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.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cisplatin / pharmacology
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / pharmacology
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Heterocyclic Compounds, 3-Ring / chemical synthesis
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Humans
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Indoles / chemical synthesis
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Indoles / pharmacology*
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Mice
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Pemetrexed / pharmacology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacology*
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Pyrroles / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
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Thymidylate Synthase / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Xenograft Model Antitumor Assays
Substances
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3-(4-dimethylamino-benzylidenyl)-2-indolinone
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Folic Acid Antagonists
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Heterocyclic Compounds, 3-Ring
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Indoles
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Pemetrexed
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Semaxinib
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Thymidylate Synthase
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Receptor Protein-Tyrosine Kinases
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Receptor, Platelet-Derived Growth Factor beta
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Vascular Endothelial Growth Factor Receptor-2
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Cisplatin