Improved Procedures for Gram-Scale Synthesis of Galeterone 3β-Imidazole and Galeterone 3β-Pyridine Methoxylate, Potent Androgen Receptor/Mnk Degrading Agents

Abstract

Galeterone (1) and its C-3 analogs are of substantial interest because of their multitarget anticancer activities, including AR and Mnk degrading activities. Here, we describe improved and efficient procedures for the gram-scale synthesis of 3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (galeterone 3β-imidazole, 2) and 3β-(pyridine-4-ylmethoxy)-17-(1H-benzimidazol-1-yl)­androsta-5,16-diene (galeterone 3β-pyridine methoxylate, 3). Whereas compound 2 was synthesized in 63% overall yield from galeterone (1) over four steps, via key intermediate, 3β-azido galeterone (8); compound 3 was synthesized in 61% overall yield from 1 in one step. This article also reports on the facile synthesis of other potential AR/Mnk degrading agents (ARDAs/MNKDAs), including galeterone 3α-imidazole (5) and galeterone 3β-amine (10), both in excellent overall yields. Notably, except for the one-step synthesis of compound 3 which required purification by flash column chromatography, none of the intermediates and target compound 2 required extensive chromatographic purifications or multiple crystallizations.

Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer

“…The ester group was hydrolyzed by KOH to obtain 10-a–10-k , which reacted with mesyl chloride (MsCl) in the presence of Et 3 N in dichloromethane (DCM) at room temperature to afford the corresponding 3β-mesylate compounds 11-a–11-k . The configuration-preserved compounds 12-a–12-k were subsequently obtained by treating 11-a–11-k with trimethylsilyl azide (TMSN 3 ) and boron trifluoride diethyl etherate (BF 3 ·OEt 2 ) in DCM at room temperature . Then, the 3β-N 3 group was reduced by Staudinger reaction to furnish 3β-NH 2 compounds 13-a–13-k , which underwent acylation reactions with isonicotinoyl chloride to afford the corresponding analogs 14-a–14-c , or reacted with pyridazine-4-carboxylic acid in the presence of HATU and N , N -diisopropylethylamine (DIPEA) in DMF to yield 15-a–15-k .…”

Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer

“…The synthesis of compounds 12−22 is shown in Scheme 1. Galeterone (6) was reacted with mesyl chloride (MsCl) in the presence of Et 3 N in dichloromethane (DCM) at room temperature to give the desired 3β-mesylate (9) followed by the treatment with trimethylsilyl azide (TMSN 3 ) and boron trifluoride etherate (BF 3 •OEt 2 ) to afford configuration-preserved compound 10, 51 which was then reduced to 3β-amine (11) by LiAlH 4 in anhydrous THF under the ice bath condition. 11 underwent acylation reactions to afford the corresponding analogs 12−14 and 16−22 or reacted with 4-(bromomethyl)pyridine hydrobromide in the presence of potassium carbonate in DMF to yield 15 via nucleophilic substitution.…”

Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

“…Galeterone and analogs (VNPT55, VNPP414, and VNPP433-3β), and were all designed and synthesized in our laboratory as previously reported [3,8,49,66]. Enzalutamide was purchased from Sequoia Research Products, Pangbourne, RG8 7AP, UK and docetaxel and mitoxantrone was purchased from Cell Signaling.…”