Abstract 6335: Structure-activity relationship (SAR) studies identify region B capsaicin analogs with growth-inhibitory activity in human small cell lung carcinoma

Abstract Purpose of the Study: The long-term research objective of our laboratory is to identify natural phytochemicals that could have potential applications for the treatment of human small-cell lung cancers (SCLC). Specifically, published data from our laboratory shows that capsaicin (the hot and spicy component of chili peppers) potently abrogates the growth and progression of human SCLC in vitro and in vivo. Conventionally, capsaicin is recognized as a powerful pain-relieving agent which is present in many over-the-counter creams and lotions. However, the clinical applications of capsaicin as a viable pain-relieving agent (and an anti-cancer drug) are hindered by its adverse side effects, such as gastric irritation, stomach cramps, and burning sensation. Such drawbacks of capsaicin may be circumvented by the rational design of non-pungent capsaicin analogs with comparable/greater bioactivity than capsaicin. The structure of capsaicin may be divided into three regions: Region A (the aromatic ring), Region B (the amide group), and Region C (the hydrophobic side chain). As a first step, we synthesized a panel of compounds with variations in Region C of capsaicin. Experimental Procedures: The growth-suppressive activity of these Region C capsaicin analogs was evaluated using an MTT-based screening assay. The results of the MTT assay were confirmed by measuring the pro-apoptotic activity of these compounds. Based on our findings, our hit compounds were “ARVANIL” and “DOHEVANIL”. Using these two compounds as the template, we then sought to design analogs that would have different chemical groups in Region B of the molecule. The growth-suppressive activity of these Region B analogs was measured using an MTT-based screening assay in human SCLC cells. The results obtained from the MTT experiments were verified by soft agar assays and experiments in patient-derived organoids. Results: SAR studies led to the identification of a panel of synthetic Region B capsaicin analogs with varying growth-inhibitory activity in human SCLC cells. The pro-apoptotic activity of these compounds correlates well with their ability to inhibit the viability of human SCLCs. Conclusions: The Region B capsaicin analogs may have applications in the therapy of human SCLC. Our future studies will examine the anti-cancer activity of selected Region B capsaicin analogs in vivo. Support or Funding Information Funding for our study was supported by a NIH R15-AREA Grant (2R15CA161491-03) and a Center for Natural Products pilot grant from the WV-INBRE Grant Program (P20GM103434, PI: Gary Rankin). Furthermore, this study was supported in part by an Institutional Development Award (IDeA) Grant number P20GM104932 from the National Institute of General Medical Sciences (NIGMS) and the Research Core B of COBRE, a component of the National Institutes of Health (NIH). Citation Format: Amanda B. Sugrue, Kushal J. Modi, Reagan S. Light, Rama S. Gadepalli, John M. Rimoldi, Stephen D. Richbart, Justin C. Merritt, Piyali Dasgupta. Structure-activity relationship (SAR) studies identify region B capsaicin analogs with growth-inhibitory activity in human small cell lung carcinoma [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 6335.