1,2,3-Triazole Tethered Hybrid Capsaicinoids as Antiproliferative Agents Active against Lung Cancer Cells (A549)

Abstract

A series of novel 1,2,3-triazole derivatives of capsaicin and its structural isomer (new natural product hybrid capsaicinoid) were synthesized by exploiting one-/two-point modification of capsaicin without altering the amide linkage (neck). The newly synthesized compounds were screened for their antiproliferative activity against an NCI panel of 60 cancer cell lines at a single dose of 10 μM. Most of the compounds have demonstrated reduced growth between 55 and 95%, whereas capsaicin (<b>10</b>) has shown reduced growth between 0 and 24%. Compounds showing more than 50% growth inhibition were further evaluated for the IC₅₀ value. Among the cell lines tested, lung cancer cell lines (A549, NCI-H460) were found to be more susceptible toward most of the synthesized compounds. Compounds <b>14g</b> and <b>14j</b> demonstrated good antiproliferative activity in NCI-H460 with IC₅₀ values of 6.65 and 5.55 μM, respectively, while compounds <b>18b</b>, <b>18c</b>, <b>18f</b>, and <b>18m</b> demonstrated potential antiproliferative activity in A549 cell lines with IC₅₀ values ranging between 2.9 and 10.5 μM. Among the compounds, compound <b>18f</b> was found to demonstrate the best activity with an IC₅₀ value of 2.91 μM against A549. Furthermore, <b>18f</b> induces cell cycle arrest at the S-phase and disrupts the mitochondrial membrane potential, reducing cell migration potential by inducing cellular apoptosis and higher ROS generation along with a decrease in mitochondrial membrane potential in addition to surface and nuclear morphological alterations such as a reduction in the number and shrinkage of cells coupled with nuclear blabbing indicating the sign of apoptosis of A549 non-small cell lung cancer cell lines. Compound <b>18f</b> has emerged as a lead molecule and may serve as a template for further discovery of capsaicinoid scaffolds.