Synthesis, in vitro anticancer activity, and pharmacokinetic profiling of the new tetrahydropyrimidines: Part I

Different vanillin-based aldehydes were used to synthesize novel tetrahydropyrimidines (THPMs) via conventional Biginelli reaction. The THPMs were tested against human normal cells (MRC-5) and cancer cell lines (HeLa, K562, and MDA-MB-231). With IC50 values of 10.65, 10.70, and 12.76 mu M, compounds 4g, 4h, and 4i exerted the strongest cytotoxic effects against K562 cells. The best activity was achieved for 4g on MDA-MB-231 cells (IC50 = 9.20 +/- 0.14 mu M). The effects of compounds 4g, 4h, and 4i on the cell-cycle phase distribution of K562 cells were analyzed. Principal component analysis was carried out for the chemometrics analysis to comprehend the relationship between the anticancer activity of the THPMs, pharmacokinetic properties, and partition coefficients, as well as the relationship between the chromatographic behavior and retention parameters. The highest retention rates are found for molecules 4g, 4h, and 4i, which have the longest carbon chains, indicating that the length of the alkyl chain positively affects the molecule's anticancer activity but only if the number of carbon atoms is not higher than seven. Additionally, molecular docking analysis was performed to determine the preferred binding modes of the investigated ligands (4g, 4h, and 4i) with a DNA dodecamer and bovine serum albumin. Tetrahydropyrimidines (THPMs) containing vanillic fragments have shown good to high cytotoxicity against K562 and MDA-MB-231 cells. The most active compounds are THPMs, which contain heptyl, octyl, and decyl alkyl chains. These three compounds activated apoptosis in K562 cells through the main effector caspase-3 and the initiator caspase-8 involved in the extrinsic apoptotic pathway. image