New potent P-glycoprotein modulators with the cucurbitane scaffold and their synergistic interaction with doxorubicin on resistant cancer cells

Bioorg Med Chem. 2009 Oct 1;17(19):6942-51. doi: 10.1016/j.bmc.2009.08.020. Epub 2009 Aug 15.

Abstract

The novel cucurbitacins, balsaminagenin A and B (1-2) and balsaminoside A (3) and the know cucurbitacin karavelagenin C (4), together with five new mono or diacylated derivatives (5-9) of karavelagenin C were evaluated for multidrug resistance reversing activity on human MDR1 gene transfected mouse lymphoma cells. Compounds 2-6 exhibited a strong activity compared with that of the positive control, verapamil. Structure-activity relationships are discussed. Moreover, in the checkerboard model of combination chemotherapy, the interaction between doxorubicin and compounds 2-5 synergistically enhanced the effect of the anticancer drug. Compounds 1-4 were isolated from the aerial parts of Momordica balsamina L. The structures of the compounds were established on the basis of spectroscopic methods including 2D NMR experiments (COSY, HMQC, HMBC and NOESY).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cucurbitacins / pharmacokinetics*
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Glycosides / chemistry*
  • Humans
  • Lymphoma / drug therapy*
  • Lymphoma / pathology
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship
  • Transfection
  • Triterpenes / chemistry*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Glycosides
  • Triterpenes
  • cucurbitane
  • Cucurbitacins
  • Doxorubicin