Synthesis and uptake of fluorescence-labeled Combi-molecules by P-glycoprotein-proficient and -deficient uterine sarcoma cells MES-SA and MES-SA/DX5.

Abstract

Here, we report on the first synthesis of fluorescent-labeled epidermal growth factor receptor-DNA targeting combi-molecules, and we studied the influence of P-glycoprotein status of human sarcoma MES-SA cells on their growth inhibitory effect and cellular uptake. The results showed that 6, bearing a longer spacer between the quinazoline ring and the dansyl group, was more stable and more cytotoxic than 4. In contrast to the latter, it induced significant levels of DNA damage in human tumor cells. Moreover, in contrast to doxorubicin, a drug known to be actively effluxed by P-gp, the more stable combi-molecule 6 induced almost identical levels of drug uptake and DNA damage in P-gp-proficient and -deficient cells. Likewise, in contrast to doxorubicin, 4 and 6 exerted equal levels of antiproliferative activity against the two cell types. The results in toto suggest that despite their size, the antiproliferative effects of 4 and 6 were independent of P-gp status of the cells.

• Authors: Anne-Laure Larroque-Lombard, Margarita Todorova, Nahid Golabi, Christopher Williams, Bertrand J Jean-Claude
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 5 Pg. 2104-13 (Mar 11 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20151639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Dansyl Compounds
• Quinazolines
• DNA
• ErbB Receptors

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (deficiency, metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacokinetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Comet Assay
• DNA (antagonists & inhibitors, metabolism)
• DNA Damage
• Dansyl Compounds (chemical synthesis, chemistry, pharmacokinetics)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Flow Cytometry
• Half-Life
• Humans
• Magnetic Resonance Spectroscopy
• Microscopy, Fluorescence
• Quinazolines (chemical synthesis, chemistry, pharmacokinetics)
• Sarcoma (metabolism)
• Spectrometry, Mass, Electrospray Ionization
• Structure-Activity Relationship
• Uterine Neoplasms (metabolism)