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Bioorg Med Chem Lett. 2017 Apr 1;27(7):1602-1607. doi: 10.1016/j.bmcl.2017.02.018. Epub 2017 Feb 11.

Synthesis and evaluation of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.

Author information

1
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
2
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, United States.
3
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, United States.
4
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.

Abstract

In an effort to optimize the structural requirements for combined cytostatic and cytotoxic effects in single agents, a series of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines 3-7 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs) as well as thymidylate synthase (TS). The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo/5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate aryl thiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six-step sequence. Biological evaluation of these compounds indicated dual activity in RTKs and human TS (hTS). In the VEGFR-2 assay, compound 5 was equipotent to the standard compound semaxanib and was better than standard TS inhibitor pemetrexed, in the hTS assay. Compounds 3, 6 and 7 were nanomolar inhibitors of hTS and were several fold better than pemetrexed.

KEYWORDS:

Antiangiogenic agents; Combination chemotherapeutic potential in single agents; Multiple receptor tyrosine kinase inhibitors; Pyrimido[4,5-b]indole synthesis; Thymidylate synthase inhibitors

PMID:
28258797
PMCID:
PMC5398096
DOI:
10.1016/j.bmcl.2017.02.018
[Indexed for MEDLINE]
Free PMC Article

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