ABSTRACT
OBJECTIVE: A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d]pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts. RESULTS: Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3Kα related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Kα inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3). CONCLUSION: Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4- aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Proliferation/drug effects , Phosphoinositide-3 Kinase Inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Amination , Breast/drug effects , Breast/metabolism , Breast Neoplasms/metabolism , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , Male , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Prostate/drug effects , Prostate/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacologyABSTRACT
A number of new aminosubstituted benzofuran analogues have been prepared and their cytotoxic/cytostatic activity was investigated against five human tumor cell lines (MCF-7, SKBR3, SKOV3, HCT-116 and HeLa). Certain compounds showed noticeable tumor cell growth inhibition, indicative of possible structure-activity relationships.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzofurans/chemical synthesis , Cell Proliferation/drug effects , Drug Design , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzofurans/chemistry , Benzofurans/pharmacology , Cell Survival/drug effects , HCT116 Cells , HeLa Cells , Humans , Inhibitory Concentration 50 , MCF-7 Cells , Molecular Structure , Structure-Activity RelationshipABSTRACT
A sensitive and selective high-performance liquid chromatographic method has been developed and validated for the determination of nateglinide in human plasma. Nateglinide and the internal standard, undecylenic acid, were extracted from plasma by liquid-liquid extraction using a mixture of ethyl acetate-diethyl ether, 50:50 (v/v). Pre-column derivatization reaction was performed using a coumarin-type fluorescent reagent, N-(7-methoxy-4-methyl-2-oxo-2H-6-chromenyl)-2-bromoacetamide. The derivatization proceeded in acetone in the presence of potassium carbonate and catalyzed by 18-crown-6 ether. The fluorescent derivatives were separated under isocratic conditions on a Hypersil BDS-C8 analytical column (250.0 mm x 2.1 mm i.d., particle size 5 microm) with a mobile phase that consisted of 65% acetonitrile in water and pumped at a flow rate of 0.50 mL min(-1). The excitation and emission wavelengths were set at 345 and 435 nm, respectively. The assay was linear over a concentration range of 0.05-16.00 microg mL(-1) for nateglinide with a limit of quantitation of 0.05 microg mL(-1). Quality control samples (0.05, 4.50 and 16.00 microg mL(-1)) in five replicates from five different runs of analysis demonstrated intra-assay precision (%coefficient of variation <6.8%), inter-assay precision (%coefficient of variation <1.6%) and an overall accuracy (%relative error) less than -3.4%. The method can be used to quantify nateglinide in human plasma covering a variety of pharmacokinetic or bioequivalence studies.
