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The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents. 2015

Xin Zhang, and Sudhir Raghavan, and Michael Ihnat, and Ernest Hamel, and Cynthia Zammiello, and Anja Bastian, and Susan L Mooberry, and Aleem Gangjee
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.

A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound 1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds 2, 3, 7 and 10 showed microtubule depolymerizing activity comparable to or better than the lead 1, some with nanomolar EC50 values. While compound 8 had no effect on microtubules, 8 and 10 both showed potent RTK inhibition with nanomolar IC50s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog 10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-β). Compound 10 has highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies.

UI MeSH Term Description Entries
D008870 Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein TUBULIN and are influenced by TUBULIN MODULATORS. Microtubule
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D002642 Chick Embryo The developmental entity of a fertilized chicken egg (ZYGOTE). The developmental process begins about 24 h before the egg is laid at the BLASTODISC, a small whitish spot on the surface of the EGG YOLK. After 21 days of incubation, the embryo is fully developed before hatching. Embryo, Chick,Chick Embryos,Embryos, Chick
D005663 Furans Compounds with a 5-membered ring of four carbons and an oxygen. They are aromatic heterocycles. The reduced form is tetrahydrofuran. Tetrahydrofurans
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein

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