Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential

Ravi Kumar Vyas Devambatla; Shruti Choudhary; Michael Ihnat; Ernest Hamel; Susan L Mooberry; Aleem Gangjee

doi:10.1016/j.bmcl.2018.07.039

Design, synthesis and preclinical evaluation of 5-methyl-N⁴-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential

Bioorg Med Chem Lett. 2018 Oct 1;28(18):3085-3093. doi: 10.1016/j.bmcl.2018.07.039. Epub 2018 Jul 27.

Authors

Ravi Kumar Vyas Devambatla¹, Shruti Choudhary¹, Michael Ihnat², Ernest Hamel³, Susan L Mooberry⁴, Aleem Gangjee⁵

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, 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, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States.
⁴ Department of Pharmacology, Mays Cancer 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.
⁵ 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: 30098869
DOI: 10.1016/j.bmcl.2018.07.039

Abstract

The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6-10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6-10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3-10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4-11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.

Keywords: Angiogenesis; Combination chemotherapy; Furo[2,3-d]pyrimidines; Structure-activity relationships; Tubulin inhibitors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Mice
Molecular Docking Simulation
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor beta / metabolism
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
EGFR protein, human
ErbB Receptors
Receptor, Platelet-Derived Growth Factor beta
Vascular Endothelial Growth Factor Receptor-2