Abstract
The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / pathology
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Animals
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Bacterial Proteins / antagonists & inhibitors
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Cell Division / drug effects
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Crystallography, X-Ray
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Drug Design
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Drug Evaluation, Preclinical
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Escherichia coli / enzymology
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Glucuronates / chemical synthesis
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Glucuronates / chemistry
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Glucuronates / pharmacology
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology*
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Leukemia / drug therapy
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Leukemia / pathology
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Leukemia L1210 / drug therapy
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Leukemia L1210 / pathology
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Mice
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Protein Conformation
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology
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Structure-Activity Relationship
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Thymidylate Synthase / antagonists & inhibitors*
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Tumor Cells, Cultured / drug effects
Substances
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Bacterial Proteins
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Glucuronates
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Indoles
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Pyridines
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Thymidylate Synthase