Discovery of tetrahydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis.
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.
Nakamura
Masahiko
M
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Hamasaki
Takayuki
T
Tokitou
Maiko
M
Baba
Masanori
M
Hashimoto
Yuichi
Y
Aoyama
Hiroshi
H
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*
D000970:Antineoplastic Agents; D012176:Retinoids; D054852:Small Molecule Libraries; D013764:Tetrahydronaphthalenes