Novel DNA-directed alkylating agents: Design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker Journal Article
| Authors: | Kapuriya, N.; Kapuriya, K.; Dong, H.; Zhang, X.; Chou, T. C.; Chen, Y. T.; Lee, T. C.; Lee, W. C.; Tsai, T. H.; Naliapara, Y.; Su, T. L. |
| Article Title: | Novel DNA-directed alkylating agents: Design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker |
| Abstract: | 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 IC<sub>50</sub> 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 MX-1 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. © 2008 Elsevier Ltd. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; cisplatin; drug efficacy; nonhuman; paclitaxel; neoplasms; mouse; animals; mice; mus; animal experiment; animal model; alkylating agent; antineoplastic activity; cancer cell culture; drug potency; tumor xenograft; drug effect; dose-response relationship, drug; xenograft model antitumor assays; cell line, tumor; drug design; drug synthesis; vinblastine; mus musculus; dna; mice, nude; antineoplastic agents, alkylating; rats; rattus; 9-anilinoacridines; cytotoxic; drug cytotoxicity; pharmacophore; drug half life; tumor; ic 50; inhibitory concentration 50; dna cross linking; dna-directed alkylating agents; phenyl nitrogen mustards; [2 methyl 5 (4 methylacridin 9 ylamino)phenyl]carbamic acid 4 [bis(2 chloroethyl)amino]phenyl ester; [3 (acridin 9 ylamino) 5 hydroxymethylphenyl]carbamic acid 4 [bis(2 chloroethyl)amino]phenyl ester; [3 (acridin 9 ylamino) 5 methoxyphenyl]carbamic acid 4 [bis(2 chloroethyl)amino]phenyl ester; [3 hydroxymethyl 5 (4 methylacridin 9 ylamino)phenyl]carbamic acid 4 [bis(2 chloroethyl)amino]phenyl ester; acridine derivative; carbamic acid; carbonic acid; carbonic acid 3 (acridin 9 ylamino) 5 ethoxycarbonylaminobenzyl ester 4 [bis(2 chloroethyl)amino]phenyl ester; phenyl n mustard 9 anilinoacridine derivative; acridines; carbamates; carbonates; half-life; brassicaceae |
| Journal Title: | Bioorganic & Medicinal Chemistry |
| Volume: | 17 |
| Issue: | 3 |
| ISSN: | 0968-0896 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2009-02-01 |
| Start Page: | 1264 |
| End Page: | 1275 |
| Language: | English |
| DOI: | 10.1016/j.bmc.2008.12.022 |
| PUBMED: | 19124250 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: BMECE" - "Source: Scopus" |
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