5-Amino-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indoles: relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits.
A series of 5-amino-seco-CBI compounds, designed for use as effectors for prodrugs, were prepared to study structure-activity relationships for the cytotoxicity of side chain analogues. Compounds were prepared by coupling 1-(chloromethyl)-5-nitro-1, 2-dihydro-3H-benz[e]indole to appropriate carboxylic acids, followed by nitro group reduction, or by coupling suitable 5-amino-protected indolines to alpha,beta-unsaturated acids, followed by deblocking. These AT-specific DNA alkylating agents were evaluated for cytotoxicity in a series of tumor cell lines (AA8, UV4, EMT6, SKOV3). For those analogues bearing an indolecarbonyl side chain, the 5'-methoxy derivative was the most cytotoxic (IC(50) 1.3 nM in AA8 cells, 4 h exposure), comparable to that of the parent CBI-TMI (5', 6',7'-trimethoxyindole) derivative (IC(50) 0.46 nM in the above assay). A subset of solubilized derivatives bearing O(CH(2))(2)NMe(2) substituents were about 10-fold less potent. For compounds containing an acryloyl linker in the side chain, the 4'-methoxycinnamoyl derivative proved the most cytotoxic (IC(50) 0. 09 nM in the above assay). A number of these 5-amino-seco-CBI-TMI analogues (including the solubilized compounds) are of interest both as cytotoxins and as components of amine-based prodrugs designed for tumor-specific activation.
Atwell
G J
GJ
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Milbank
J J
JJ
Wilson
W R
WR
Hogg
A
A
Denny
W A
WA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D007211:Indoles; D004247:DNA