PUBLICATION
General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation In Vivo
- Authors
- Sun, T., Lv, T., Wu, J., Zhu, M., Fei, Y., Zhu, J., Zhang, Y., Huang, Z.
- ID
- ZDB-PUB-210123-1
- Date
- 2020
- Source
- Journal of medicinal chemistry 63: 13899-13912 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Disease Models, Animal*
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/drug effects*
- Activation, Metabolic/drug effects*
- Female
- Antineoplastic Agents/pharmacology*
- Prodrugs/pharmacology*
- Cisplatin/chemistry*
- Ovarian Neoplasms/drug therapy*
- Ovarian Neoplasms/pathology
- Zebrafish
- Animals
- Humans
- Tumor Cells, Cultured
- PubMed
- 33141588 Full text @ J. Med. Chem.
Citation
Sun, T., Lv, T., Wu, J., Zhu, M., Fei, Y., Zhu, J., Zhang, Y., Huang, Z. (2020) General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation In Vivo. Journal of medicinal chemistry. 63:13899-13912.
Abstract
Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping