Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Paolo Coghi
- Jerome PL Ng
- Onat Kadioglu
- Betty Yuen Kwan Law
- Alena Congling Qiu
- Mohamed EM Saeed
- Xi Chen
- Chi Kio Ip
- Thomas Efferth
- Liang Liu
- Vincent Kam Wai Wong
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000703110000008&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.ejmech.2021.113676
- eISSN
- 1768-3254
- Externe Identifier
- Clarivate Analytics Document Solution ID: WA8BY
- PubMed Identifier: 34256125
- ISSN
- 0223-5234
- Zeitschrift
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- Schlüsselwörter
- Celastrol derivatives
- P-glycoprotein
- Antitumor activity
- Molecular docking
- Traditional Chinese medicine
- SERCA
- Artikelnummer
- ARTN 113676
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy
- Sub types
- Article
- Ausgabe der Zeitschrift
- 224
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Paolo Coghi
- Jerome PL Ng
- Onat Kadioglu
- Betty Yuen Kwan Law
- Alena Congling Qiu
- Mohamed EM Saeed
- Xi Chen
- Chi Kio Ip
- Thomas Efferth
- Liang Liu
- Vincent Kam Wai Wong
- DOI
- 10.1016/j.ejmech.2021.113676
- ISSN
- 0223-5234
- Zeitschrift
- European Journal of Medicinal Chemistry
- Sprache
- en
- Artikelnummer
- 113676
- Paginierung
- 113676 - 113676
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.ejmech.2021.113676
- Datum der Datenerfassung
- 2021
- Titel
- Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy
- Ausgabe der Zeitschrift
- 224
Data source: Crossref
- Abstract
- A series of eleven celastrol derivatives was designed, synthesized, and evaluated for their in vitro cytotoxic activities against six human cancer cell lines (A549, HepG2, HepAD38, PC3, DLD-1 Bax-Bak WT and DKO) and three human normal cells (LO<sub>2</sub>, BEAS-2B, CCD19Lu). To our knowledge, six derivatives were the first example of dipeptide celastrol derivatives. Among them, compound 3 was the most promising derivative, as it exhibited a remarkable anti-proliferative activity and improved selectivity in liver cancer HepAD38 versus human normal hepatocytes, LO<sub>2</sub>. Compound 6 showed higher selectivity in liver cancer cells against human normal lung fibroblasts, CCD19Lu cell line. The Ca<sup>2+</sup> mobilizations of 3 and 6 were also evaluated in the presence and absence of thapsigargin to demonstrate their inhibitory effects on SERCA. Derivatives 3 and 6 were found to induce apoptosis on LO<sub>2</sub>, HepG2 and HepAD38 cells. The potential docking poses of all synthesized celastrol dipeptides and other known inhibitors were proposed by molecular docking. Finally, 3 inhibited P-gp-mediated drug efflux with greater efficiency than inhibitor verapamil in A549 lung cancer cells. Therefore, celastrol-dipeptide derivatives are potent drug candidates for the treatment of drug-resistant cancer.
- Addresses
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Autoren
- Paolo Coghi
- Jerome PL Ng
- Onat Kadioglu
- Betty Yuen Kwan Law
- Alena Congling Qiu
- Mohamed EM Saeed
- Xi Chen
- Chi Kio Ip
- Thomas Efferth
- Liang Liu
- Vincent Kam Wai Wong
- DOI
- 10.1016/j.ejmech.2021.113676
- eISSN
- 1768-3254
- Externe Identifier
- PubMed Identifier: 34256125
- Open access
- false
- ISSN
- 0223-5234
- Zeitschrift
- European journal of medicinal chemistry
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Antineoplastic Agents
- Drug Screening Assays, Antitumor
- Apoptosis
- Cell Proliferation
- Binding Sites
- Structure-Activity Relationship
- Drug Design
- Drug Resistance, Neoplasm
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
- Pentacyclic Triterpenes
- Molecular Docking Simulation
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2021
- Paginierung
- 113676
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2021
- Titel
- Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 224
Data source: Europe PubMed Central
- Abstract
- A series of eleven celastrol derivatives was designed, synthesized, and evaluated for their in vitro cytotoxic activities against six human cancer cell lines (A549, HepG2, HepAD38, PC3, DLD-1 Bax-Bak WT and DKO) and three human normal cells (LO2, BEAS-2B, CCD19Lu). To our knowledge, six derivatives were the first example of dipeptide celastrol derivatives. Among them, compound 3 was the most promising derivative, as it exhibited a remarkable anti-proliferative activity and improved selectivity in liver cancer HepAD38 versus human normal hepatocytes, LO2. Compound 6 showed higher selectivity in liver cancer cells against human normal lung fibroblasts, CCD19Lu cell line. The Ca2+ mobilizations of 3 and 6 were also evaluated in the presence and absence of thapsigargin to demonstrate their inhibitory effects on SERCA. Derivatives 3 and 6 were found to induce apoptosis on LO2, HepG2 and HepAD38 cells. The potential docking poses of all synthesized celastrol dipeptides and other known inhibitors were proposed by molecular docking. Finally, 3 inhibited P-gp-mediated drug efflux with greater efficiency than inhibitor verapamil in A549 lung cancer cells. Therefore, celastrol-dipeptide derivatives are potent drug candidates for the treatment of drug-resistant cancer.
- Date of acceptance
- 2021
- Autoren
- Paolo Coghi
- Jerome PL Ng
- Onat Kadioglu
- Betty Yuen Kwan Law
- Alena Congling Qiu
- Mohamed EM Saeed
- Xi Chen
- Chi Kio Ip
- Thomas Efferth
- Liang Liu
- Vincent Kam Wai Wong
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/34256125
- DOI
- 10.1016/j.ejmech.2021.113676
- eISSN
- 1768-3254
- Zeitschrift
- Eur J Med Chem
- Schlüsselwörter
- Antitumor activity
- Celastrol derivatives
- Molecular docking
- P-glycoprotein
- SERCA
- Traditional Chinese medicine
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Apoptosis
- Binding Sites
- Cell Line, Tumor
- Cell Proliferation
- Drug Design
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Humans
- Molecular Docking Simulation
- Pentacyclic Triterpenes
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
- Structure-Activity Relationship
- Sprache
- eng
- Country
- France
- Paginierung
- 113676
- PII
- S0223-5234(21)00525-0
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 224
Data source: PubMed
- Beziehungen:
- Property of