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

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 mu M. Most of the compounds have demonstrated reduced growth between 55 and 95%, whereas capsaicin (10) 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 14g and 14j demonstrated good anti -proliferative activity in NCI-H460 with IC50 values of 6.65 and 5.55 mu M, respectively, while compounds 18b, 18c, 18f, and 18m demonstrated potential antiproliferative activity in A549 cell lines with IC50 values ranging between 2.9 and 10.5 mu M. Among the compounds, compound 18f was found to demonstrate the best activity with an IC50 value of 2.91 mu M against A549. Furthermore, 18f 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 18f has emerged as a lead molecule and may serve as a template for further discovery of capsaicinoid scaffolds. IOI H iota Capsaicin MO � center dot Ή�N One point phi theta di beta cation GI = 13.84 -48.99 IC5o=5.55-32.50 WV. ..... Apoptosis N 'i O N iota N N v v v H center dot Two point modifications il % GI= 4.63-46.72 A549; IC. = 2.91 mu M: ,.. : MMP center dot center dot center dot......-_ ROS S-Phase Cell cycle Anti-migrafim property

Automated summary

A series of novel 1,2,3-triazole derivatives of capsaicin, including a new natural product hybrid capsaicinoid, were synthesized. Most of the synthesized compounds showed antiproliferative activity against various cancer cell lines, with lung cancer cell lines being the most sensitive. Compound 18f demonstrated the best antiproliferative activity and acted through inducing cell apoptosis and altering mitochondrial membrane potential.