Total Synthesis and Structural Determination of XR774, a Tyrosine Kinase Inhibitor.

Total synthesis and structural determination of XR774 has been accomplished. The benzo[ j]fluoranthene skeleton has been constructed by regioselective coupling between tetraline 3 and tetralone 4 successively followed by the sequential transformation including the Birch reduction to prepare allylic alcohol, simultaneous bromination of vinylic and aromatic moieties, and the nickel-mediated intramolecular coupling reaction. The optical resolution of racemic 17 led to the first total synthesis of (-)-XR774.

Total synthesis of hibarimicinone, a v-Src tyrosine kinase inhibitor possessing the pseudo-dimer structure of tetracycline.

The total synthesis of hibarimicinone, a potent v-Src tyrosine kinase inhibitor possessing thirteen stereogenic centers and an axial chirality, has been achieved. The key step to constructing the eight-ring skeleton was the double Michael–Dieckmann-type cyclization (Hauser annulation) using a thiolactone pseudo-dimer. These synthetic studies indicated the efficiency of the thiolactone-employed route to synthesize the multiply functionalized polycyclic compounds.

Total synthesis of the big four antibiotics and related antibiotics.

The first total syntheses of a variety of antibiotics have been accomplished by using carbohydrates as a chiral source. The key target molecules were members of the 'Big Four' classes of antibiotics (macrolides, aminoglycosides, β-lactams and tetracyclines), naphthoquinone antibiotics and their related antibiotics.

RNA separation by in-capillary denaturing polymer electrophoresis with 1,2,5-thiadiazole as an additive.

1,2,5-Thiadiazole improved RNA separation with in-capillary denaturing polymer electrophoresis. 1,2,5-Thiadiazole was synthesized as an extraction solvent substituted for a halogenated solvent. While 1,2,5-thiadiazole was an excellent extraction solvent and an environmentally friendly solvent, we found that 1,2,5-thiadiazole was a strong hydrophobic compound for RNA and the RNA separation performance by in-capillary denaturing polymer electrophoresis was dramatically improved.

Total synthesis and development of bioactive natural products.

The first total synthesis and development of a variety of bioactive natural products have been accomplished by using carbohydrates as a chiral source. In addition, practically useful intermediates have been created, analogs of natural products have been prepared, their structure-activity relationships studied, and the large-scale preparations of medicinally useful compounds established. The key target molecules have been the "Big Four" antibiotics (macrolides, aminoglycosides, beta-lactams and tetracyclines), pyranonaphthoquinone antibiotics, glycosidase inhibitors, and a side-chain of cephem antibiotics.

Total synthesis of an anti-Helicobacter pylori agent, actinopyrone A.

Actinopyrone A, an anti-Helicobacter pylori agent, was synthesized in nine steps from a silyl dienol ether. A vinylogous anti-aldol was stereoselectively synthesized by our developed remote stereoinduction methodology; coupling of this with a sulfone and a phosphonate species led to the construction of a vinylpyrone compound. This was submitted to reductive de-conjugation to give actinopyrone A.

NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.

ErbB2-negative breast tumors represent a significant therapeutic hurdle because of a lack of effective molecular targets. Although NOTCH proteins are known to be involved in mammary tumorigenesis, the functional significance of these proteins in ErbB2-negative breast tumors is not clear. In the present study, we examined the expression of activated NOTCH receptors in human breast cancer cell lines, including ErbB2-negative and ErbB2-positive cell lines.

FoxA1 as a lineage-specific oncogene in luminal type breast cancer.

The forkhead transcription factor FoxA1 is thought to be involved in mammary tumorigenesis. However, the precise role of FoxA1 in breast cancer development is controversial. We examined expression of FoxA1 in 35 human breast cancer cell lines and compared it with that of ErbB2, a marker of poor prognosis in breast cancer.

YCM1008A, a novel Ca2+-signaling inhibitor, produced by Fusarium sp. YCM1008.

In the course of screening for drugs that suppress the Ca(2+)-mediated growth inhibition in a yeast mutant, we found that the metabolite of Fusarium sp. strain YCM1008 inhibited Ca(2+)-signaling. A novel pyrano-pyridone, YCM1008A was isolated from the fermentation broth using HLB column chromatography followed by HPLC, and the structure was elucidated by spectral analysis.

Structure-activity relationships of xanthocillin derivatives as thrombopoietin receptor agonist.

Xanthocillin derivatives, which show thrombopoietin receptor agonist activity, were synthesized through our developed method. Bioassay data suggest the importance of alkene geometry, the presence of substituents at the benzene ring that support hydrophobic character, and the moderate size of the molecule. One of the two isonitrile group of the natural product appears to be dispensable.

Total syntheses of polyketide-derived bioactive natural products.

Recent progress of total syntheses in our laboratory has been described along with our background and methodologies. The target bioactive polyketides are classified into three categories according to their structures: (i) lactone-fused polycyclic compounds [(+)-cochleamycin A, (+)-tubelactomicin A, and (-)-tetrodecamycin], (ii) aromatic compounds [(-)-tetracycline, (-)-BE-54238B, lymphostin, and (-)-lagunamycin], and (iii) acyclic polyketides [xanthocillin X dimethylether, (+)-trichostatin D, and (+)-actinopyrone A]. Features of the total syntheses are described.

Synthetic inhibitors of proline-rich ligand-mediated protein-protein interaction: potent analogs of UCS15A.

The proline-rich motif in proteins is known to function as a ligand sequence that binds to protein modules such as SH3, WW, and several other protein interaction domains. These proline-rich ligand-mediated protein-protein interactions (abbreviated PLPI) are important in many signaling pathways that are involved in various diseases. Our previous studies showed that UCS15A, produced by Streptomyces species, inhibited PLPI.

Isolation and synthesis of a new bioactive ellagic acid derivative from Combretum yunnanensis.

A new ellagic acid derivative (1) was isolated from the branches of Combretum yunnanensis, and its structure was assigned as 4-(4' '-O-acetyl-alpha-rhamnopyranosyl)ellagic acid by analysis of its spectral data. Total synthesis of 1 was achieved by the glycosylation of 3,3'-di-O-benzylellagic acid (5) with 4-O-acetyl-2,3-di-O-benzyl-l-rhamnose (4) as a key reaction, and the absolute configuration of 1 was determined. Compound 1 showed weak inhibitory activity against the growth of various tumor cells and inhibited HIV-1 protease.