β′‐Hydroxy‐α,β‐unsaturated ketones: A new pharmacophore for the design of anticancer drugs. Part 2

• Published in: ChemMedChem 2008-11, Vol.3 (11), p.1740-1747
• Main Authors: León, Leticia G., Carballo, Rubén M., Vega‐Hernández, María C., Miranda, Pedro O., Martín, Víctor S., Padrón, Juan I., Padrón, José M.
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Annexin A5 - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; antitumor agents; apoptosis; Apoptosis - drug effects; Cell Cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Pharmaceutical - methods; Chlorides; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Ferric Compounds - chemistry; Humans; iron(III) chloride; Ketones - chemistry; Ketones - pharmacology; Models, Chemical; structure–activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200800212

Novel antiproliferative β′‐acyloxy‐α,β‐unsaturated ketones were obtained by means of an iron(III)‐catalyzed multicomponent domino process (ABB′ 3CR). The most active derivatives displayed GI50 values in the range of 0.5–3.9 μM against a panel of representative human solid tumor cell lines: A2780, SW1573, HBL‐100, T‐47D and WiDr. Analysis of cells following 24 h exposure to these drugs showed cell cycle arrest in the S and G2/M phase, in a dose‐dependent manner. Our data indicate that the β′‐acyloxy‐α,β‐unsaturated ketones cause permanent damage to the cells and induce apoptosis. An iron(III)‐catalyzed multicomponent domino process is the key step in the synthesis of β′‐acyloxy‐α,β‐unsaturated ketones. These novel compounds arrest the cell cycle and trigger apoptosis by irreparably damaging cancer cells. The biological activity of these compounds seem parallel to those observed with the antitumor natural product, persin.