Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.
We achieved a total synthesis of terprenin, a novel potent immunoglobulin E antibody suppressant which was obtained from the fermentation broth of Aspergillus candidus RF-5672 and has a highly oxygenated p-terphenyl skeleton with a prenyloxy side chain. The key steps relied on the Suzuki reaction to construct the terphenyl skeleton and on regioselective halogenations to selectively combine the aromatic rings. The highly efficient and practical production of this important natural product offers promise for the development of a new type of antiallergic drug.
The first synthesis using an original procedure and a practical large-scale process using an improved procedure for the synthesis of the N-PNZ-protected 2-aminomethylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate (S-4661), a novel parenteral 1 -methylcarbapenem antibiotic, are described. trans-4-Hydroxy-L-proline (4) was converted in an efficient process to (2S,4S)-4-acetylthio-2-(N-sulfamoyl-tertbutoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3) in 55-56% overall yield via a six-step sequence, which includes the two alternative routes to intermediate 13. This process requires no chromatographic purifications, no cryogenic temperatures, no haloalkane solvents, and short operating times and is amenable to a multikilogram-scale preparation. Several kilograms of the side chain 3 were successfully prepared by this process.
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