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A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties

Kupchinsky, S; Centioni, S; Howard, T; Trzupek, J; Roller, S; Carnahan, V; Townes, H; ... Lee, M; + view all (2004) A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties. Bioorganic and Medicinal Chemistry , 12 (23) pp. 6221-6236.

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Abstract

The synthesis, DNA binding properties, and in vitro and in vivo anticancer activity of fifteen achiral seco-cyclopropylindoline (or achiral seco-CI) analogs (5a-o) of CC-1065 and the duocarmycins are described. The achiral seco-CI analogs contain a 4-hydroxyphenethyl halide moiety that is attached to a wide range of indole, benzimidazole, pyrrole, and pyridyl-containing noncovalent binding components. The 4-hydroxyphenethyl halide moiety represents the simplest mimic of the seco- cyclopropylpyrroloindoline (seco-CPI) pharmacophore found in the natural products, and it lacks a chiral center. The sequence and minor groove specificity of the achiral compounds was ascertained using a Taq DNA polymerase stop assay and a thermal induced DNA cleavage experiment using either a fragment of pBR322 or pUC18 plasmid DNA. For example, seco-CI-InBf (5a) and seco-CI-TMI (5c) demonstrated specificity for AT-rich sequences, particularly by reacting with the underlined adenine-N3 position of 5'-AAAA (A) under bar (865)-3'. This is also the sequence that CC-1065 and adozelesin prefer to alkylate. The achiral seco-CI compounds were subjected to cytotoxicity studies against several human (K562, LS174T, PC3, and MCF-7) and murine cancer cell lines (L 12 10 and P815). Following continuous drug exposure, the achiral compounds were found to be cytotoxic, with IC50 values in the muM range. Interestingly, the carbamate protected compound 5p was significantly less cytotoxic than agent 5c, supporting the hypothesis that loss of HCI and formation of a spiro[2,5]cyclopropylcyclohexadienone intermediate is necessary for biological activity. The achiral seco-CI compounds 5a and 5c were submitted to the National Cancer Institute for further cytotoxicity screening against a panel of 60 different human cancer cell lines. Both compounds showed significant activity, particularly against several solid tumor cell lines. Flow cytometry studies of P815 cells that were incubated with compound 5c at its IC50 concentration for 24 h showed induction of apoptosis in a large percentage of cells. Compounds 5a and 5c were selected by the NCI for an in vivo anticancer hollow- fiber test, and received composite scores of 18 and 22, respectively. These two compounds were subsequently evaluated for in vivo anticancer activity against the growth of a human advanced stage SC UACC-257 melanoma in skid mice. At a dose of 134mg/kg administered IP, compound 5c gave a T/C value of 40% (for day 51), and the median number of days of doubling tumor growth was 27.7, versus 15.8 for untreated animals. For compound 5a, at 200 mg/kg, the T/C was 58% and the median number of days of doubling tumor growth was 20.0 versus 8.7 for untreated animals. At these doses no toxicity or weight loss was observed for either compound. Furthermore, compound 5c was not toxic to murine bone marrow cell growth in culture, at a dose that was toxic for the previously reported seco-CBI (cyclopropylbenzoindoline)-TMI (4). (C) 2004 Elsevier Ltd. All rights reserved

Type: Article
Title: A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties
Additional information: WoS ID: 000225050600018 JournalEnglishArticle68PERGAMON-ELSEVIER SCIENCE LTDABBRUZZESE JL, 1996, P AM ASSOC CANC RES, V37, P165; ALBERTS SR, 1996, P AM ASSOC CANC RES, V37, P393; AMISHIRO N, 2000, BIOORGAN MED CHEM, V8, P381; ARCAMONE FM, 1989, J MED CHEM, V32, P774; ARISTOFF PA, 1992, J ORG CHEM, V57, P6234; ASAI A, 1999, BIOORG MED CHEM LETT, V9, P2995; ATWELL GJ, 1997, BIOORG MED CHEM LETT, V7, P1493; BAIRD R, 1963, J AM CHEM SOC, V85, P567; BARALDI PG, 1997, ANTI-CANCER DRUG DES, V12, P67; BOGER DL, 1995, ACCOUNTS CHEM RES, V28, P20; BOGER DL, 1996, ANGEW CHEM INT EDIT, V35, P1438; BOGER DL, 1996, BIOORG MED CHEM LETT, V6, P659; BOGER DL, 1995, BIOORGAN MED CHEM, V3, P1429; BOGER DL, 1993, BIOORGAN MED CHEM, V1, P27; BOGER DL, 1991, CHEMTRACTS ORG CHEM, V4, P329; BOGER DL, 1994, J AM CHEM SOC, V116, P1635; BOGER DL, 1994, J AM CHEM SOC, V116, P7996; BOGER DL, 1992, J AM CHEM SOC, V114, P9318; BOGER DL, 1990, J AM CHEM SOC, V112, P8961; BOGER DL, 1995, J ORG CHEM, V60, P1271; BOGER DL, 1995, P NATL ACAD SCI USA, V92, P3642; BOGER DL, 1991, TETRAHEDRON, V47, P2661; BOYD MR, 1989, CANCER PRINCIPLES PR, V3, P1; BOYD RB, 1997, ANTICANCER DRUG DEV, P23; BREUSEGEM SY, 2002, J MOL BIOL, V315, P1049; BRYSON TA, 1988, TETRAHEDRON LETT, V29, P2197; BURRIS H, 1992, P AM ASSOC CANC RES, V33, P265; BURRIS HA, 1997, ANTI-CANCER DRUG, V8, P588; CARMICHAEL J, 1987, CANCER RES, V47, P936; COTE S, 1993, ANTI-CANCER DRUG, V4, P327; FLEMING GF, 1994, J NATL CANCER I, V86, P368; FOSTER BJ, 1996, INVEST NEW DRUGS, V13, P321; GOMI K, 1992, JPN J CANCER RES, V83, P113; HANKA LJ, 1978, J ANTIBIOT, V31, P1211; HIGHTOWER RD, 1992, GYNECOL ONCOL, V42, P186; HOLLINGSHEAD MG, 1995, LIFE SCI, V57, P131; HOWARD TT, 2002, BIOORGAN MED CHEM, V10, P2941; HURLEY LH, 1993, MOL ASPECTS ANTICANC, V1, P89; HURLEY LH, 1984, SCIENCE, V226, P843; ICHIMURA M, 1990, J ANTIBIOT, V43, P1037; ICHIMURA M, 1993, ONCOL RES, V5, P165; JENNINGS SA, 2002, HETEROCYCL COMMUN, V7, P7; JONES GB, 1998, ADV DNA SEQUENCE SPE, V3; LI LH, 1992, CANCER RES, V52, P4904; LI LH, 1991, INVEST NEW DRUG, V9, P137; LI LH, 1987, INVEST NEW DRUG, V5, P329; LIN CH, 1992, CHEM RES TOXICOL, V5, P167; MCGOVERN JP, 1983, J ANTIBIOT, V37, P63; MOHAMADI F, 1994, J MED CHEM, V37, P232; NAGAMURA S, 1996, BIOORG MED CHEM LETT, V6, P2147; NEIDLE S, 2001, NAT PROD REP, V18, P291; NIITANI H, 1995, P AM ASSOC CANC RES, V36, P243; PECERE T, 2000, CANCER RES, V60, P2800; PITOT HC, 1999, P AM ASSOC CANC RES, V40, P91; PONTI M, 1991, NUCLEIC ACIDS RES, V19, P2929; REYNOLDS VL, 1985, BIOCHEMISTRY-US, V24, P6228; SKEHAN P, 1990, J NATL CANCER I, V82, P1107; STINSON SC, 1997, CHEM ENG NEWS 0602, P28; VANTELLINGEN O, 1998, CANCER CHEMOTH PHARM, V41, P377; VOLPE DA, 1996, CANCER CHEMOTH PHARM, V39, P143; WALKER DL, 1994, CANCER CHEMOTH PHARM, V34, P317; WANG YQ, 2000, J MED CHEM, V43, P1541; WARPEHOSKI MA, 1992, ADV DNA SEQUENCE SPE, V1, P217; WARPEHOSKI MA, 1988, J MED CHEM, V31, P590; WHITE RH, 1995, BIOORG MED CHEM LETT, V5, P1869; WRASIDLO W, 1994, BIOORG MED CHEM LETT, V4, P631; YASUZAWA T, 1995, CHEM PHARM BULL, V43, P378; YASZAWA T, 1991, J ANTIBIOT, V44, P4451DEC 1870IKOXFORDLee M Furman Univ, Dept Chem, 3300 Poinsett Highway, Greenville, SC 29613 USABIOORGAN MED CHEMTHE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
Keywords: AGENT, ANTITUMOR ANTIBIOTIC CC-1065, ASSAY, BINDING, BIOLOGICAL- ACTIVITY, BONE, C2BI ALKYLATION SUBUNIT, CANCER, CBI-TMI, CC-1065, CELLS, CHEMICAL SOLVOLYTIC STABILITY, CULTURE, cytotoxicity, DESIGN, DNA, DNA alkylation, duocarmycins, FUNCTIONAL ANALOGS, GROWTH, IN-VITRO, IN-VIVO, INTRAVENOUS-INFUSION, PHASE-I, SEQUENCE SPECIFICITY, STREPTOMYCES SP, TOXICITY, TUMOR, VITRO
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/109053
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