Laboratory of Drug Discovery, Center for Research and Education on Drug Discovery

Research

1. Synthesis of physiologically active natural products

Physiologically active natural products become good drug discovery leads. There is data that almost half of all the medicines approved in the U.S.A. were developed on the clues of natural products. So, as the main compound targets we settle natural products which will be seeds of remedies to cancers or infectious diseases which have severe problems of drug resistance, at first locate compounds of effective physiologically active natural products having as the starting line, and organic chemical synthesis aiming at structure-activity relationship, and conduct the development of methodology required.
So far we have achieved these studies.

(1)Nucleoside natural product

Caprazamycin and muraymycin groups, which are nucleoside natural products having a different mechanism of action from conventional antibacterial drugs, are anticipated as new antimicrobials against drug-resistant bacteria that have issues at the moment. Having complex structures that contain nucleoside, sugar, peptide and lipid, those total synthesis had not been achieved. In the process of developing synthetic route targeting derivatives of these natural products, we developed β-selective ribosylating reaction without the neighboring group participation of acyl group, which has been supposed to be a key factor. At first, we succeeded in the total synthesis of caprazol, which is core structure, and by using C-H amination reaction and multicomponent reaction, accomplished the total synthesis of muraymycin D2. Moreover, we are finding derivatives that would be effective on drug-resistant bacteria MRSA or VRE, expanding synthesis of various derivatives and the research on the structure-activity relationship. As other findings, we achieved total synthesis of herbicidin B, nucleoside natural products, pacidamycin D having anti-Pseudomonas aeruginosa selective activity. These total syntheses on natural products have been achieved for the first time in the world.

(2)Peptide natural products

We have accomplished the total synthesis of sandramycin, which is a cyclic peptide having strong anticancer activity, and syringolin A, which is a proteasome inhibitor, by using diastereoselective Ugi three-component reaction. We have found syringolin A derivatives strongly enhanced in proteasomal inhibitory activity and human myeloma cytostatic activity, after reviewing the structure-activity relationship.

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