Abstract
A simple environmentally friendly microwave-assisted protocol was developed for the synthesis of 3,5-bis(styryl)pyrazoles 2a-l, allowing their rapid generation and screening for anti-proliferative activity in the PC3 prostate cancer cell line. Two analogues (2a and 2l) had GI50 values in the low micromolar range and so were selected for further biological evaluation (apoptosis and cell cycle analysis, and effects on tubulin and microtubules). 3,5-Bis[(1E)-2(2,6-dichlorophenyl)ethenyl]-1H-pyrazole 2l induces cell death in PC3 cells even after the removal of the compound. The compound binds to tubulin (Kd 0.4±0.1 μM), inhibits tubulin polymerization in vitro (with no effect on the polymerization of bacterial cell division protein FtsZ, a homolog of tubulin). In addition, pyrazole 2l is competitive with paclitaxel for binding to tubulin but not with vinblastine, crocin, or colchicine. Treatment with pyrazole 2l results in microtubule depolymerization in PC3 cells; these 3,5-bis(styryl)pyrazoles thus warrant further investigation as lead compounds for the treatment of castration-resistant prostate cancer (CRPC)
SIGNIFICANCE STATEMENT The taxanes (paclitaxel, docetaxel and cabazitaxel) are important components of prostate cancer chemotherapy regimens, but their oral administration is hampered by their very low and highly variable oral bioavailabilities. For example, the mean oral bioavailability of paclitaxel is below 10% as a result of its poor absorption, which is due to its poor solubility, high first-pass metabolism, and efficient efflux by P-glycoprotein, which is abundant in the gastrointestinal tract. New chemical entities (NCEs) for the treatment of prostate cancer are thus required, which would ideally be much simpler than the structurally complex taxanes. We report here the facile synthesis and extensive investigation of the mechanism of action of some bis(styryl)pyrazoles and demonstrate their potential as lead compounds for the treatment of prostate cancer.
- The American Society for Pharmacology and Experimental Therapeutics