Abstract

We prepared extracts of Alisma orientalis from Sichuan and Fujian Province, China. Based on the ratio of alisol B 23-acetate (23B) to alisol A 24-acetate (24A) in two Alisma orientalis extracts, we prepared two mixtures of 24A and 23B (24A:23B = 1:3 or 1:10). The antitumor molecular mechanism of the monomers 24A and 23B, the two mixtures and the effective components of Alisma orientalis from different habitats were studied. The MTT assay suggested that the difference in the antitumor activity of Alisma orientalis from different habitats was correlated to the ratio of 24A to 23B. The multi-spectroscopic analysis suggested that the effective components, the monomers and mixtures interacted with c-myc DNA in a partial intercalation manner. The binding strength of the alisol acetates to c-myc DNA was consistent with the anticancer activity, indicating that c-myc DNA was the anticancer target. The molecular simulation indicated that the mixtures were all directly bound to different base pairs of c-myc DNA for a superimposed effect, which led to the binding strength of the mixtures to c-myc DNA was stronger than that of the monomers. The molecules in the 1:3 mixture were all bound to different base pairs of c-myc DNA. However, for the 1:10 mixture, seven molecules of 23B bound to the side chain of 24A, resulting in the mixture with a long chain structure which increased the steric hindrance of 24A. As a result, affinity between 24A and c-myc DNA in the 1:10 mixture was weaker than that in the 1:3 mixture. The antitumor molecular mechanism of the alisol monomers 24A and 23B, the mixtures with different proportions and the effective components of Alisma orientalis from different habitats were studied. The order of the antitumor activity was as follows: Sichuan > Fujian, 24A-23B (1:3) > 24A-23B (1:10) > 23B > 24A. The antitumor activity of Alisma orientalis from different habitats was consistent with the mixtures which were designed according to the contents of the active ingredients of the medicinal materials, indicating that the antitumor activity of Alisma orientalis from Sichuan is better than that from Fujian which is related to the contents of 24A and 23B and the proportion of 1:3 is better than 1:10. The binding strength of the mixtures to c-myc DNA was consistent with the anticancer activity. The mixtures were all directly bound to different base pairs of c-myc DNA for a superimposed effect, which led to the strength of the interaction of the mixtures to c-myc DNA was stronger than that of the monomers. For the 24A-23B (1:3) mixture, the four small molecules bound to c-myc DNA directly and interacted with different base pairs of c-myc DNA. While for the 24A-23B (1:10) mixture, 24A and three 23B molecules interacted with c-myc DNA, the remaining seven 23B molecules bound to the side chain of 24A, which increased the steric hindrance. The binding of the mixture to c-myc DNA was decreased. Communicated by Ramaswamy H. Sarma

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