Large-scale synthesis of galeterone and lead next generation galeterone analog VNPP433-3ß.
Steroids
; 185: 109062, 2022 09.
Article
em En
| MEDLINE
| ID: mdl-35690119
ABSTRACT
VNPP433-3ß (compound 2, (3ß-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). Here, we describe a large multi-gram (92 g) scale synthesis of compound 2 starting from the commercially available dehydroepiandrosterone-3-acetate (DHEA, 6) via Galeterone (Gal, 1), in 8 steps with a 26% overall yield and 99.5% purity. The overall yield for the synthesis of Gal from DHEA improved from previously reported 47% to 59%. The advantages of this synthesis are as follows (1) In the first two steps of Scheme 2, the change of solvents and reagents enabled the isolation of compounds 7 and 8 from heptane triturations, as column chromatography was eliminated in both steps. (2) In step 3 (deformylation) the catalyst required was reduced from 50% to 10% (wt/wt) of compound 8 which enable easy purification of compound 9, with modest increased yield. (3) The fourth step to produce Gal (1) was improved by using methanol, eliminating the use of tetrahydrofuran (THF) and dichloromethane, solvent which may be a problem as residual solvent contaminant. (4) In the final step 8, the imidazole-ring formation, inexpensive glyoxal (40% aqueous solution) was used in the reaction instead of expensive glyoxal trimer dihydrate. The structure of the target product (2, VNPP433-3ß) was established by NMR spectroscopy, mass spectrometry and elemental analysis. Gal and VNPP433-3ß exhibit more potent antiproliferative activities against CWR22Rv1 human prostate cancer cells compared to clinical drugs, Abiraterone and Enzalutamide.
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MEDLINE
Assunto principal:
Benzimidazóis
/
Desidroepiandrosterona
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article