Syntheses and bioactivities of substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrones. Unusual reactivities with amines

J Org Chem. 2002 May 3;67(9):2907-12. doi: 10.1021/jo010958s.

Abstract

A number of substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrones have been synthesized and their anticancer and antimalarial activities evaluated. A one-pot synthesis of 2,5,8-trimethoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4-dione (4) was achieved by heating a mixture of 1,4-dimethoxyanthracene, methoxyhydroquinone, silver oxide, and zinc iodide in toluene. Regioselective bromination of 4 and 2-methoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone (7) with N-bromosuccinimide provided 2-bromo-3,5,8-trimethoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4-dione and 2-bromo-3-methoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone (1), respectively. The reactions of 1 with aliphatic primary amines and secondary amines, respectively, produced different products, a result most likely attributed to the different basicities (or nucleophilicities) and steric effects of the two kinds of amines. The structure of the displacement product, 2-bromo-3-[2-(tert-butoxycarbonyl)ethylamino]-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone, from the reaction of 1 with tert-butyl 3-aminopropanoate was unequivocally determined by a single-crystal X-ray analysis. IC(50) values of triptycene bisquinones for the inhibition of L1210 leukemia cell viability are in the 0.11-0.27 microM range and for the inhibition of Plasmodium falciparum 3D7 are in the 4.7-8.0 microM range.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amines / chemistry*
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benz(a)Anthracenes / chemical synthesis*
  • Benz(a)Anthracenes / chemistry
  • Benz(a)Anthracenes / pharmacology
  • Catalysis
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Hydrocarbons, Brominated / chemical synthesis
  • Hydrocarbons, Brominated / chemistry
  • Hydrocarbons, Brominated / pharmacology
  • Inhibitory Concentration 50
  • Leukemia
  • Mice
  • Molecular Conformation
  • Molecular Structure
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship
  • Tumor Cells, Cultured / drug effects

Substances

  • 2,5,8-trimethoxy-9,10-dihydro-9,10-(1,2)benzenoanthracene-1,4-dione
  • 2-bromo-3-methoxy-9,10-dihydro-9,10-(1,2)benzenoanthracene-1,4,5,8-tetrone
  • 2-methoxy-9,10-dihydro-9,10-(1,2)benzenoanthracene-1,4,5,8-tetrone
  • Amines
  • Antimalarials
  • Antineoplastic Agents
  • Benz(a)Anthracenes
  • Hydrocarbons, Brominated