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
Preprint
Repository Citation
Zaware, N., Kisliuk, R., Bastian, A., Ihnat, M., & Gangjee, A. (2017). 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. Bioorganic and Medicinal Chemistry Letters, 27 (7), 1602-1607. https://doi.org/10.1016/j.bmcl.2017.02.018