44(P-3) 超天然物の設計と創製 : 抗腫瘍性抗生物質C-1027の合理的改変による安定化(ポスター発表の部)

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The antitumor antibiotic C-1027 is a 1:1 complex of a highly labile enediyne chromophore (1) and a carrier apoprotein. C-1027 exhibited the potent cytotoxicity toward various cancer cells. The p-benzyne biradical (2), which is in equilibrium with 1, abstracts hydrogens from DNA to exert its biological activity. The apoprotein functions as both the stabilizer and the drug delivery system of 1. Recently, we found that the biradical 2 slowly abstracts α-proton of Gly96 of the apoprotein, which caused the oxidative cleavage of the peptides and led to a self-degradation of C-1027. To create a more stable analog of antibiotic C-1027, we designed a Gly96-deuterated (D-Gly) apoprotein. The D-Gly apoprotein was expressed in Escherichia coli in the presence of glycine-d_5. The unstable chromophore 1, isolated from natural C-1027, was then incorporated into the D-Gly apoprotein using HPLC techniques to obtain the D-Gly C-1027. Stability tests revealed that the D-Gly C-1027 was 1.8 and 4.9 times as stable as the natural one under solid and solution states, respectively. Cytotoxicity test also reflected the stability of D-Gly C-1027. Thus, we achieved the creation of supranatural products by rational design utilizing kinetic isotope effect. The presented work demonstrated the novel design principle to create the supra-natural products by integrating the data of physicochemical property of the small molecule and the atomic-level 3D-structure of the protein, which will be applicable to other biologically important natural products and proteins.
天然有機化合物討論会の論文
2003-09-01

44(P-3) 超天然物の設計と創製 : 抗腫瘍性抗生物質C-1027の合理的改変による安定化(ポスター発表の部)

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