Inhibition of aberrant complement activation by a dimer of acetylsalicylic acid

Neurobiol Aging. 2015 Oct;36(10):2748-56. doi: 10.1016/j.neurobiolaging.2015.06.018. Epub 2015 Jun 17.


We here report synthesis for the first time of the acetyl salicylic acid dimer 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS). DAS inhibits aberrant complement activation by selectively blocking factor D of the alternative complement pathway and C9 of the membrane attack complex. We have previously identified aurin tricarboxylic and its oligomers as promising agents in this regard. DAS is much more potent, inhibiting erythrocyte hemolysis by complement-activated serum with an IC50 in the 100-170 nanomolar range. There are numerous conditions where self-damage from the complement system has been implicated in the pathology, including such chronic degenerative diseases of aging as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and age-related macular degeneration. Consequently, there is a high priority for the discovery and development of agents that can successfully treat such conditions. DAS holds considerable promise for being such an agent.

Keywords: Age-related macular degeneration; Alzheimer's disease; C9; Factor B; Factor D; Membrane attack complex; Properdin.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / etiology
  • Animals
  • Aspirin / analogs & derivatives*
  • Aspirin / chemical synthesis
  • Aspirin / pharmacology
  • Aurintricarboxylic Acid
  • Benzhydryl Compounds / chemical synthesis
  • Benzhydryl Compounds / pharmacology*
  • Cats
  • Cells, Cultured
  • Complement Activation / drug effects*
  • Complement C6 / antagonists & inhibitors
  • Complement Factor D / antagonists & inhibitors*
  • Complement Membrane Attack Complex
  • Complement Pathway, Alternative
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Erythrocytes / drug effects
  • Hemolysis / drug effects
  • Humans
  • Macular Degeneration / drug therapy
  • Macular Degeneration / etiology
  • Molecular Targeted Therapy
  • Rats


  • 5,5'-methylenebis(2-acetoxybenzoic acid)
  • Benzhydryl Compounds
  • Complement C6
  • Complement Membrane Attack Complex
  • Aurintricarboxylic Acid
  • Complement Factor D
  • Aspirin