title: Antiproliferative activity of aroylacrylic acids. Structure-activity study based on molecular interaction fields.
abstract: Antiproliferative activity of 27 phenyl-substituted 4-aryl-4-oxo-2-butenoic acids (aroylacrylic acids) toward Human cervix carcinoma (HeLa), Human chronic myelogenous leukemia (K562) and Human colon tumor (LS174) cell lines in vitro are reported. Compounds are active toward all examined cell lines. The most active compounds bear two or three branched alkyl or cycloalkyl substituents on phenyl moiety having potencies in low micromolar ranges. One of most potent derivatives arrests the cell cycle at S phase in HeLa cells. The 3D QSAR study, using molecular interaction fields (MIF) and derived alignment independent descriptors (GRIND-2), rationalize the structural characteristics correlated with potency of compounds. Covalent chemistry, most possibly involved in the mode of action of reported compounds, was quantitatively accounted using frontier molecular orbitals. Pharmacophoric pattern of most potent compounds are used as a template for virtual screening, to find similar ones in database of compounds screened against DTP-NCI 60 tumor cell lines. Potency of obtained hits is well predicted.
authors.affiliation: Department of Chemistry-Institue of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia. bdrakuli@chem.bg.ac.rs
authors.forename: Branko J
authors.initials: BJ
authors.lastname: Drakulić
authors.forename: Tatjana P
authors.initials: TP
authors.lastname: Stanojković
authors.forename: Zeljko S
authors.initials: ZS
authors.lastname: Zižak
authors.forename: Milan M
authors.initials: MM
authors.lastname: Dabović
mesh_terms: D000179:Acrylates / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003437:Crotonates / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D013816:Thermodynamics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000179:Acrylates; D003437:Crotonates; D010636:Phenols