9-substituted acridine derivatives with long half-life and potent antitumor activity: Synthesis and structure-activity relationships Journal Article
| Authors: | Su, T. L.; Chou, T. C.; Kim, J. Y.; Huang, J. T.; Ciszewska, G.; Ren, W. Y.; Otter, G. M.; Sirotnak, F. M.; Watanabe, K. A. |
| Article Title: | 9-substituted acridine derivatives with long half-life and potent antitumor activity: Synthesis and structure-activity relationships |
| Abstract: | A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)-acridines, and 9-(3′,5′-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3′,5′-disubstituted anilino)-acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD × 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed. © 1995, American Chemical Society. All rights reserved. |
| Keywords: | controlled study; leukemia; unclassified drug; drug efficacy; nonhuman; antineoplastic agents; antineoplastic agent; animal cell; mouse; animal; mice; animal tissue; cell division; melanoma; etoposide; animal model; antineoplastic activity; drug potency; drug screening assays, antitumor; tumor cells, cultured; drug synthesis; structure-activity relationship; magnetic resonance spectroscopy; lung carcinoma; 9 anilinoacridine derivative; amsacrine; drug half life; breast adenocarcinoma; dna topoisomerase (atp hydrolysing); acridines; half-life; dna topoisomerases, type ii; gyrase inhibitor; drug dna binding; aerobic metabolism; intraperitoneal drug administration; subcutaneous drug administration; human; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; 3 (9 acridinylamino) 5 (hydroxymethyl)aniline; asulacrine isethionate; intercalating agent |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 38 |
| Issue: | 17 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1995-08-01 |
| Start Page: | 3226 |
| End Page: | 3235 |
| Language: | English |
| DOI: | 10.1021/jm00017a006 |
| PUBMED: | 7650675 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 28 August 2018 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work