Synthesis and biological evaluation of novel 2,6-diaminobenz[cd]indole inhibitors of thymidylate synthase using the protein structure as a guide.
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.
Varney
M D
MD
Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
Palmer
C L
CL
Deal
J G
JG
Webber
S
S
Welsh
K M
KM
Bartlett
C A
CA
Morse
C A
CA
Smith
W W
WW
Janson
C A
CA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000201:enzymology; D005965:Glucuronates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001426:Bacterial Proteins; D005965:Glucuronates; D007211:Indoles; D011725:Pyridines; D013940:Thymidylate Synthase