Bioactive Secondary Metabolite Of Five Marine Actinomycetes

Microorganisms are particularly important sources of innovative drugs and lead compounds,marine microorganisms have complex and unique metabolic pathways and may produce lots of secondary metabolites with novel structures and strong biological activities,these active metabolites provide abundant lead compounds for the development of new drugs.In this thesis,five marine actinomycetes with good antitumor activity were selected for the systematic study of metabolites.The antitumor and kinase inhibitory activities of the obtained compounds were evaluated.Methods such as silica gel column chromatography,high performance preparative liquid chromatography and Sephadex LH-20 chromatography were used for the separation and purification of the culture extracts.Spectroscopic techniques were used for stru ctural identification of the isolated compounds.76 compounds were isolated and identified from 5 marine streptomyces,including 19 new compounds which were nine staurosporine derivatives streptocarbazoles C(1),3’-epi-K252d(2),2’,4’-epi-K252d(3),7-oxo-holyrine A(16),4’-N-formyl-7-oxo-holyrine A(17),3’-(hydroxyl(oxiran-2-yl)methoxy)-holyrine A(18),3’-epi-5’-methoxy-K252d(19),7-oxo-MLR-52(20),7-oxo-K252b(21);a new type of medermycins purmedermycin A(35)and purmedermycin B(36),three new medermycin compounds lactoquinomycin C-E(37,38,64);two new angucyclinone derivatives gephyyamycin(54)and cysrabelomycin(55);three new napthopyrrdediones nitroquinomycin A-C(61-63).The antitumor,antibacterial and kinase inhibition activities of the compounds were evaluated.Compounds 22 and 39 exhibited significant cytotoxicity against PC-3 cell lines with IC50 values of 0.06 and 0.02 μM,respectively;compounds 2 and 3 show moderate inhibitory activity against PC-3 cell with IC50 values of 9.7 and 6.8μM,respectively.Additionally,they were also tested for enzyme inhibition activities of Protein Kinase C and Brution Tyrosine Kinase,and showed moderate activity with IC50 values of 0.25～1.91 μM;compounds 35 and 36 showed moderate inhibitory activity against PC-3 cells and HCT-116 cells,with IC50 ranging from 1.33 μM to 7.33 μM;compounds 63 and 64 showed moderate inhibitory activity against ovarian cancer A2789 cells,with IC50 of 4.77 and 2.92 μM,respectively.The target strain was fermented by rice solid medium,and some new secondary metabolites were found from conventional microorganisms,indicating that changing the culture medium was an effective way to discover marine active metabolites,and some new secondary metabolites might also be produced by using conventional microorganisms.