生物活性物質の効率的合成法の開発とその創薬化学への展開
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The compounds not only bearing intriguing structures from the viewpoint of organic synthesis but also exhibiting interesting biological activities from the viewpoint of medicinal chemistry were selected as synthetic targets and their efficient synthesis in optically active forms were studied. Thus, efficient syntheses of antitumor agents such as anthracyclines, duocarmycins, quinocarcin, FR 900482,sesbanimides, nogalamycins, a neocarzinostatin chromophore model compound were accomplished in optically active forms. Synthetic studies on optically active carzinophilin, popolohuanone E, and roseophilin showing pronounced antitumor activities were also briefly reviewed. A number of efficient synthetic routes to the optically active key intermediates of the 1β-methylcarbapenem antibiotic (meropenem), the antibacterial quinolonecarboxylic acid (DU-6859), the antihypertensive renin inhibitor (KRI-1314), the acetylcholinesterase inhibitor (huperzine A), and the HIV protease inhibitors were successfully explored by employing optical resolution, asymmetric synthesis, and/or chemical transformation. Especially, in the synthetic studies on antitumor agents and acetylcholinesterase inhibitors, we attempted, during or after the synthetic studies, to prepare the congeners of target molecule and to explore some novel aspects of the structure-activity relationships. These studies aiming at developing novel congeners which may show more excellent characteristics than the target molecule, were carried out by taking into account increasing social requirements for prominent antitumor agents and for promising agents for treating Alzheimer's and memory-impaired patients. On the basis of these studies, we have succeeded in exploring a novel cyclopropapyrroloindole derivative AT3510 as a highly efficient antitumor agent. The novel glycosylation reaction usable in anthracycline synthesis and the effective synthetic methods for 1β-methylcarbapenem antibiotic featuring the Reformatsky reaction, have also been explored, both of which are presently being utilized for the industrial preparations of amrubicin and meropenem.
- 社団法人日本薬学会の論文
- 1998-09-01
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