Synthesis and optimization of a new family of type 3 17 beta-hydroxysteroid dehydrogenase inhibitors by parallel liquid-phase chemistry.
Type 3 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) transforms 4-androstene-3,17-dione (Delta(4)-dione) into the androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we performed parallel liquid-phase synthesis of 3beta-substituted androsterone (ADT) libraries (A-D) in good yields and average high-performance liquid chromatography (HPLC) purities of 92-94%. The first library (A) of 3 beta-amidomethyl-ADT derivatives (168 members), including two levels of molecular diversity on the amide (R(1) and R(2)), was synthesized with a parallel liquid-phase method (method I) in less time than with the classic chemistry method. The screening of library A revealed that relatively small hydrophobic chains at R(1) (5-8 carbons) and small hydrophobic substituents at R(2) (1-4 carbons) provided the most potent inhibitors. In accordance with these inhibition results, a second library (B) of 3 beta-amidomethyl-ADT derivatives (56 members) was generated in a very short time using an improved method based on scavenger resins and liquid-phase parallel chemistry. Library B produced more potent inhibitors than library A and provided useful structure-activity relationships that directed the design of a third library (C) of 49 members. Once again, very potent inhibitors were identified from library C and 3 beta-[(N-adamantylmethyl-N-butanoyl)aminomethyl]-3 alpha-hydroxy-5 alpha-androstan-17-one (C-7-3) was identified as the most potent inhibitor of the three libraries with an inhibitory activity (IC(50) = 35 nM) 18-fold higher than that of the natural substrate of the enzyme, Delta(4)-dione, (IC(50) = 650 nM) used itself as inhibitor. Finally, we designed a library (D) of 3-carbamate-ADT derivatives (25 members) using the efficient parallel liquid-phase method III, which allowed the synthesis of more rigid molecules with two levels of molecular diversity (R(1)/R(2) and R(3)) in the local area occupied by the adamantane group of C-7-3. Interestingly, one of the most potent inhibitors of library D, the 3R-spiro-[3'-[3' '-N-morpholino-2' '-(3' "-cyclopentyl-propionyloxy)propyl]-2'-oxo-oxazolidin-5'-yl]-5 alpha-androstan-17-one (D-5-4), showed an inhibitory activity on type 3 17 beta-HSD similar to that of compound C-7-3, while exhibiting a nonandrogenic profile.
Maltais
René
R
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec and Université Laval, 2705 Laurier Boulevard, Sainte-Foy, Québec G1V 4G2, Canada.
Luu-The
Van
V
Poirier
Donald
D
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000731:Androstanes / Q000138:chemical synthesis* / Q000737:chemistry; D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005260:Female; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C446948:3-((N-adamantylmethyl-N-butanoyl)aminomethyl)-3-hydroxyandrostan-17-one; D000731:Androstanes; D000732:Androstanols; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; C446949:spiro(3'-(3'-N-morpholino-2'-(3'''-cyclopentylpropionyloxy)propyl)-2'-oxooxazolidin-5'-yl)androstan-17-one; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase