Synthesis and Cytotoxic Activity of Benzo[a]pyrano[3,2-h] and [2,3-i]xanthone Analogues of Psorospermine, Acronycine, and Benzo[a]acronycine

• Published in: Chemical & pharmaceutical bulletin Vol. 54; no. 8; pp. 1113 - 1118
• Main Authors: Sittisombut, Chavalit, Boutefnouchet, Sabrina, Van-Dufat, Hanh Trinh, Tian, Wen, Michel, Sylvie, Koch, Michel, Tillequin, François, Pfeiffer, Bruno, Pierré, Alain
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-08-2006; Japan Science and Technology Agency
• Subjects: Acronine - analogs & derivatives; Acronine - chemical synthesis; Acronine - chemistry; Acronine - pharmacology; acronycine; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzo(a)pyrene - analogs & derivatives; Benzo(a)pyrene - chemistry; Benzo(a)pyrene - pharmacology; benzopyranoxanthone; Cell Line, Tumor; Cell Proliferation - drug effects; cytotoxicity; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mice; Molecular Structure; synthesis; Xanthones - chemical synthesis; Xanthones - chemistry; Xanthones - pharmacology
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.54.1113

Condensation of 2-hydroxy-1-naphthalenecarboxylic acid with phloroglucinol afforded 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6). Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to 6-hydroxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (12) and 5-hydroxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (13), which were methylated into 6-methoxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (14) and 5-methoxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (15), respectively. Osmium tetroxide oxidation of 14 and 15 gave the corresponding (±)-cis-diols 16 and 17, which afforded the corresponding esters 18—21 upon acylation. Similarly, condensation of 2-hydroxy-1-naphthalenecarboxylic acid with 3,5-dimethoxyaniline gave 11-amino-9-methoxy-12H-benzo[a]xanthen-12-one (23) which was converted into 11-amino-9-hydroxy-12H-benzo[a]xanthen-12-one (24) upon treatment with hydrogen bromide in acetic acid. Alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement afforded 6-amino-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (25) and 5-amino-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (26). The new benzopyranoxanthone derivatives only displayed marginal antiproliferative activity when tested against L1210 and KB-3-1 cell lines. The only compounds found significantly active against L1210 cell line, 16 and 20, belong to the benzo[a]pyrano[3,2-h]xanthen-7-one series, which possess a pyran ring fused angularly onto the xanthone basic core.