Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Development of 3-(9-Acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives as potential topoisomerase II-mediated anticancer agents

TL Su PhD 1, TC Chou PhD 2

1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, 2 Memorial Sloan-Kettering Cancer Center, New York, NY, USA,

AIMS: Development of potential DNA topoisomerase II mediated anticancer agents, 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives and their alkylcarbamates. METHODS: AHMA were synthesized by the condensation of 9-chloroacridines with 3,5-diaminobenzyl alcohol. Treatment of AHMA with alkyl chloroformates afforded various AHMA-alkylcarbamates, which were then subjected to in vitro and in vivo antitumor evaluation. RESULTS: It revealed that AHMA has greater efficacy against murine leukemia and solid tumors than m-AMSA or VP-16 (currently used to treat cancer patient) and yet is less toxic toward the host. AHMA-alkylcarbamates, in general, are more cytotoxic than their corresponding AHMA parent compounds against human leukemic HL-60 cell growth in culture. Among these compounds, 4'-methyl-AHMA-ethylcarbamate and 5'-methyl-4'-(N,N-dimethylaminoethylcarboxamide)-AHMA-ethylcarbamate are as potent as or more potent than AHMA-ethylcarbamate. AHMA-ethylcarbamate was shown to have potent antitumor efficacy in B6D2F1 mice bearing sarcoma and Lewis lung carcinoma. The antileukemic effects of AHMA and its alkylcarbamates, AHMA-ethylcarbamate and AHMA-tert-butylcarbamate, along with m-AMSA and adriamycin were compared. Percent increase in lifespan (%ILS) were measured in B6D2F1 mice bearing P388 leukemia. The three AHMAs and adriamycin showed potent antileukemic effects whereas m-AMSA had a rather poor anticancer activity. In addition, AHMA-ethylcarbamate and AHMA-tert-butylcarbamate have better therapeutic effects than adriamycin on human xenografts in nude mice bearing MX-1 and MCF-7/Adr tumors. CONCLUSIONS: These studies demonstrate that AHMA-alkylcarbamates have a broad spectrum of antitumor activity and exhibit better therapeutic efficacy than some other anticancer drugs currently used in clinic.

KEY WORDS: 9-anilinoacridine, topoisomerase II inhibitor.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on novel therapies.