Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity.

Five 4,5-dihydro-1,3-oxazole derivatives of [17(20)E]-21-norpregnene, comprising 3β-hydroxy-5-ene (1), 3,6-dioxo-4-ene (2), 3-oxo-4-ene (3), 3α,5α-cyclo-6-oxo (4), 3β-hydroxy-6-oxo (5) fragments were synthesized. Synthesis was conducted with improved procedure, based on reaction of suitably protected [17(20)E]-pregnen-21-oic acids with ethanolamine in presence of triphenyl phosphine, carbon tetrachloride, and triethyl amine. Potency of the compounds 1-5 to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity was studied by highly sensitive electrochemical method, using the enzyme immobilization technique.

[Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1].

In order to find novel inhibitors of 17a-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: 1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; 2) the localization of the steroid moiety of all compounds in the active site is basically the same; 3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; 4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; 5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; 6) oxazoline--and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.

Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors.

New oxazolinyl derivatives of [17(20)E]-pregna-5,17(20)-diene: 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4',5'-dihydro-1',3'-oxazole 1 and 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4',4'-dimethyl-4',5'-dihydro-1',3'-oxazole 2 were evaluated as potential CYP17A1 inhibitors in comparison with 17-(pyridin-3-yl)androsta-5,16-dien-3β-ol 3 (abiraterone). Differential absorption spectra of human recombinant CYP17A1 in the presence of compound 1 (λmax=422 nm, λmin=386 nm) and compound 2 (λmax=416 nm) indicated significant differences in enzyme/inhibitors complexes. CYP17A1 activity was measured using electrochemical methods.

[Molecular modeling of interaction of 17(20)Z- and 17(20)E-pregna-5,17(20)-dien-21-oyl amides with the nuclear receptor LXRbeta].

Aiming the search of novel regulators of lipid metabolism and their potential targets, in this study we performed molecular modeling of eight isomeric 17(20)Z- and 17(20)E-pregna-5,17(20)-dien-21-oyl amides differing in structure of the amide moiety. Analysis of the low energy conformers revealed that all 17(20)E-isomers had three main energy minima (corresponding to values of the dihedral angle theta20,21 (C17 = C20-C21 = 0) to approximately 0 degrees, to approximately 120 degrees and to approximately 240 degrees), the most occupied minimum was found to correspond to theta20,21 to approximately 0 degrees; while 17(20)Z-isomers had either one or two pools of low energy conformations. Molecular docking of these compounds to the ligand-binding site of the nuclear receptor LXRbeta (a potential target) indicates high probability of binding for E-isomers and the absence of that for Z-isomers.

Synthesis and molecular modeling of (4'R)- and (4'S)- 4'-substituted 2'-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines.

Synthesis of four novel (4'R)- and (4'S)- 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]-methyl} oxazolines, comprising 4'-hydroxymethyl (1 and 2) and 4'-methoxycarbonyl (3 and 4) substituents is presented. Reaction of 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one with either (L)-serine methyl ester, or (D)-serine methyl ester resulted in methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(L)-serinate and methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(D)-serinate (as mixtures of related [17(20)E]- and [17(20)Z]-isomers). Cyclization of obtained amides led to methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'S)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate and methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'R)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate which were transformed to titled compounds 1-4.