title: Synthesis and evaluation of (2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (NSC23925) isomers to reverse multidrug resistance in cancer.
abstract: 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.
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. duanz@helix.mgh.harvard.edu
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Haoxi
authors.initials: H
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Shao-Liang
authors.initials: SL
authors.lastname: Zheng
authors.forename: Xianzhe
authors.initials: X
authors.lastname: Liu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: David
authors.initials: D
authors.lastname: Harmon
authors.forename: Henry
authors.initials: H
authors.lastname: Mankin
authors.forename: Francis
authors.initials: F
authors.lastname: Hornicek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C546115:(2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010880:Piperidines; D011804:Quinolines; D017239:Paclitaxel