Synthesis and In Vitro Antitumor Activity of Novel Ring D Analogues of the Marine Pyridoacridine Ascididemin: Structure−Activity Relationship

• Published in: Journal of medicinal chemistry Vol. 45; no. 17; pp. 3765 - 3771
• Main Authors: Delfourne, Evelyne, Darro, Francis, Portefaix, Philippe, Galaup, Chantal, Bayssade, Sylvie, Bouteillé, Anne, Le Corre, Laurent, Bastide, Jean, Collignon, Françoise, Lesur, Brigitte, Frydman, Armand, Kiss, Robert
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 15.08.2002
• Subjects: Acridines - chemical synthesis; Acridines - pharmacology; Acridines - toxicity; Alkaloids - chemical synthesis; Alkaloids - pharmacology; Alkaloids - toxicity; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Ascidiacea; Biological and medical sciences; Cell Division - drug effects; Drug Screening Assays, Antitumor; General aspects; Humans; Inhibitory Concentration 50; Marine; Medical sciences; Mice; Pharmacology. Drug treatments; Phenanthrolines; Quinolines; Structure-Activity Relationship; Tumor Cells, Cultured; Antineoplastic agent; Pentacyclic compound; Nitro compound; Intraperitoneal administration; Nitrogen heterocycle; Toxicity; Cytotoxicity; Structure activity relation; Chlorine Organic compounds; Bromine Organic compounds; Aromatic compound; Chemical synthesis; Tumor cell; Human; Acute; Rodentia; Ketone; In vitro; Vertebrata; Mammalia; Cell line; Mouse; Animal; Tertiary amine; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0208774

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC50 value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.