arcyriaflavin-a and Leukemia-P388

Topics: Actinobacteria; Alkaloids; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Coculture Techniques; Leukemia P388; Mice; Streptomyces

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Bacillus cereus; Carbazoles; Escherichia coli; Indoles; Leukemia P388; Mice; Microbial Sensitivity Tests; Protein Kinase C; Streptococcus; Topoisomerase I Inhibitors; Tumor Cells, Cultured

Staurosporine aglycone (K252-c) (compound 1) and arcyriaflavin A (2) were isolated from a specimen of the marine ascidian, Eudistoma sp., collected off the coast of West Africa. In addition to expressing micromolar and submicromolar inhibition of enzyme activity against seven protein kinase C isoenzymes and inhibition of proliferation of the human lung cancer A549 and P388 murine leukemia cell lines, 1 also inhibited cell adhesion of the EL-4.IL-2 cell line and expressed activity in the K562 bleb and neutrophil assays.

Topics: Africa, Western; Animals; Antineoplastic Agents; Carbazoles; Cell Adhesion; Cell Division; Humans; Indole Alkaloids; Isoenzymes; Leukemia P388; Lung Neoplasms; Mice; Protein Kinase C; Tumor Cells, Cultured; Urochordata