2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2015 May 15;23(10):2408-23. doi: 10.1016/j.bmc.2015.03.061.
Xin Zhang 1,  Sudhir Raghavan 1,  Michael Ihnat 2,  Ernest Hamel 3,  Cynthia Zammiello 4,  Anja Bastian 2,  Susan L Mooberry 5,  Aleem Gangjee 6
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
  • 2 College of Pharmacy, Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
  • 3 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States.
  • 4 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.
  • 5 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. Electronic address: mooberry@uthscsa.edu.
  • 6 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.
PMID: 25882519 DOI: 10.1016/j.bmc.2015.03.061
Abstract

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/KDR/Flk-1 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.

Keywords

Antitubulin; Conformation restriction; Multitargeted inhibitors; Receptor tyrosine kinase inhibitors; Synthesis.

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