Discovery of tetrahydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis

Bioorg Med Chem. 2009 Jul 1;17(13):4740-6. doi: 10.1016/j.bmc.2009.04.044. Epub 2009 May 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Design
  • Human T-lymphotropic virus 1 / isolation & purification
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / drug therapy*
  • Leukemia-Lymphoma, Adult T-Cell / virology
  • Models, Molecular
  • Molecular Structure
  • Retinoids
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / virology
  • Tetrahydronaphthalenes / chemistry*
  • Tetrahydronaphthalenes / pharmacology*

Substances

  • Antineoplastic Agents
  • Retinoids
  • Small Molecule Libraries
  • Tetrahydronaphthalenes