Antineoplastic agents 442. Synthesis and biological activities of dioxostatin.
A high-yield regioselective synthesis of (E)-combretastatin A-1 2b was completed using methoxymethyl (MOM) protection and a Wadsworth-Emmons reaction as key steps. In turn, (E)-stilbene 11 was converted by convenient syntheses to both (S,S)- and (R,R)-1,3-dioxolanes 5a and 6a. A Sharpless asymmetric dihydroxylation reaction was employed for preparation of intermediates (S,S)-12 and (R,R)-13. The (4S,5S)-4-(2',3'-dihydroxy4'-methoxyphenyl)-5-(3",4",5"-trimethoxyphenyl)-1, 3-dioxolane 5a was found to be a highly potent inhibitor of microtubule assembly (IC50 = 0.59 microM) and was designated dioxostatin. Conversion to sodium phosphate 17 (P388 lymphocytic leukemia cell line: ED50 = 0.2 microg/ml) provided a very useful water-soluble prodrug.
Pettit
G R
GR
Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-2404, USA.
Lippert
J W
JW
Boyd
M R
MR
Verdier-Pinard
P
P
Hamel
E
E
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000187:drug effects; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D013267:Stilbenes; C427163:dioxostatin