Large-scale synthesis of galeterone and lead next generation galeterone analog VNPP433-3β

Puranik Purushottamachar; Elizabeth Thomas; Retheesh S Thankan; Vladimir Rudchenko; Guangfei Huang; Vincent C O Njar

doi:10.1016/j.steroids.2022.109062

Large-scale synthesis of galeterone and lead next generation galeterone analog VNPP433-3β

Steroids. 2022 Sep:185:109062. doi: 10.1016/j.steroids.2022.109062. Epub 2022 Jun 8.

Authors

Puranik Purushottamachar¹, Elizabeth Thomas², Retheesh S Thankan³, Vladimir Rudchenko⁴, Guangfei Huang⁴, Vincent C O Njar⁵

Affiliations

¹ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Electronic address: PPuranik@som.umaryland.edu.
² Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
³ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Flavocure Biotech, 701 E. Pratt Street, Suite 2033, Baltimore MD 21202, USA; Isoprene pharmaceuticals, Inc., 875 Hollins Street, Suite 102D, Baltimore, MD 21201, USA.
⁴ Alchem Laboratories Corporation. 13305 Rachael Blvd., Alachua, FL 32615, USA.
⁵ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Isoprene pharmaceuticals, Inc., 875 Hollins Street, Suite 102D, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Electronic address: VNjar@som.umaryland.edu.

PMID: 35690119
DOI: 10.1016/j.steroids.2022.109062

Abstract

VNPP433-3β (compound 2, (3β-(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, VNPP433-3β) was established by NMR spectroscopy, mass spectrometry and elemental analysis. Gal and VNPP433-3β exhibit more potent antiproliferative activities against CWR22Rv1 human prostate cancer cells compared to clinical drugs, Abiraterone and Enzalutamide.

Keywords: Galeterone; Large-scale synthesis; VNPP433-3β.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Androstadienes
Benzimidazoles* / chemistry
Dehydroepiandrosterone*
Glyoxal
Humans
Male
Solvents

Substances

Androstadienes
Benzimidazoles
Solvents
Dehydroepiandrosterone
Glyoxal
3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene

Grants and funding

R01 CA224696/CA/NCI NIH HHS/United States