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

DOI

10.1016/j.bmcl.2017.02.018

Document Type

Journal Article

Publication Date

1-1-2017

Publication Title

Bioorganic and Medicinal Chemistry Letters

Volume

27

Issue

7

First Page

1602

Last Page

1607

ISSN

0960894X

Keywords

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

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.

Open Access

Green Accepted

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