Antitumor Agents. VII. Synthesis and Antitumor Activity of Novel Hexacyclic Camptothecin Analogs

Autor:	Hiroaki Tagawa, Akio Ejima, Ikuo Mitsui, K Matsumoto, M Yasuoka, Satoru Ohsuki, Masamichi Sugimori, Keiki Sato, Yasuyoshi Kawato, Kouichi Uoto
Rok vydání:	1994
Předmět:	chemistry.chemical_classification Ketone Bicyclic molecule Stereochemistry Biological activity chemistry.chemical_compound Polycyclic compound chemistry Drug Discovery medicine Lactam Molecular Medicine Structure–activity relationship Lactone Camptothecin medicine.drug
Zdroj:	Journal of Medicinal Chemistry. 37:3033-3039
ISSN:	1520-4804 0022-2623
Popis:	Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedlander condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::313d1d7c7e7d812a76dab192bbc37aa7 https://doi.org/10.1021/jm00045a007 Zobrazit plný text záznamu