; Quintana, H.; Bratoeff, E. Comparison between two different hamster models used for the determination of testosterone and finasteride activity. Asian J. Anim. Vet. Adv., 2010, 5(3), 202-209.
[http://dx.doi.org/10.3923/ajava.2010.202.209]
[31]
Arellano, Y.; Bratoeff, E.; Heuze, Y.; Bravo, M.; Soriano, J.; Cabeza, M. Activity of steroid 4 and derivatives 4a-4f as inhibitors of the enzyme 5α-reductase 1. Bioorg. Med. Chem., 2018, 26(14), 4058-4064.
[http://dx.doi.org/10.1016/j.bmc.2018.06.030] [PMID: 30007568]
[32]
Benayoun, B.; Esnard-Fève, A.; Castella, S.; Courty, Y.; Esnard, F. Rat seminal vesicle FAD-dependent sulfhydryl oxidase. Biochemical characterization and molecular cloning of a member of the new sulfhydryl oxidase/quiescin Q6 gene family. J. Biol. Chem., 2001, 276(17), 13830-13837.
[http://dx.doi.org/10.1074/jbc.M010933200] [PMID: 11278790]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [179 - 189]
Pages: 11
DOI: 10.2174/1573408015666191105144355
Price: $65

Article Metrics

PDF: 13
HTML: 4