Novel DNA-directed alkylating agents: Design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker

被引：26

作者：

Kapuriya, Naval ^{[1
]}

Kapuriya, Kalpana ^{[1
]}

Dong, Huajin ^{[2
]}

Zhang, Xiuguo ^{[2
]}

Chou, Ting-Chao ^{[2
]}

Chen, Yu-Ting ^{[1
]}

Lee, Te-Chang ^{[1
,4
]}

Lee, Wen-Chuan ^{[3
]}

Tsai, Tung-Hu ^{[3
]}

Naliapara, Yogesh ^{[5
]}

Su, Tsann-Long ^{[1
,6
]}

机构：

[1] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, Preclin Pharmacol Core Lab, New York, NY 10021 USA

[3] Natl Yang Ming Univ, Inst Tradit Med, Taipei 112, Taiwan

[4] Natl Res Inst Chinese Med, Taipei 112, Taiwan

[5] Saurashtra Univ, Dept Chem, Rajkot 360005, Gujarat, India

[6] China Med Univ, Grad Inst Pharmaceut Chem, Taichung, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 03期

关键词：

DNA-directed alkylating agents; Cytotoxic; Phenyl nitrogen mustards; 9-Anilinoacridines; PRODRUG THERAPY MDEPT; N-MUSTARD RESIDUE; BIOLOGICAL-ACTIVITY; ANILINE MUSTARDS; NITROGEN MUSTARDS; SEQUENCE SELECTIVITY; CYTOTOXICITY ASSAY; ANTICANCER AGENTS; CELL-LINE; DERIVATIVES;

D O I：

10.1016/j.bmc.2008.12.022

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：

A series of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker was synthesized for antitumor evaluation. The carbamate or carbonate linker is able to lower the reactivity of the phenyl N-mustard pharmacophore and thus, these conjugates are rather chemically stable. The in vitro studies revealed that these derivatives possessed significant cytotoxicity with IC50 in sub-micromolar range in inhibiting human lymphoblastic leukemia (CCRF-CEM), breast carcinoma (MX-1), colon carcinoma (HCT-116) and human non-small cell lung cancer (H1299) cell growth in vitro. Compounds 10a, 10b, 10e, 10i, and 15a were selected for evaluating their antitumor activity in nude mice bearing MX1 and HCT-116 xenografts. Remarkably, total tumor remission was achieved by these agents with only one cycle of treatment. Interestingly, no tumor relapse was found in mice treated with 10a over 129 days. This agent is capable of inducing DNA interstrand cross-linking in human non-small lung cancer H1299 cells in a dose dependent manner by modified comet assay and has a long half-life in rat plasma. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1264 / 1275

页数：12

共 39 条

[1]

[Anonymous], 2005, CompuSyn for drug combinations and for general dose-effect analysis

[2] Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives [J].