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Synthesis and Structure–Activity Evaluation of Isatin-β-thiosemicarbazones with Improved Selective Activity toward Multidrug-Resistant Cells Expressing P-Glycoprotein
- Source :
- Journal of Medicinal Chemistry. 54:5878-5889
- Publication Year :
- 2011
- Publisher :
- American Chemical Society (ACS), 2011.
-
Abstract
- Cancer multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters presents a significant unresolved clinical challenge. One strategy to resolve MDR is to develop compounds that selectively kill cells overexpressing the efflux transporter P-glycoprotein (MDR1, P-gp, ABCB1). We have previously reported structure-activity studies based around the lead compound NSC73306 (1, 1-isatin-4-(4'-methoxyphenyl)-3-thiosemicarbazone, 4.3-fold selective). Here we sought to extend this work on MDR1-selective analogues by establishing whether 1 showed "robust" activity against a range of cell lines expressing P-gp. We further aimed to synthesize and test analogues with varied substitution at the N4-position, and substitution around the N4-phenyl ring of isatin-β-thiosemicarbazones (IBTs), to identify compounds with increased MDR1-selectivity. Compound 1 demonstrated MDR1-selectivity against all P-gp-expressing cell lines examined. This selectivity was reversed by inhibitors of P-gp ATPase activity. Structural variation at the 4'-phenyl position of 1 yielded compounds of greater MDR1-selectivity. Two of these analogues, 1-isatin-4-(4'-nitrophenyl)-3-thiosemicarbazone (22, 8.3-fold selective) and 1-isatin-4-(4'-tert-butyl phenyl)-3-thiosemicarbazone (32, 14.8-fold selective), were selected for further testing and were found to retain the activity profile of 1. These compounds are the most active IBTs identified to date.
- Subjects :
- Isatin
Indoles
Cell Survival
ATP-binding cassette transporter
CHO Cells
Crystallography, X-Ray
Article
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Cricetulus
Cell Line, Tumor
Cricetinae
Drug Discovery
Animals
Humans
Structure–activity relationship
ATP Binding Cassette Transporter, Subfamily B, Member 1
P-glycoprotein
Molecular Structure
biology
Chemistry
Chinese hamster ovary cell
Drug Resistance, Multiple
Multiple drug resistance
HEK293 Cells
Models, Chemical
Biochemistry
Cell culture
NIH 3T3 Cells
biology.protein
Molecular Medicine
Efflux
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....add0ea9ae9b5c69d9b9cbaa082154e33