title: QSAR modeling, synthesis and bioassay of diverse leukemia RPMI-8226 cell line active agents.
abstract: A rigorous QSAR modeling procedure employing CODESSA PRO descriptors has been utilized for the prediction of more efficient anti-leukemia agents. Experimental data concerning the effect on leukemia RPMI-8226 cell line tumor growth of 34 compounds (treated at a dose of 10 μM) was related to their chemical structures by a 4-descriptor QSAR model. Four bis(oxy)bis-urea and bis(sulfanediyl)bis-urea derivatives (4a, 4b, 8, 11a) predicted as active by this model, together with 11b predicted to be of low activity, were synthesized and screened for anti-tumor activity utilizing 55 different tumor cell lines. Compounds 8 and 11a showed anti-tumor properties against most of the adopted cell lines with growth inhibition exceeding 50%. The highly promising preliminary anti-tumor properties of compounds 8 and 11a, were screened at serial dilutions (10(-4)-10(-8) μM) for determination of their GI(50) and TGI against the screened human tumor cell lines. Compound 11a (GI(50) = 1.55, TGI = 8.68 μM) is more effective than compound 8 (GI(50)=58.30, TGI = > 100 μM) against the target leukemia RPMI-8226 cell line. Compound 11a also exhibits highly pronounced anti-tumor properties against NCI-H226, NCI-H23 (non-small cell lung cancer), COLO 205 (colon cancer), SNB-75 (CNS cancer), OVCAR-3, SK-OV-3 (ovarian cancer), A498 (renal cancer) MDA-MB-231/ATCC and MDA-MB-468 (breast cancer) cell lines (GI(50) = 1.95, 1.61, 1.38, 1.56, 1.30, 1.98, 1.18, 1.85, 1.08, TGI = 8.35, 6.01, 2.67, 8.59, 4.01, 7.01, 5.62, 6.38, 5.63 μM, respectively). Thus 11a could be a suitable lead towards the design of broad spectrum anti-tumor active agents targeting various human tumor cell lines.
authors.affiliation: Center for Heterocyclic Compounds, University of Florida, Department of Chemistry, Gainesville, FL 32611-7200, United States. katritzky@chem.ufl.edu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Katritzky
authors.forename: Adel S
authors.initials: AS
authors.lastname: Girgis
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Slavov
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Tala
authors.forename: Iva
authors.initials: I
authors.lastname: Stoyanova-Slavova
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
chemical_list: D000970:Antineoplastic Agents