title: Discovery of tetrahydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis.
abstract: Adult T cell leukemia (ATL), caused by infection of human T-lymphotropic virus type 1 (HTLV-1), has a poor prognosis and curative therapy is unavailable, so it is important to find or design superior lead compounds for the drug treatment of ATL. We used our micro-reversed fragment-based drug design hypothesis and multi-template hypothesis to extract the tetrahydrotetramethylnaphthalene (TMN) skeleton from tamibarotene, a useful medicament for the treatment of acute promyelocytic leukemia (APL). Structural development of TMN yielded highly ATL cell-selective growth inhibitors, including 2-acetyl-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (6). Structure-activity relationship analysis suggests the existence of a specific target molecule for ATL cell-selective inhibition of proliferation through G2 arrest.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamasaki
authors.forename: Maiko
authors.initials: M
authors.lastname: Tokitou
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoyama
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D015368:Human T-lymphotropic virus 1 / Q000302:isolation & purification; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000821:virology; D008958:Models, Molecular; D015394:Molecular Structure; D012176:Retinoids; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D012176:Retinoids; D054852:Small Molecule Libraries; D013764:Tetrahydronaphthalenes