New Seco-DSP derivatives as potent chemosensitizers.

Abstract

Thirty-four seco-3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (seco-DSP) derivatives were designed, synthesized and evaluated for chemo-reversal activity when combined with paclitaxel or vincristine in P-gp overexpressing A2780/T and KB-VIN drug-resistant cancer cell lines. Most of the compounds displayed moderate to significant MDR reversal activities. Compound 7e showed the most potent chemo-sensitization activity with more than 1471 reversal ratio at a concentration of 10 μM, which was higher than verapamil (VRP) (212-fold). Unexpectedly the newly synthesized compounds did not show chemosensitization activities in a non-P-gp overexpressing cisplatin resistant human ovarian cancer cell line (A2780/CDDP), implying that the MDR reversal effects might be associated with P-gp overexpression. Moreover, the compounds did not exhibit significant anti-proliferative activities against non-tumorigenic cell lines (HUVEC, HOSEC and T29) compared to VRP at the tested concentration and might be safer than VRP. In preliminary pharmacological mechanism studies, the compounds increased accumulation of DOX and promoted P-gp ATPase activity in A2780/T cell lines. Western blot analysis indicated they did not affect the expression level of P-gp in the tested MDR cell lines. Thus, further studies on these seco-DSP derivatives are merited with the goal of developing a desirable chemosensitizer drug candidate.

• Authors: Qi Wan, Xin Jin, Yalan Guo, Zhihui Yu, Shiqi Guo, Susan Morris-Natschke, Kuo-Hsiung Lee, Hongrui Liu, Ying Chen
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 204 Pg. 112555 (Oct 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32750634 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Chromones

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Chromones (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans