Total synthesis of 12-methoxydihydrochelerythrine and anti-tumour activity of its quaternary base: toward an efficient synthetic route for 12-alkoxybenzo[c]phenanthridine bases via naphthoquinone monooxime from 2-benzofuranyl-1-tetralone derivative.
A concise total synthesis of 12-methoxydihydrochelerythrine (6), isolated from Bocconia integrifolia, is described. The synthesis features an efficient route to a 12-alkoxybenzo[c]phenanthridine skeleton via naphthoquinone monooxime 11 as a key compound. Starting from 7-methoxy-2-methylbenzo[b]furan (9), 3-aryl-1-tetralone 10 was synthesised, followed by aromatisation to 3-aryl-1-naphthol 17. After oxidative cleavage of the furan ring, basic nitrosation of naphthol 22 gave the naphthoquinone 11. The benzo[c]phenanthridine skeleton was formed by reductive cyclisation of 11. Deoxygenation of the lactam moiety in 23 afforded nor-base 32 and methylation of 32 under reductive conditions gave the target dihydro base 6 (23 steps from benzofuran 9 in 10% overall yield). The corresponding quaternary base 7 showed moderate anti-tumour activity against cancer cell lines; on NCI-H460: IC50 4.5 microM and on MDA-MB-231: IC50 1.2 microM. Introduction of a methoxy group into the 12-position of the benzo[c]phenanthridine skeleton could cause enhanced activity against MDA-MB-231 by comparison of 7 with chelerythrine (35) (IC50 5.3 microM).
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry*; D053119:Benzophenanthridines; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry*; D010091:Oximes / Q000737:chemistry*; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000494:pharmacology; D044024:Tetralones / Q000737:chemistry*
C483059:12-methoxydihydrochelerythrine; C483061:2-benzofuranyl-1-tetralone; D000970:Antineoplastic Agents; D001572:Benzofurans; D053119:Benzophenanthridines; D009285:Naphthoquinones; D010091:Oximes; D010617:Phenanthridines; D044024:Tetralones; C483060:naphthoquinone monooxime