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Design and synthesis of novel mitochondria-targeted CDDO derivatives as potential anti-cancer agents.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2021 Oct; Vol. 115, pp. 105249. Date of Electronic Publication: 2021 Aug 08. - Publication Year :
- 2021
-
Abstract
- A large number of derivatives of natural pentacyclic triterpenoid oleanolic acid (OA) with various activities have been reported, including CDDO derivatives (CDDOs). CDDOs show potent antitumor activity, but they lack selectivity for tumor cells which causes serious side effects. In this study, based on the truth that tumor cells display higher mitochondrial membrane potential, to improve their mitochondrial-targeting ability, triphenylphosphine cations (TPP <superscript>+</superscript> ) or tricyclohexylphosphine cations (TCP <superscript>+</superscript> ) were linked to CDDO. Among these compounds, the TPP <superscript>+</superscript> derivative 5b exhibited greater activity against the tumor cells than CDDO-Me, and the selectivity for the tumor cells was obviously improved. Further investigation revealed that the uptake of 5b in the mitochondria of MCF-7 cells was increased compared to CDDO-Me. In addition, 5b was able to cause mitochondrial membrane potential decline and cell cycle arrest. Furthermore, 5b caused apoptosis mainly through the mitochondria-mediated intrinsic pathway. Taken together, our study provides a possible solution to the poor selectivity of CDDOs, and regains confidence in the treatment of tumor with CDDOs.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Mitochondria metabolism
Molecular Structure
Oleanolic Acid chemical synthesis
Oleanolic Acid chemistry
Oleanolic Acid pharmacology
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Drug Design
Mitochondria drug effects
Oleanolic Acid analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 115
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34390971
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105249