Chemical synthesis of fluorinated and iodinated 17?-HSD3 inhibitors and evaluation for imaging prostate cancer tumors and tissue biodistribution
BIOORGANIC CHEMISTRY(2022)
摘要
Prostate cancer is the most common cancer among men and the development of new therapeutic agents is needed for its treatment and/or diagnosis. 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3) is involved in the production of androgens, which stimulates the proliferation of prostate cancer cells. Piperazinomethylandrosterone sulfonamide derivatives were developed as 17 beta-HSD3 inhibitors and the concentration of a representative sulfonamide derivative (compound 1) was found to accumulate in prostate tumor tissues relatively to plasma in a mouse xenograft experiment. This finding gives us the opportunity to specifically target the prostate cancer tumors through the development of a radiolabelled version of compound 1 toward targeted molecular radiotherapy or radioimaging diagnosis. The chemical synthesis of fluorinated and iodinated analogs of compound 1 was achieved, leading to a series of compounds with similar levels of inhibition as the initial candidate. From 17 beta-HSD3 inhibition activity, molecular modeling and mouse plasma-concentration studies, the most promising compound of this series was selected, its 18F-radiolabelled version (18F-3) synthesized, and imaging/biodistribution studies engaged. When injected in mice, however, 18F-3 uptake in the target tissues (LNCaP[17 beta-HSD3] tumors and testicles) was not sufficient to allow their visualization by positron emission tomography. Plasma concentration values of compounds 3-8 administered orally, however, showed that the para-iodo compound 7 is the most metabolically stable and could therefore be an interesting alternative for radiolabelling and radiotreatment.
更多查看译文
关键词
Imaging,Hydroxysteroid dehydrogenase,17?-HSD3,Enzyme inhibitor,Steroid,Chemical synthesis,Prostate cancer,Molecular modeling
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要