1. Asymmetric 1,5-diarylpenta-1,4-dien-3-ones: Antiproliferative activity in prostate epithelial cell models and pharmacokinetic studies
- Author
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Chengsheng Chen, Manee Patanapongpibul, Yan Dong, Xiaojie Zhang, Qiu Zhong, German Ruiz Perez, Shanchun Guo, Qiao-Hong Chen, Qiang Zhang, Guangdi Wang, Shilong Zheng, Rubing Wang, Nithya Subrahmanyam, Joshua Keith, Changde Zhang, and Guanglin Chen
- Subjects
Male ,0301 basic medicine ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Article ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,Pharmacokinetics ,Prostate ,Cell Line, Tumor ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Potency ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell growth ,Chemistry ,Cell Cycle ,Organic Chemistry ,Prostatic Neoplasms ,Epithelial Cells ,General Medicine ,medicine.disease ,Rats ,Bioavailability ,Alkadienes ,030104 developmental biology ,medicine.anatomical_structure ,Microsomes, Liver ,Curcumin ,Drug Screening Assays, Antitumor - Abstract
To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones ( 25 – 58 ) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic prostate epithelial cell line. All these asymmetric dienones are sufficiently more potent than curcumin and their corresponding symmetric counterparts. The optimal dienone 58 , with IC 50 values in the range of 0.03–0.12 μM, is 636-, 219-, and 454-fold more potent than curcumin in three prostate cancer cell models. Dienones 28 and 49 emerged as the most promising asymmetric dienones that warrant further preclinical studies. The two lead compounds demonstrated substantially improved potency in cell models and superior bioavailability in rats, while exhibiting no acute toxicity in the animals at the dose of 10 mg/kg. Dienones 28 and 46 can induce PC-3 cell cycle regulation at the G 0 /G 1 phase. However, dienone 28 induces PC-3 cell death in a different way from 46 even though they share the same scaffold, indicating that terminal heteroaromatic rings are critical to the action of mechanism for each specific dienone.
- Published
- 2017