| Cursusones A-D is a kind of natural diterpenoids with anticancer activity whitch are isolated from jatropha curcas.Natural anticancer drugs can induce apoptosis,and inhibit proliferation of cancer cells proliferation,and but they also have certainshow toxicity to on normal cells.In some studies,Curcusones A-D were modified by chemical reaction,and the anticancer activity of a series ofthe obtained compounds was not significantly improved.Therefore,it is necessary to find a new structural modification method for diterpenoids.Some difficult modification sites and groups which are difficult to be modified by chemical reaction can be modified by bioconversion.Moreover,the environmentcondition of biological transformation is relatively mild,and thus the complex structure of natural drugs and their active parts can be well preserved in the process of modification.In this paper,the feasibility of transforming Curcusones A-D series compounds by microbial transformation was explored,and the transformation mechanism was preliminarily explored.The main study results as follows:1.Ten commonly used diterpene transformation strains and 88 wild bacteria collected in the field were selected for to transformation study with Curcusones A/B and Curcusones C/D as substrates.Five strains of wild bacteria with transformation activity to on Curcusones A/B were obtained,one of which was a terrestrial microorganism and the other four were Marine microorganisms.The five microorgaanism were identified by morphology and molecular biology way,and strain S622 was a new strain.Strains L21 and S231 are Alternaria sp..Strains S413 and S611 are Cladosporium sp..None of the strains screened by the experiment had any transformation activity against Curcusones C/D.2.Two new compounds,Curcusone A1(1)and Curcusone A2(2),were obtained by selectingusing the bacterium L21,with which showed the best transformation effect to on transform Curcusones A/B,and the The transformation route was speculated to be Curcusones A/B ? 1 ? 2,in which the conversion yield ofcompound 2 and compound 1 was were about 5.9% and that of compound 1 was0.46%,respectively.The experimental antitumor activity results of the transformed products showed that compounds 1 and 2 had a weak inhibitory effect on Hep G-2 the hepg-2 and MCF-7Mc F-7 cell lines at the dose of 20 ?M,and the epoxy modification activity of the c-ring terminal double bond was significantly improved the antitumor activity.3.The whole genome sequencing analysis results on 622 strains L21 and 622,found the conversion related enzymes.the The 5-carbonyl in the B ring of substrate Cursusones A/B B ring was reducted to hydroxyl group under the action of a keto reductase C5 ketone group on the reduction of hydroxyl,and the C6-C7 double bond at C6-C7 was also reducted toreduction reaction happened also generate product 1,the terminal double bond at C15-C16 in the C ring of compound 1 was oxidized under the effect of P450 enzyme,which produced compound 2 catalysis the C ring C15-2 C16 a double bond at the end of epoxidation.The modification of natural products by microbial transformation is an important means to improve the biological activity of natural products and to discover new compounds.Marine microorganisms are significant both in the development of new drugs and the discovery of new strains. |
PDF Full Text Request