title: Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase.
abstract: The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17β-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Δ(4)-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17β-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17β-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.
authors.affiliation: a Departamento de Sistemas Biológicos y de Producción Agrícola y Animal , Universidad Autónoma Metropolitana-Xochimilco , México D.F ., Mexico .
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
authors.affiliation: b Departamento de Farmacia , Facultad de Química, Universidad Nacional Autónoma de México , México D.F ., Mexico , and.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Posada
authors.affiliation: a Departamento de Sistemas Biológicos y de Producción Agrícola y Animal , Universidad Autónoma Metropolitana-Xochimilco , México D.F ., Mexico .
authors.forename: Araceli
authors.initials: A
authors.lastname: Sánchez-Márquez
authors.affiliation: a Departamento de Sistemas Biológicos y de Producción Agrícola y Animal , Universidad Autónoma Metropolitana-Xochimilco , México D.F ., Mexico .
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Heuze
authors.affiliation: a Departamento de Sistemas Biológicos y de Producción Agrícola y Animal , Universidad Autónoma Metropolitana-Xochimilco , México D.F ., Mexico .
authors.forename: Isabel
authors.initials: I
authors.lastname: Moreno
authors.affiliation: c Departamento de Patología , Hospital General de México , México D.F ., Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Soriano
authors.affiliation: b Departamento de Farmacia , Facultad de Química, Universidad Nacional Autónoma de México , México D.F ., Mexico , and.
authors.forename: Mariana
authors.initials: M
authors.lastname: Garrido
authors.affiliation: b Departamento de Farmacia , Facultad de Química, Universidad Nacional Autónoma de México , México D.F ., Mexico , and.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cortés
authors.affiliation: b Departamento de Farmacia , Facultad de Química, Universidad Nacional Autónoma de México , México D.F ., Mexico , and.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D003687:Dehydroepiandrosterone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D011467:Prostate / Q000201:enzymology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011720:Pyrazoles; C031280:pyrazole; D003687:Dehydroepiandrosterone; C029899:imidazole; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
keywords: 17β-HSD5 inhibitors; benign prostatic hyperplasia; flank organs; imidazole and pyrazole-dehydroepiandrosterone derivatives; prostate cancer; seminal vesicles