| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
In order to develop new antitumor agents, we have searched for antitumor an or cytotoxrc metabolites from varieties of microorganisms separated from marine alga and animals, and the results are as follows
1. Isolation and struclure determination
(1) The following twenty-five new compounds were isolated from varieties of microorganisms and their stereostructures were determined ; gymnastatins L-N and P-U, gymnasterone G, dankasterone B, halodelides A-C, pioletins A and B, anthocolorins G and H, penochalasins D-H, halichoblelide A, and seco-macrosphlide E
(2) The absolute stereostructures of macrosphelides C and E-H, previously undetermined, were established
2.Evaluation of biological activity
(1) All the above-mentioned compounds except for gymnastatins L-N and seco-macrosphelide E exhibited cytotoxic activities against cultured P388 cells. Among them, halichoblelide A and gymnastatins S-U showed potent activities
(2) Halichoblelide A, and leptosin M and gymnastatin I, isolated previously, ex
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hibited appreciable cytotoxic activities against the 39 human cancer cell lines, and evaluation of the pattern of differential cytotoxlclty using the COMPARE program suggested the possibility that the mode of their action might be different from that show by any other anticancer drug developed to date. Moreover, leptosin M inhibited protein kinases and topoisomerase II, and gymnastatin I showed inhibitory activities against protein kinases and tublines.
(3) Macrosphelides E-H, L and their two derivatives were found to inhibit the adhesion of human-leukemia HL-60 cells to HUVEC.
3. Synthesis and structure-activity relationship studies of gymnastatin I analogues
A lot of analogues of gymnastatin I, which exhibited appreciable cytotoxic activities against the 39 human cancer cell lines, and inhibitory activities against protein kinases, topoisomerase and tubulins, were synthesized. Bioiogical evaluation of synthetic analogues suggested important functional groups for the expression of these inhibitory activities. Less
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