Abstract |
In this study, various 3'R,4'R-disubstituted-2',2'-dimethydihydropyrano[2,3-f] chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogues (5-28) were synthesized and evaluated against a multidrug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogues exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI₅₀ value of VCR by 12-349-fold. At a concentration of 1 μg/mL, three compounds, 11, 14, and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a 2-fold increase compared to verapamil, a first-generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3' and 4' substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.
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Authors | Ting Zhou, Qian Shi, Kenneth F Bastow, Kuo-Hsiung Lee |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 53
Issue 24
Pg. 8700-8
(Dec 23 2010)
ISSN: 1520-4804 [Electronic] United States |
PMID | 21082774
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Chromones
- Pyrans
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Cell Line, Tumor
- Chromones
(chemical synthesis, chemistry, pharmacology)
- Drug Design
- Drug Interactions
- Drug Resistance, Multiple
(drug effects)
- Drug Resistance, Neoplasm
(drug effects)
- Drug Screening Assays, Antitumor
- Humans
- Pyrans
(chemical synthesis, chemistry, pharmacology)
- Stereoisomerism
- Structure-Activity Relationship
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