title: Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer.
abstract: The effect of 24 newly synthesized quinoline derivatives on tumor cell multidrug resistance (MDR) was examined in vitro. At low concentrations, these compounds enhanced the accumulation of [3H]vincristine in K562/ADM cells and reversed tumor cell MDR. The results of the structure-activity relationship analysis indicate that in highly active compounds the two aryl rings in the hydrophobic moiety deviate from a common plane, so they are capable of interacting with hydrogen bond donors of P-170 glycoprotein (P-gp) via pi-hydrogen-pi interactions. Other major structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen atom in piperazine. Furthermore, in highly active compounds, the distance between the hydrophobic moiety and the basic nitrogen atom (an atom connected to 2-hydroxypropoxyquinoline) must be at least 5 A. Several compounds were found to reverse vincristine resistance in K562/ADM cells in vitro, and compound 16 (MS-209) was selected for clinical studies.
authors.affiliation: Medicinal Chemistry Department, Mitsui Toatsu Chemicals Inc., Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Fukazawa
authors.forename: K
authors.initials: K
authors.lastname: San-nohe
authors.forename: W
authors.initials: W
authors.lastname: Sato
authors.forename: O
authors.initials: O
authors.lastname: Yano
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011804:Quinolines; C087719:dofequidar; D014750:Vincristine