著者

平間 正博

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.41, no.5, pp.418-431, 1983-05-01 (Released:2009-11-13)

参考文献数

40

被引用文献数

2 3

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Convergent and enantiospecific syntheses of compactin (1 a) and mevinolin (1 b), potent competitive inhibitor of HMG-CoA reductase, have been achieved via asymmetric intramolecular Diels-Alder reaction of acyclic (E, E, E) -trienone 4 leading to trans-octalone 3, a common intermediate for congeners. Chirality of C13 in 4 was designed to induce the four asymmetric centers with desired configuration by this reaction : the chirality controlled the approach of the dienophile from a single diastereotopic face. Trienone 4 was expeditiously constructed by the combination of two segments 5 and 6. Enantio- and stereo-specific synthesis of 6, a chiral 1, 3, 5- triol derivative, rested on the two novel methodologies, i.e, the convenient asymmetric reduction of β-keto carboxylate 19 d with baker's yeast and the regio- and stereo-selective iodofunctionalization (1, 3-asymmetric induction) of homoallylic carbamate. Preparation of 5 in its optically active form was accomplished by the elaboration of readily available γ-lactone 12.

著者

石塚 みどり 田中 俊之 福田 純子 平間 正博 大谷 敏夫

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.42, pp.331-336, 2000

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C-1027 is a potent antitumor antibiotic, in which a nonprotein chromophore is tightly and specifically bound to an apoprotein. The chromophore, which has an endiyne structure and is responsible for DNA cleavage, is very labile when isolated, but greatly stabilized through binding to the apoprotein. Their binding structure and stabilizing interactions are very interesting problems in terms of molecular recognition and protein transport. The 3D structure of C-1027 apoprotein was determined by the X-PLOR calculation using 1539 experimental restrains derived from NMR spectroscopy. The apoprotein has three antiparallel β-sheets, and the hydrophobic pocket is formed by four-stranded β-sheet (DCHI) and two loops (residues 75-79, 97-100)(Fig.3). The overall shape of the apoprotein is quite similar to those of neocarzinostatin (NCS) and actinoxanthin (AXN). The binding structure of C-1027 complex was calculated based on 1539 NMR-derived constraints which include 38 intermolecular restraints between the aromatized chromophore and the apoprotein. The aromatized chromophore is bound to the hydrophobic pocket of the apoprotein. The benzodihydropentalene core locates in the center of the pocket with its molecular plane almost perpendicular to the bottom of the pocket. The β-tyrosine unit locates on the left side of the core, and both benzoxazine and aminosugar moieties on the right side (Fig.4). The hydrophobic interaction is most likely the major binding interaction between the apoprotein and the aromatized chromophore. Moreover, the 18-amino group of the chromophore locates in the proximity of either the carboxylate of Asp101 or the imidazole ring of His104, which indicates there could be a salt-bridge or a hydrogen bond type interaction between the aromatized chromophore and these side chains. To confirm the predicted binding interactions, we made several mutant apoproteins whose specific amino acid residue is replaced with the amino acid of different type and examined their binding abilities for the aromatized chromophore by NMR. The results obtained will be discussed.

著者

臼杵 豊展 井上 将行 平間 正博 田中 俊之 細井 文仁 大家 真治 大谷 敏夫

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.45, pp.257-262, 2003

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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.

著者

平間 正博

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.49, no.11, pp.1032-1042, 1991-11-01 (Released:2009-11-16)

参考文献数

16

被引用文献数

7 9

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The first generation of 10 membered ring analogues (11-13) of the neocarzinostatin chromophore (1) could undergo the thiol or radical triggered Masamune-Bergman type cycloaromatization, but they were not able to show the antibiotic nor antitumor activities. New analogues (2729) of the second generation exhibited the remarkable DNA cleaving activities as well as the biological activities. The unprecedented guanine specific DNA cleavage by the simple chiral alcohol 28 is striking, while the complex of the possible intercalator 29 with the neocarzinostatin apoprotein (2) did not show an evident specificity.

著者

小林 正治 平間 正博

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.62, no.3, pp.184-193, 2004-03-01 (Released:2009-11-13)

参考文献数

25

被引用文献数

3 4

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A novel nine-membered enediyne antibiotic N 1999-A 2 was chemically synthesized and its absolute stereochemistry was determined. Chemical evidence of the thiol-triggered activation as well as the DNA cleavage profiles of N 1999-A 2 and its stereoisomers proved that the configuration of the C 11-naphthoate moiety played a dominant role in governing not only the orientation of the thiol attack but also the specificity of DNA cleavage.

著者

平間 正博

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.41, no.5, pp.418-431, 1983

被引用文献数

3

---

Convergent and enantiospecific syntheses of compactin (1 a) and mevinolin (1 b), potent competitive inhibitor of HMG-CoA reductase, have been achieved via asymmetric intramolecular Diels-Alder reaction of acyclic (<I>E, E, E</I>) -trienone 4 leading to <I>trans</I>-octalone 3, a common intermediate for congeners. Chirality of C13 in 4 was designed to induce the four asymmetric centers with desired configuration by this reaction : the chirality controlled the approach of the dienophile from a single diastereotopic face. Trienone 4 was expeditiously constructed by the combination of two segments 5 and 6. Enantio- and stereo-specific synthesis of 6, a chiral 1, 3, 5- triol derivative, rested on the two novel methodologies, <I>i.e</I>, the convenient asymmetric reduction of β-keto carboxylate 19 d with baker's yeast and the regio- and stereo-selective iodofunctionalization (1, 3-asymmetric induction) of homoallylic carbamate. Preparation of 5 in its optically active form was accomplished by the elaboration of readily available γ-lactone 12.