title: Direct semi-synthesis of the anticancer lead-drug protoapigenone from apigenin, and synthesis of further new cytotoxic protoflavone derivatives.
abstract: Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1'-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1'-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1'-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1', comparing to that of the non-substituted compound.
authors.affiliation: Institute of Pharmacognosy, University of Szeged, Szeged, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Hunyadi
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Chuang
authors.forename: Balazs
authors.initials: B
authors.lastname: Danko
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Chiang
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Lee
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Wang
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047310:Apigenin / Q000737:chemistry*; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003512:Cyclohexanones; D047309:Flavones; C524112:protoapigenone; D047310:Apigenin