Antineoplastic agents 460. Synthesis of combretastatin A-2 prodrugs.
The original synthesis of combretastatin A-2 (1a) was modified to provide an efficient scale-up procedure for obtaining this antineoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by phosphorylation employing in situ formation of dibenzylchlorophosphite followed by cleavage of the benzyl ester protective groups with bromotrimethylsilane to afford the phosphoric acid intermediate 11. The latter was immediately treated with sodium methoxide to complete a practical route to the disodium phosphate prodrug (2a). The phosphoric acid precursor (11) of phosphate 2a was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts (2a-q) was evaluated with respect to relative solubility behavior, cancer cell growth inhibition and antimicrobial activity.
Pettit
G R
GR
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-2404, USA.
Moser
B R
BR
Boyd
M R
MR
Schmidt
J M
JM
Pettit
R K
RK
Chapuis
J C
JC
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007201:Indicator Dilution Techniques; D007202:Indicators and Reagents; D007536:Isomerism; D008826:Microbial Sensitivity Tests; D009369:Neoplasms / Q000378:metabolism; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013267:Stilbenes; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D007202:Indicators and Reagents; D010710:Phosphates; D011355:Prodrugs; D013267:Stilbenes; C040105:combretastatin