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

[Display omitted] •Discovered a new class of single agents for cancer chemotherapy.•Compounds are highly potent inhibitors of tubulin and angiogenesis pathway.•Optimized Ullmann coupling, a key step in the synthesis of target compounds.•Compound 1 showed efficacy in human renal (A498) xenograft mode...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-10, Vol.28 (18), p.3085-3093
Main Authors: Devambatla, Ravi Kumar Vyas, Choudhary, Shruti, Ihnat, Michael, Hamel, Ernest, Mooberry, Susan L., Gangjee, Aleem
Format: Article
Language:English
Subjects:
Angiogenesis
Combination chemotherapy
Furo[2,3-d]pyrimidines
Structure-activity relationships
Tubulin inhibitors
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Summary:[Display omitted] •Discovered a new class of single agents for cancer chemotherapy.•Compounds are highly potent inhibitors of tubulin and angiogenesis pathway.•Optimized Ullmann coupling, a key step in the synthesis of target compounds.•Compound 1 showed efficacy in human renal (A498) xenograft model in mice. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.07.039