US EPA

1037859 

Journal Article 

Synthesis and Evaluation of (2-(4-Methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (NSC23925) Isomers To Reverse Multidrug Resistance in Cancer 

Duan, Z; Li, X; Huang, H; Yuan, W; Zheng, SL; Liu, X; Zhang, Z; Choy, E; Harmon, D; Mankin, H; Hornicek, F 

2012 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

AMER CHEMICAL SOC 

WASHINGTON 

55 

7 

3113-3121 

English 

22400811 

10.1021/jm300117u 

WOS:000302591100021 

https://pubs.acs.org/doi/10.1021/jm300117u
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Development of multidrug resistance (MDR) during chemotherapy is a fundamental obstacle associated with cancer care. Prior studies have identified (2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (5) (NSC23925) to be a small molecule agent that reverses MDR in cancer cells. We synthesized all four isomers of 5 and analyzed them by liquid chromatography-mass spectrometry (LCMS). Structure-activity relationships for reversing MDR were evaluated. Isomer 11 demonstrated the most potent activity. 11 reversed MDR in several drug-resistant cell lines expressing Pgp, including ovarian, breast, colon, uterine, and sarcoma cancer. 11 resensitized these cell lines to paclitaxel, doxorubicin, mitoxantrone, vincristine, and trabectedin with no effect on cell sensitivity to cisplatin, topotecan, and methotrexate. 11 significantly enhanced in vivo antitumor activity of paclitaxel in MDR xenograft models, without increasing the level of paclitaxel toxicity. In conclusion, 11 and derivatives of this compound may hold therapeutic value in the treatment of MDR-dependent cancers.