title: The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents.
abstract: The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11-13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor β (PDGFR-β), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-β. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both βIII-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Raghavan
authors.affiliation: College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Ihnat
authors.affiliation: College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Thorpe
authors.affiliation: College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Disch
authors.affiliation: College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
authors.forename: Anja
authors.initials: A
authors.lastname: Bastian
authors.affiliation: College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
authors.forename: Lora C
authors.initials: LC
authors.lastname: Bailey-Downs
authors.affiliation: Department of Pharmacology, Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dybdal-Hargreaves
authors.affiliation: Department of Pharmacology, Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Rohena
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Institutes of Health, 1050 Boyles Street, Frederick, MD 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Department of Pharmacology, Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000593983:N-(4-methoxyphenyl)-N,2,6-trimethylfuro(2,3-d)pyrimidin-4-amine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014867:Water; D020794:Receptor Protein-Tyrosine Kinases
keywords: Anticancer agents; Microtubule targeting agents; Single agent combination chemotherapy; Tyrosine kinase inhibitors