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

Jorge De La Chapa, Matthew Valdez, Franscisco Ruiz, Keith Gonzales, Wes Mitchell, Stanton F. McHardy, Matthew Hart, Srikanth R. Polusani, Cara B Gonzales

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)208-215
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2019

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Cells
Lead compounds
Tumors
Nude Mice
Neoplasms
Prostatic Neoplasms
Cell Survival
Artificial Receptors
Breast Neoplasms
Assays
Tumor Burden
Heterografts
Non-Small Cell Lung Carcinoma
Uterine Cervical Neoplasms
Inhibitory Concentration 50
Squamous Cell Carcinoma
Calcium
Animals
Cell Line
capsazepine

Keywords

  • Cancer therapy
  • Capsazepine
  • Solid tumors
  • Structure-activity relationships
  • TRPV1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Chapa, J. D. L., Valdez, M., Ruiz, F., Gonzales, K., Mitchell, W., McHardy, S. F., ... Gonzales, C. B. (2019). Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types. Bioorganic and Medicinal Chemistry, 27(1), 208-215. https://doi.org/10.1016/j.bmc.2018.11.040

Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types. / Chapa, Jorge De La; Valdez, Matthew; Ruiz, Franscisco; Gonzales, Keith; Mitchell, Wes; McHardy, Stanton F.; Hart, Matthew; Polusani, Srikanth R.; Gonzales, Cara B.

In: Bioorganic and Medicinal Chemistry, Vol. 27, No. 1, 01.01.2019, p. 208-215.

Research output: Contribution to journalArticle

Chapa, JDL, Valdez, M, Ruiz, F, Gonzales, K, Mitchell, W, McHardy, SF, Hart, M, Polusani, SR & Gonzales, CB 2019, 'Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types' Bioorganic and Medicinal Chemistry, vol. 27, no. 1, pp. 208-215. https://doi.org/10.1016/j.bmc.2018.11.040
Chapa, Jorge De La ; Valdez, Matthew ; Ruiz, Franscisco ; Gonzales, Keith ; Mitchell, Wes ; McHardy, Stanton F. ; Hart, Matthew ; Polusani, Srikanth R. ; Gonzales, Cara B. / Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types. In: Bioorganic and Medicinal Chemistry. 2019 ; Vol. 27, No. 1. pp. 208-215.
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