A modular synthesis of annonaceous acetogenins.
A synthesis of four Annonaceous acetogenins, asiminocin, asimicin, asimin, and bullanin, by a modular approach from seven fundamental subunits, A-G, is described. The approach employs a central core aldehyde segment, C, to which are appended an aliphatic terminus, A or B, a spacer subunit, D or E, and a butenolide terminus, F or G. Coupling of the A, B, D, and E segments to the core aldehyde unit is effected by highly diastereoselective additions of enantiopure allylic indium or tin reagents. The butenolide termini are attached to the ACD, BCE, or BCD intermediates by means of a Sonogashira coupling. The design of the core, spacer, and termini subunits is such that any of the C30, C10, or C4 natural acetogenins or stereoisomers thereof could be prepared. IC50 values for the four aforementioned acetogenins against H-116 human colon cancer cells were found to be in the 10(-3) to 10(-4) microM range. The IC90 activities were ca. 10(-3) microM for asimicin and asimin but only 0.1-1 microM for bullanin and asiminocin.
Marshall
James A
JA
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA. jam5x@virginia.edu
Piettre
Arnaud
A
Paige
Mikell A
MA
Valeriote
Frederick
F
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D003110:Colonic Neoplasms; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014961:X-Ray Diffraction
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D007202:Indicators and Reagents; D007783:Lactones; C100552:asiminocin; C061022:bullatacin; C088264:asimin