| Objective : In recent years, Securinega alkaloids have become a research highlight of natural product, due to their special structures and potential prospects for pharmacy. Among these compounds securinine and its derivatives have been reported to possess activities such as neurobiological, antineoplastic, differentiation inducing, antimalarial, insecticidal, antimicrobial and antioxidative activities. However, there were few reports on structural modification of securinine up to now, because of the complicated chemical reactivity. This paper makes an exploration on the chemical reactivity of securinine including Michael reaction, [2+2] photochemical cycloaddition, 1,3-dipolar cycloaddition and Baylis-Hillman reaction, which can be offered as a guidance to the relevant structural modification and the activity optimization.The new research finds that the differential level of glioma is closely related to the mutant of IDH. In our previous works, it has been found that the designed flexible dimers and isolated proline ethyl ester conjugate of securinine showed neuroblastoma tumor cells differentiation- inducing activity. According to the relationship among mutant IDH1, securinine derivatives and nerve cell differentiation-inducing activity, this paper focuses on the synthesis of nonflexible dimers and amino acid conjugates of securinine, so as to obtain new compounds with desirable biological activity.Method:(1) Study on chemical reactivity of securinine: In order to explore the reason of the selectivity of photodimerization of securinine, polarity of the solvent, reaction time, concentration of substrate, Gaussian calculation, steric hindrance and reversibility of the photodimerization were investigated. To verify the presence of transannular conjugation and its effect on the reactivity of securinine and norsecurinine, the ultraviolet absorption spectrums of these two compounds were tested.(2) Biomimetic synthesis of the nonflexible dimers of securinine: according to the structural characteristics and biosynthesis of the natural nonflexible Securinega alkaloids dimers, this paper focuses on synthesizing a series of nonflexible dimers of securinine by [2+2] photochemical cycloaddition, 1,3-dipolar cycloaddition and Baylis-Hillman reaction.(3) Structural modification of securinine by introducing esters and amides of amino acids via Michael reaction, so as to obtained a series of amino acid conjugates of securinine.Result:(1) [2+2] photochemical cycloaddition reaction of securinine-type and norsecurinine-type alkaloids produced a single type of anti- head-head dimer with high regioselectivity and stereo selectivity. It is believed that the selective dimer formation is related to the reversible photodimerization, the thermodynamical stability of dimeric products and the complex spatial structure. In addition, the norsecurinine-type alkaloids were more prone to dimerize under photochemical conditions, which might result from the transannular conjugation confirmed in the securinine-type molecules. Conversely, the reactivity of securinine-type alkaloids would be signally improved after destroying the transannular conjugation effect. Compared to norsecurinine,the Baylis-Hillman reaction of securinine occured in a more severe condition.(2) Through oxidation, rearrangement and subsequent re-oxidation of the open- loop, the secuirinine converted to a nitrone intermediate which reacted with another molecule of secuirinine to generate the isoxazole-containing alkaloids dimer by 1,3-dipolar cycloaddition reaction. This process also gave an anti-head-head dimer, showing the same selectivity as the photodimerization of secuirinine.(3) Unlike norsecuirinine, the Baylis-Hillman reaction of secuirinine didn’t occur under normal conditions, due to its relatively more stable chemical properties. However, in the system of DMF and H2 O, secuirinine was catalyzed by the DBU and heated at 90 oC, which led to the reaction producing a nonflexible dimer with the structure of two molecules of secuirinine linked by C-C chain.(4) In order to introduce the amino acid derivatives to the molecule of secuirinine, this paper selected eleven amino acid esters of different kinds as substrate for Michael reaction, but only four of them successfully reacted. The corresponding amino acid amides of the non-reactive amino acid matrices were also incapable of the reaction, which could be explained by the fact that the nucleophilicity of these amino acid matrices are not enough to induce the Michael reaction of securinine.(5) In this paper, 38 compounds were synthesized, including 16 nonflexible dimers and seven amino acid conjugates of securinine, and 22 intermediate compounds. Structures of all the compounds were confirmed by spectral analysis, like ESI-MS, HRMS, 1H-NMR, 13C-NMR, DEPT-135, 1H-1H COSY, HSQC, HMBC, NOESY.Conclusion:(1) External factors have an influence on the productivity of photodimerization of securinine, but not on division of the product. It is believed that the selectivity of photodimerization of securinine is related to the reversible photodimerization, the thermodynamical stability of dimeric products and the complex spatial structure. The chemical property of securinine is more stable than that of norsecurinine, which is related to the transannular conjugation confirmed in the molecule of securinine. Conversely, the reactivity of securinine would be signally improved after destroying the transannular conjugation effect.(2) A series of nonflexible dimers of securinine were respectively obtained by the [2+2] photochemical cycloaddition, 1,3-dipolar cycloaddition and Baylis-Hillman reaction of securinine. Some amino acid derivatives were successfully introduced to the molecule of securinine via Michael reaction, giving the amino acid conjugates of securinine. However, this part of the research remains to be further explored. |
