Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types.

Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types. Bioorg Med Chem. 2018 Nov 29;: Authors: Chapa J, Valdez M, Ruiz F, Gonzales K, Mitchell W, McHardy SF, Hart M, Polusani SR, Gonzales CB Abstract We previously demonstrated that capsazepine (CPZ), a synthetic transient receptor potential Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-cancer effects in vivo. The purpose of this study was to develop more potent analogs based upon CPZ pharmacophore and structure-activity relationships (SAR) across analogs. We generated 30 novel compounds and screened for their anti-proliferative effects in cultured HeLa cervical cancer cells. Cell viability assays identified multiple compounds with IC50s < 15 μM and one compound, 29 with an IC50 < 5 μM; six fold more potent than CPZ. We validated the anti-proliferative efficacy of two lead compounds, 17 and 29, in vivo using HeLa-derived xenografts in athymic nude mice. Both analogs significantly reduced tumor volumes by day 8 compared to control treated animals (p < 0.001) with no observable adverse effects. Calcium imaging determined that compound 17 activates TRPV1 whereas 29 neither activates nor inhibits TRPV1; indicating a unique mechanism-of-action that does not involve TRPV1 signaling. Cell viability assays using a panel of additional tumor types including oral squamous cell carcinoma, non-small ce...
Source: Bioorganic and Medicinal Chemistry - Category: Chemistry Authors: Tags: Bioorg Med Chem Source Type: research