A novel achiral seco-cyclopropylpyrido[e]indolone (CPyI) analog of CC-1065 and the duocarmycins: Synthesis, DNA interactions, in vivo anticancer and anti-parasitic evaluation

被引：12

作者：

Chavda, Sameer ^{[1
]}

Babu, Balaji ^{[1
]}

Yanow, Stephanie K. ^{[2
,3
]}

Jardim, Armando ^{[3
]}

Spithill, Terry W. ^{[3
,4
]}

Kiakos, Konstantinos ^{[5
]}

Kluza, Jerome ^{[5
]}

Hartley, John A. ^{[5
]}

Lee, Moses ^{[1
,6
]}

机构：

[1] Hope Coll, Div Nat Sci, Holland, MI 49423 USA

[2] Univ Alberta, Dept Publ Hlth Sci, Edmonton, AB T6G 2J2, Canada

[3] Inst Parasitol, Ste Ann De Bellevue, PQ HX9 3V9, Canada

[4] Charles Sturt Univ, Sch Anim & Vet Sci, Wagga Wagga, NSW 2678, Australia

[5] UCL, UCL Canc Inst, London WC1E 6BT, England

[6] Furman Univ, Dept Chem, Greenville, SC 29613 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 14期

基金：

美国国家科学基金会;

关键词：

Duocarmycins; Centanamycin; Achiral; Minor groove; DNA; Alkylation; Adenine-N3; Anticancer; Anti-parasite; Antimalaria; Antitrypanosoma; Antileishmania; CHEMICAL SOLVOLYTIC STABILITY; ANTITUMOR ANTIBIOTIC CC-1065; ALKYLATING AGENT; PHASE-II; BIOLOGICAL EVALUATION; GENOME SEQUENCE; CBI ANALOGS; ADOZELESIN; CYTOTOXICITY; CARZELESIN;

D O I：

10.1016/j.bmc.2010.05.078

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5016 / 5024

页数：9

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