Antineoplastic agents. 548. Synthesis of iodo- and diiodocombstatin phosphate prodrugs.
Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line. Of the diiodo series, 12a was also found to markedly inhibit growth of pediatric neuroblastoma, and monoiodocombstatin 9a strongly inhibited HUVEC growth. Overall, the strongest activity was found against the breast, CNS, leukemia, lung, and prostate cancer cell lines and the least activity against the pancreas and colon lines. Parallel biological investigations of tubulin interaction, antiangiogenesis, and antimicrobial effects were also conducted.
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, United States. bpettit@asu.edu
George R
GR
Pettit
Heidi J
HJ
Rosenberg
Rachel
R
Dixon
John C
JC
Knight
Ernest
E
Hamel
Jean-Charles
JC
Chapuis
Robin K
RK
Pettit
Fiona
F
Hogan
Brandy
B
Sumner
Kenneth B
KB
Ain
Brindi
B
Trickey-Platt
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002648:Child; D004354:Drug Screening Assays, Antitumor; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D006847:Hydrocarbons, Iodinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D006847:Hydrocarbons, Iodinated; D009943:Organophosphorus Compounds; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin