| RRC ID |
58703
|
| Author |
Nakagawa Y, Sawaki Y, Miyanishi W, Shimomura S, Shibata T, Ojika M.
|
| Title |
Relationship among structure, cytotoxicity, and Michael acceptor reactivity of quinocidin.
|
| Journal |
Bioorg Med Chem
|
| Abstract |
Quinocidin (QCD) is a cytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium skeleton. We previously found that QCD captures thiols in neutral aqueous media via a Michael addition-type reaction. However, it remains unclear whether the Michael acceptor reactivity of QCD is responsible for its cytotoxicity. In this study, we synthesized thirteen analogs of QCD to examine the relationship among its structure, cytotoxicity, and reactivity toward thiols. Thiol-trapping experiments and cytotoxicity tests collectively suggested that the Michael acceptor function of QCD is independent of its cytotoxic activity, and that the pyridinium moiety with the hydrophobic side chain is a key structural factor for cytotoxicity. These findings further led us to demonstrate that incorporation of an amide group into the side chain of QCD significantly reduced its toxicity but hardly affected the Michael acceptor function. The present study lays the foundation for QCD-based drug design and highlights the potential of QCD as a unique electrophile for use in the development of covalent inhibitors and protein-labeling probes.
|
| Volume |
28(4)
|
| Pages |
115308
|
| Published |
2020-2-15
|
| DOI |
10.1016/j.bmc.2020.115308
|
| PII |
S0968-0896(19)31902-9
|
| PMID |
31956051
|
| MeSH |
Antibiotics, Antineoplastic / chemical synthesis
Antibiotics, Antineoplastic / chemistry
Antibiotics, Antineoplastic / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Molecular Structure
Quinolizines / chemical synthesis
Quinolizines / chemistry
Quinolizines / pharmacology*
Structure-Activity Relationship
|
| IF |
3.073
|
| Times Cited |
0
|
| Resource |
| Human and Animal Cells |
HeLa S3 (SC)(RCB0271) |
