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

被引:33
作者
Atwell, GJ [1 ]
Milbank, JJB [1 ]
Wilson, WR [1 ]
Hogg, A [1 ]
Denny, WA [1 ]
机构
[1] Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc, Res Ctr, Auckland 1, New Zealand
关键词
D O I
10.1021/jm990136b
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 5-amino-seco-CBI compounds, designed for use as effecters 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 (IC50 1.3 nM in AA8 cells, 4 h exposure), comparable to that of the parent CBI-TMI (5',6',7'-trimethoxyindole) derivative (IC50 0.46 nM in the above assay). A subset of solubilized derivatives bearing O(CH2)(2)NMe2 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 (IC50 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.
引用
收藏
页码:3400 / 3411
页数:12
相关论文
共 33 条
[1]   Synthesis and cytotoxicity of amino analogues of the potent DNA alkylating agent seco-CBI-TMI [J].
Atwell, GJ ;
Wilson, WR ;
Denny, WA .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (12) :1493-1496
[2]   Synthesis and cytotoxicity of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (amino-seco-CBI-TMI) and related 5-alkylamino analogues:: New DNA minor groove alkylating agents [J].
Atwell, GJ ;
Tercel, M ;
Boyd, M ;
Wilson, WR ;
Denny, WA .
JOURNAL OF ORGANIC CHEMISTRY, 1998, 63 (25) :9414-9420
[3]   SYNTHESIS OF N-(TERT-BUTYLOXYCARBONYL)-CBI, CBI, CBI-CDPI1, AND CBI-CDPI2 - ENHANCED FUNCTIONAL ANALOGS OF CC-1065 INCORPORATING THE 1,2,9,9A-TETRAHYDROCYCLOPROPA[C]BENZ[E]INDOL-4-ONE (CBI) LEFT-HAND SUBUNIT [J].
BOGER, DL ;
ISHIZAKI, T ;
KITOS, PA ;
SUNTORNWAT, O .
JOURNAL OF ORGANIC CHEMISTRY, 1990, 55 (23) :5823-5832
[4]   (+)- AND ENT-(-)-DUOCARMYCIN SA AND (+)- AND ENT-(-)-N-BOC-DSA DNA ALKYLATION PROPERTIES - ALKYLATION SITE MODELS THAT ACCOMMODATE THE OFFSET AT-RICH ADENINE N3 ALKYLATION SELECTIVITY OF THE ENANTIOMERIC AGENTS [J].
BOGER, DL ;
JOHNSON, DS ;
YUN, WY .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1994, 116 (05) :1635-1656
[5]   Examination of the role of the duocarmycin SA methoxy substituents: Identification of the minimum, fully potent DNA binding subunit [J].
Boger, DL ;
Bollinger, B ;
Johnson, DS .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (18) :2207-2210
[6]   CBI-TMI - SYNTHESIS AND EVALUATION OF A KEY ANALOG OF THE DUOCARMYCINS - VALIDATION OF A DIRECT RELATIONSHIP BETWEEN CHEMICAL SOLVOLYTIC STABILITY AND CYTOTOXIC POTENCY AND CONFIRMATION OF THE STRUCTURAL FEATURES RESPONSIBLE FOR THE DISTINGUISHING BEHAVIOR OF ENANTIOMERIC PAIRS OF AGENTS [J].
BOGER, DL ;
YUN, WY .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1994, 116 (18) :7996-8006
[7]   Duocarmycin SA shortened, simplified, and extended agents: A systematic examination of the role of the DNA binding subunit [J].
Boger, DL ;
Hertzog, DL ;
Bollinger, B ;
Johnson, DS ;
Cai, H ;
Goldberg, J ;
Turnbull, P .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1997, 119 (21) :4977-4986
[8]   1,2,9,9A-TETRAHYDROCYCLOPROPA[C]BENZ[E]INDOL-4-ONE (CBI) ANALOGS OF CC-1065 AND THE DUOCARMYCINS - SYNTHESIS AND EVALUATION [J].
BOGER, DL ;
YUN, WY ;
HAN, NH .
BIOORGANIC & MEDICINAL CHEMISTRY, 1995, 3 (11) :1429-1453
[9]   CC-1065 and the duocarmycins: Understanding their biological function through mechanistic studies [J].
Boger, DL ;
Johnson, DS .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 1996, 35 (13-14) :1438-1474
[10]   Phase I study with the DNA sequence-specific: Agent adozelesin [J].
Burris, HA ;
Dieras, V ;
Tunca, M ;
Earhart, RH ;
Eckardt, JR ;
Rodriguez, GI ;
Shaffer, DS ;
Fields, SM ;
Campbell, E ;
Schaaf, L ;
Kasunic, D ;
VonHoff, DD .
ANTI-CANCER DRUGS, 1997, 8 (06) :588-596