Synthesis and evaluation of new 6-amino-substituted benzo[c]phenanthridine derivatives.
Different 7,8,9,10-tetrahydrobenzo[c]phenanthridin-6(5H)-ones (10a-e) were prepared by using a one-pot procedure which includes the preparation of various 6- and 7-alkoxy-1-naphthylisocyanates from 1-naphthylamines and triphosgene, followed by addition of 1-N-morpholino-1-cyclohexenes, and cyclization of the resulting amides upon heating in the presence of hydrogen chloride. Subsequent aromatization, chlorination, and substitution with (dimethylamino)alkylamines, followed by a demethylation or a selective desisopropylation, allowed us to synthesize the derivatives 6a-i and 7a-h bearing a [(dimethylamino)alkyl]amino side chain at their 6-position. These compounds, as the other analogs 5a-b, were devised to further study the structure-activity relationships in the benzo[c]phenanthridine family of antitumor alkaloids led by fagaronine (1a) and nitidine (1b). Topoisomerases I and II cleavable complex assay and evaluation of the cytotoxicity and antitumor properties were performed. In vitro cytotoxicity (L1210 and Calc 18) shows a relationship between the cytotoxicity of these compounds and their topoisomerase poisoning properties. However, all these compounds were devoid of significant antitumor effect on the P388 murine leukemia system.
Janin
Y L
YL
URA 1387 CNRS, Institut Curie, Section de Biologie, Orsay, France.
Croisy
A
A
Riou
J F
JF
Bisagni
E
E
D000230:Adenocarcinoma / Q000188:drug therapy; D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D053119:Benzophenanthridines; D001943:Breast Neoplasms / Q000188:drug therapy; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D010617:Phenanthridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C002066:fagaronine; C013615:nitidine