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Antitumor agents 286. Design, synthesis, and structure-activity relationships of 3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (DSP) analogues as potent chemosensitizers to overcome multidrug resistance.

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.
AuthorsTing Zhou, Qian Shi, Kenneth F Bastow, Kuo-Hsiung Lee
JournalJournal of medicinal chemistry (J Med Chem) Vol. 53 Issue 24 Pg. 8700-8 (Dec 23 2010) ISSN: 1520-4804 [Electronic] United States
PMID21082774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Chromones
  • Pyrans
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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