Synthesis, anticancer activity and photostability of novel 3-ethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-ones

Some derivatives of 3-ethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-ones were synthesized using ethyl 2-aminothiophene-3-carboxylates as precursors in order to estimate their cytotoxicity, respectively proliferative activity. Thienopyrimidinones containing thiosemicarbazide as well as 1,3,4-thiadiazole moieties were evaluated for their cytotoxical effect on four cancer cell lines: HT-29, breast cancer cells MDA-MB-231, HeLa, HepG2 as well as human diploid cell line Lep-3. Compounds 5b, 6a and 6b revealed cytotoxicity to the four studied cancer cell lines. The highst cytotoxicity against MDA-MB-31 exhibited the thiosemicarbazide 5b with IC50 2.31.10(-4) mu M but most active towards HT-29 cell lines was thienopyrimidine 6c with IC50 0.001 mu M. Compound 6a showed the highest inhibitory activity with IC50 - 0.99 mu M to human liver carcinoma HepG2 cells and low cytotoxicity towards Lep3 (IC50 = 191 mu M). The thienopyrimidine derivative linked to thiadiazole 6b was toxic to the four studied cancer cell lines, especially to HeLa (IC50-0.83 mu M), and besides that the compound demonstrated toxicity to Lep 3 cells at very high concentration 89 x 10(3) mu M. The solid-state photostability of the derivatives 5a-c and 6a-c was tested by irradiation with UV light. All of the studied compounds show solid-state photostability in 240 min of irradiation. Using MOE software molecular docking of the three ligands 5b, 6b and 7 was accomplished into an internal pocket formed by the activation segment and the P-loop of B-V599E-Raf. It was established that the binding of the ligands to B-V599E-Raf promotes an inactive conformation of the enzyme. (C) 2016 Elsevier Masson SAS. All rights reserved.