Prostate Cancer is the most commonly diagnosed cancer in American men and 1 in 8 US men will be diagnosed with prostate cancer during their lifetime. Castration-Resistance Prostate Cancer (CRPC) is an advanced and lethal version, and current treatments for CRPC can only prolong patients’ limited survival life. More effective treatment for CRPC is therefore urgently needed. Androgen receptor (AR) continues to serve as a critical drug target for CRPC as verified by the fact that the second generation AR antagonists have been approved by FDA for patients with CRPC. Silibinin has been demonstrated by its in vitro and in vivo data to have potential to treat CRPC. Its underlying mechanism is associated with AR transcriptional axis. However, its moderate antiproliferative potency, poor oral bioavailability and low selectivity towards AR-positive prostate cancer cell line need to be improved. This study aims to manipulate the chemical structure of Silibinin in hope to enhance its potency, oral bioavailability and selectivity towards AR-positive PC cell lines. To this end, 3-carbamolyed-5,7,20-trimethylsilibinins were designed and synthesized by introducing three different carbamoyl groups into 3-OH group of 5,7,20-trimethylsilibinins, and their antiproliferative potency and selectivity towards either AR-positive (LNCaP) or AR-negative (DU-145 & PC-3) PC cell lines were tested with WST-1 bioassay. During the synthesis process, we found out for the first time that the desired carbamoyl groups can be selectively appended to 3-OH of 5,7,20-trimethylsilibinins by reacting with carbamoyl chloride mediated by triethylamine and 4-dimethylaminopyridine. This reaction has been repeated over forty times and verified by two authors. At this point, six carbamoyled derivatives have been synthesized, and their chemical structures have been characterized by 1D-NMR, 2D-NMR, and High-Resolution Mass (HRMS) Data. Our WST-1 bioassay data indicated that four carbamoyled derivatives can selectively suppress AR positive LNCaP prostate cancer cell proliferation with IC50 values less than 1µM. The data suggest that 3-carbamoyled-5,7,20-trimethylsilibinins may affect AR-induced transcriptional activities.

3-Carbamoyled-5,7,20-trimethylsilibinins: Synthesis and antiproliferative evaluation

ACS Spring Meeting 2021

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