| Natural product is an important source of lead compound,and has its unique pharmacological properties on some human diseases.However,most natural products have many disadvantages such as strong side effects,poor water solubility,poor active selectivity and unstable metabolism,and do not posses the druggability.Therefore,structure modification of natural products to improve their druggability,by elimination of unnecessary functional groups,introduction of the target groups and modification of metabolic site etc.,could provide much more choices in lead compound development.Cytochalasin is a type of natural product with heterozygous skeleton of poly-ketone and amino acid,produced by fungi such as Phomopsis sp.,Chaetomium sp.and Aspergilinia sp.As a potential lead compound,cytochalasin compounds have been attracting much more attentions because of its diverse pharmacological activities,such as anti-tumor,immunosuppressive,nerve cell protection and so on.Chaetoglobosin F was a cytochalasin compound isolated from the culture of endophytic C.globosum in Imperata cylindrica.Previous studies had found that Chaetoglobosin F possessed antitumor,antivirus and neuroprotective activity etc.Therefore,in order to obtain more derivatives of Chaetoglobosin F to enrich the cytochalasin compounds library and providing more precursors for developing new drug,structure modification of Chaetoglobosin F was conducted in this dissertation.Different types of chemical reactions were adopted for structural modification of Chaetoglobosin F according to its structural characteristic.Reactions involved in this dissertation are:oxygen alkylation,acetylation,halogenation,elimination and esterification at C-20 hydroxyl group,C-19/20 hydrolysis reaction,oxidation reaction of C-20 hydroxyl and C-13/14 double bond individually,C-13/14 and C-17/18 double bond olefin metathesis,C-19/23 carbonyl reduction,and so on.Ten chemical reactions were successfully carried out in the experiment accompanied with LC-MS analysis,to afford 10 derivatives.Derivative 1 was obtained by m-CPBA oxidation at C-2’/3’ double bond of indole ring.Derivative 2,a C-6/7 epoxide opening and C-2’/5’ dibrominated product,was obtained by NBS bromination reaction.Derivative 3 was obtained by the oxidation of(C2H5)3O+SbCl6-through C-6/7 epoxide rearrangement and C-20 hydroxyl oxidation.Derivative 4 was obtained through 1’/2 nitrogen methylation by Mel.The HWE alkylation reaction for C-20 carbon chain extension provided Derivative 5.The Petasis’s reagent reaction and the HG-Ⅱ catalyst reaction both got the oxidation product,Derivative 6 and 7,of C-20 hydroxyl group.Derivatives 8 and 9 were derived by the NaBH4 reduction reaction at C-19/23 carbonyl group and the single crystal of 9 were obtained successfully.Derivative 10,a double bond reduction product,was obtained by Pd/C hydrogenation reaction.The reaction of benzyl isocyanate provided a C-20 hydroxyl esterified derivative 11.All derivatives were confirmed through HR-ESI-MS,1D-and 2D-NMR,X-ray single crystal diffraction;and literature comparison and structural novelty search were carried out by SciFinder database.Derivatives 1-5 and 8-11 were identified as new compounds,and derivatives 6 and 7 was identified as known Chaetoglobosin C.Inhibitory activity of compounds 1,2,3,4,5,6,8 and 9 to acetylcholinesterase was measured by the improved Ellman’s method in this dissertation,and tacrine was used as a positive control drug.Under the concentration of 100 μg/mL,compounds 1,2,3,4,5,6,8 and 9 showed inhibitory effect to AChE to some extent with inhibition rates of 35.23%,15.42%,25.53%,14.04%,17.96%,35.34%,24.17%and33.23%,respectively.Positive control tacrine inhibited AChE significantly with an IC50 value of 0.7 μg/mL. |
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