2. Academic Validation
  3. 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. 2019 Jan 1;27(1):208-215. doi: 10.1016/j.bmc.2018.11.040.
Jorge De La Chapa 1,  Matthew Valdez 2,  Franscisco Ruiz 3rd 2,  Keith Gonzales 2,  Wes Mitchell 2,  Stanton F McHardy 3,  Matthew Hart 4,  Srikanth R Polusani 2,  Cara B Gonzales 5
Affiliations

Affiliations

  • 1 Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio School of Dentistry, San Antonio, Texas 78229, USA.
  • 2 Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX 78249, USA.
  • 3 Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX 78249, USA; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. Electronic address: Stanton.mchardy@utsa.edu.
  • 4 Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX 78249, USA; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
  • 5 Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio School of Dentistry, San Antonio, Texas 78229, USA; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. Electronic address: gonzalesc5@uthscsa.edu.
PMID: 30528162 DOI: 10.1016/j.bmc.2018.11.040
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 cell lung Cancer (NSCLC), breast Cancer, and prostate Cancer cell lines (HSC-3, H460, MDA-231, and PC-3 respectively) demonstrated that both lead compounds were efficacious against every Cancer type tested. Compounds 29 displayed IC50s of 1-2.5 μM in HSC-3and PC-3cells. Thus, we propose that these novel CPZ analogs may serve as efficacious therapeutic agents against multiple tumor types that warrant further development for clinical application.

Keywords

Cancer therapy; Capsazepine; Solid tumors; Structure-activity relationships; TRPV1.

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