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Anti‐cancer activity of non‐pungent capsaicin analogs: A Structure‐Activity Study

The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound anti‐neoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps and burning sensation. This has led to extensive research focused on the identification and rational design of second‐generation capsaicin analogs. Previous studies have shown that addition of long‐chain unsaturated groups after the amide group of capsaicin were non‐pungent and retained the bioactivity of capsaicin. The chemical nature of these compounds are unsaturated N‐acylvanillamides (uN‐AVAMs). However, a majority of these uN‐AVAMs have been studied for their pain‐relieving activity. We synthesized a panel of uN‐AVAMs with 0–4 double bonds in the side chain of capsaicin. We investigated the growth‐inhibitory activity of these compounds with an MTT‐based screening assay. We selected our “hit compound” Arvanil for further studies. Next, we compared the apoptotic activity of arvanil and capsaicin in a panel of human small cell lung cancer (SCLC) cells. We observed that the non‐pungent capsaicin‐analog arvanil displayed greater magnitude of apoptosis than capsaicin. The pro‐apoptotic activity of arvanil and capsaicin was mediated by the intracellular calcium pathway. We measured the uN‐AVAM‐induced levels of intracellular calcium in SCLC cells. The pattern of uN‐AVAM‐induced intracellular calcium was analogous to the results obtained in the MTT assay. Therefore, the measurement of intracellular calcium may be used as a screening tool for capsaicin‐mimetics with anti‐cancer activity.