Synthesis and evaluation of the antitumor activity of Calix[4]arene l-proline derivatives

The unique conformational properties, functionality, low toxicity, and low cost make calixarene-based compounds a valuable candidate against cancer. The aim of the present study is the synthesis of the upper rim and lower rim-functionalized l-proline-based calix[4]arene derivatives and evaluation of their cytotoxic potential for human cancerous cells as well as to determine the death mechanism. Synthesized calix[4]arene (3, 8a, 8b 13a, and 13b) derivatives were characterized by different spectroscopic techniques such as ¹HNMR, ¹³CNMR, and FTIR. In vitro effects of compounds 3, 8a, 8b, 13a and 13b were tested on human cancerous cells (HEPG2, PC-3, A-549, and DLD-1) as well as human healthy epithelium cell (PNT1A). Results show that compounds 3, 8a, 8b and 13b have cytotoxic potential on human colorectal carcinoma cells (DLD-1) with IC₅₀ values of 43 µM, 45.2 µM, 64.57 µM, and 29.35 µM respectively. Apoptosis ratios of cell death were investigated with flow cytometer using 7-AAD and Annexin-V as markers. Cytotoxic potential of 8a was found to be higher due to increased apoptosis, when compared with healthy cells the apoptotic cell death was significantly (p < 0.0001) increased up to 1.7-fold and 2.4-fold in DLD-1 and A549 cells, respectively. In conclusion, these l-proline derived calix[4]arenes with their selective cytotoxic potential on human cancerous cells may be a potential candidate for the treatment of human CRC and lung cancer.