Overcoming vincristine resistance in cancer: Computational design and discovery of piperine-inspired P-glycoprotein inhibitors.
ATP Binding Cassette Transporter, Subfamily B
/ antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily G, Member 2
/ antagonists & inhibitors
Alkaloids
/ chemistry
Antineoplastic Agents
/ metabolism
Apoptosis
/ drug effects
Benzodioxoles
/ chemistry
Binding Sites
Cell Line, Tumor
Cell Survival
/ drug effects
Cytochrome P-450 CYP3A
/ chemistry
Drug Design
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm
/ drug effects
Humans
Molecular Docking Simulation
Multidrug Resistance-Associated Proteins
/ antagonists & inhibitors
NF-kappa B
/ metabolism
Neoplasms
/ drug therapy
Piperidines
/ chemistry
Polyunsaturated Alkamides
/ chemistry
Vincristine
/ pharmacology
CYP3A4
P-glycoprotein
anticancer drug
computer-aided drug design
multidrug resistance
piperine analogs
Journal
Chemical biology & drug design
ISSN: 1747-0285
Titre abrégé: Chem Biol Drug Des
Pays: England
ID NLM: 101262549
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
30
01
2020
revised:
05
06
2020
accepted:
28
06
2020
pubmed:
8
7
2020
medline:
24
9
2021
entrez:
8
7
2020
Statut:
ppublish
Résumé
P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB Ch
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B
0
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
Alkaloids
0
Antineoplastic Agents
0
Benzodioxoles
0
Multidrug Resistance-Associated Proteins
0
NF-kappa B
0
Piperidines
0
Polyunsaturated Alkamides
0
Vincristine
5J49Q6B70F
Cytochrome P-450 CYP3A
EC 1.14.14.1
piperine
U71XL721QK
multidrug resistance-associated protein 1
Y49M64GZ4Q
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
51-66Informations de copyright
© 2020 John Wiley & Sons Ltd.
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