Abstract 6930: Structure activity relationship (SAR) studies identify novel non-pungent capsaicin analogs which display robust growth-inhibitory activity in human ovarian carcinoma cells
Authors: Kushal J. Modi, Rama S. Gadepalli, John R. Rimoldi, Timothy E. Long, Yi Charlie Chen, Kathleen C. Brown, Stephen D. Richbart, Justin C. Meritt, Sarah L. Miles, Piyali Dasgupta
Journal: Cancer Research (2025)

Abstract Purpose of the study: The dietary compound Capsaicin is the hot and pungent ingredient of chili peppers. Preliminary data in our laboratory have found that capsaicin displays robust growth-inhibitory activity in a diverse array of human cancers. However, the clinical applications of capsaicin as a viable anti-cancer drug are hindered by its adverse side effects, such as gastric irritation, nausea, stomach cramps and a burning sensation in the gut. Clinical trials which explored the pain-relieving activity of capsaicin found that patients who orally ingested capsaicin discontinued taking the drug due to its unpleasant side effects. The primary aim of our studies was to rationally design non-pungent capsaicin analogs which would retain the anti-cancer activity of the parent molecule. Experimental procedures. (SAR) studies have shown that the pharmacophore of capsaicin may be divided into three regions: REGION A, B, AND C. The addition of long-chain unsaturated fatty acyl groups in REGION C of capsaicin generated non-pungent compounds which displayed improved pain-relieving properties, relative to capsaicin. We synthesized a panel of compounds which contained a long chain unsaturated fatty acyl side chain in Region C of the capsaicin molecule. Subsequently, we determined the growth-inhibitory activity of these compounds in human ovarian cancer cells (in cell culture and chicken chorioallantoic membrane (CAM) models. Results: The non-pungent Region C capsaicin analog DOHEVANIL displayed greater pro-apoptotic activity than capsaicin in human ovarian carcinoma cells. Most interestingly, DOHEVANIL did not impact the growth of normal human liver and kidney cells. Conclusions: The non-pungent Region C capsaicin analog DOHEVANIL may be a promising non-pungent capsaicin analog which displays robust growth-suppressive activity in human ovarian cancer cells. Support or Funding Information Funding for our study was supported by the NIH R15-AREA Grant (2R15CA161491-02 and 2R15CA161491-03), the Women's Health T3: 3P20GM103434-23W1 (PI: Dr. G Rankin) to PD and MAV and the NIAID-AI151970 grant to TEL. Furthermore, this study was supported in part by the West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE) grant (NIH grant P20GM103434; PI: Dr. G. Rankin), the National Institute of General Medical Sciences of the National Institutes of Health under the award number P30GM122733. Citation Format: Kushal J. Modi, Rama S. Gadepalli, John R. Rimoldi, Timothy E. Long, Yi Charlie Chen, Kathleen C. Brown, Stephen D. Richbart, Justin C. Meritt, Sarah L. Miles, Piyali Dasgupta. Structure activity relationship (SAR) studies identify novel non-pungent capsaicin analogs which display robust growth-inhibitory activity in human ovarian carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6930.