2021 Fiscal Year Annual Research Report
Application of gold-catalyzed glycosylation under aqueous condition for the tumor-localized in vivo synthesis of anticancer drugs
| Project/Area Number |
19K15708
|
|---|
| Research Institution | Institute of Physical and Chemical Research |
|---|
Principal Investigator |
張 宗哲 国立研究開発法人理化学研究所, 開拓研究本部, 特別研究員 (00774853)
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | Artificial metalloenzyme / Gold-mediated reaction / Glycan / Prodrug |
|---|
| Outline of Annual Research Achievements |
Due to the adverse health effects caused by anticancer drug side effects, chemotherapy can be a laborious and often painful process for patients. One solution for decreasing drug toxicity to healthy tissue is to locally synthesize cytotoxic drugs at cancer cells. The awardee succeeded in developing the gold-based artificial metalloenzyme (gold ArM) and demonstrated that the gold ArM can activate the 2'-alkylnyl-N-methyl-2-biphenylamine derivatives under physiological condition in good turnover number. In particular, the gold ArM can protect the catalytic activity of the bound gold catalyst from biomolecules such as glutathione and cell lysates, and reduce the cytotoxicity of gold catalyst. The awardee demonstrated that the gold ArM can be used as a trigger for the synthesis of a phenanthridinium-based drug, and that the resultant agent can be applied to cancer therapy. Furthermore, the 2'-alkylnyl-N-methyl-2-biphenylamine can be introduced into the C1 position of sialic acid as a leaving group via an unusual N-glycosylation. Unexpectedly, the resultant sialic acid can be converted to a sialic acid-based fluorophore via the gold ArM-mediated hydroamination, highlighting the potential application for bioimaging in vitro and in vivo. Overall, the project significantly advanced two research fields: metal-mediated prodrug strategy for cancer therapy and research focused on development of therapeutic ArMs.
|
