title: Synthesis, anticancer activity and photostability of novel 3-ethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-ones.
abstract: 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) μM, but most active towards HT-29 cell lines was thienopyrimidine 6c with IC50 0.001 μM. Compound 6a showed the highest inhibitory activity with IC50 - 0.99 μM to human liver carcinoma HepG2 cells and low cytotoxicity towards Lep3 (IC50 = 191 μM). The thienopyrimidine derivative linked to thiadiazole 6b was toxic to the four studied cancer cell lines, especially to HeLa (IC50-0.83 μM), and besides that the compound demonstrated toxicity to Lep 3 cells at very high concentration 89 × 10(3) μM. 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 (V599E)B-Raf. It was established that the binding of the ligands to (V599E)B-Raf promotes an inactive conformation of the enzyme.
authors.affiliation: University of Chemical Technology and Metallurgy, Department of Organic Synthesis, 8 Kliment Ohridski Blvd., 1756, Sofia, Bulgaria. Electronic address: anmav@abv.bg.
authors.forename: Anelia Ts
authors.initials: AT
authors.lastname: Mavrova
authors.affiliation: University of Chemical Technology and Metallurgy, Department of Organic Synthesis, 8 Kliment Ohridski Blvd., 1756, Sofia, Bulgaria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dimov
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113, Sofia, Bulgaria.
authors.forename: Denitsa
authors.initials: D
authors.lastname: Yancheva
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113, Sofia, Bulgaria.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Rangelov
authors.affiliation: Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Science, 1113, Sofia, Bulgaria.
authors.forename: Diana
authors.initials: D
authors.lastname: Wesselinova
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113, Sofia, Bulgaria.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Tsenov
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000528:radiation effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; C476003:thienopyrimidine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Anticancer activity; B-Raf; Cytotoxicity; DFT; Photo stability; Thieno[2,3-d]pyrimidin-4(3H)-ones