title: Development of Poly Unsaturated Fatty Acid Derivatives of Aspirin for Inhibition of Platelet Function.
abstract: The inhibition of platelet aggregation is key to preventing conditions such as myocardial infarction and ischemic stroke. Aspirin is the most widely used drug to inhibit platelet aggregation. Aspirin absorption can be improved further to increase its permeability across biologic membranes via esterification or converting the carboxylic acid to an anhydride. There are several reports indicating that ω-3 and ω-6 fatty acids such as linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) separately inhibit platelet aggregation. Herein, we synthesize anhydride conjugates of aspirin with linoleic acid, EPA, and DHA to form aspirin anhydrides that are expected to have higher permeability across cellular membranes. These aspirin-fatty acid anhydrides inhibited platelet aggregation in washed human platelets and platelet-rich plasma in a dose-dependent manner. In particular, the aspirin-DHA anhydride displayed similar effectiveness to aspirin. Platelet aggregation studies conducted in the presence of various platelet agonists indicated that the aspirin-lipid conjugates act through inhibition of the cyclooxygenase (COX)-thromboxane synthase (TXAS) pathway. Hence, we performed detailed biochemical studies using purified COX-1 as well as TXAS stabilized in nanoscale lipid bilayers of nanodiscs to confirm results from the platelet aggregation studies. We show that although all of the aspirin conjugates act through the COX-TXAS pathway by inhibiting COX-1, the parent fatty acids do not act via this pathway. Finally, we studied the hydrolysis of these compounds in buffer and human plasma, and we demonstrate that all of the aspirin-fatty acid conjugates hydrolyze to the parent molecules aspirin and fatty acid in a controlled manner.
authors.affiliation: Department of Chemistry (J.R.), Division of Nutritional Sciences, Departments of Comparative Biosciences, Biochemistry, and Bioengineering, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science (A.D.), University of Illinois at Urbana-Champaign, Urbana, Illinois; Division of Cardiovascular Medicine (M.H.), Department of Pharmacology (R.A., M.H.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Internal Medicine, Texas Health Science Center, McGovern Medical School, Houston, Texas (R.K.).
authors.forename: Jahnabi
authors.initials: J
authors.lastname: Roy
authors.affiliation: Department of Chemistry (J.R.), Division of Nutritional Sciences, Departments of Comparative Biosciences, Biochemistry, and Bioengineering, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science (A.D.), University of Illinois at Urbana-Champaign, Urbana, Illinois; Division of Cardiovascular Medicine (M.H.), Department of Pharmacology (R.A., M.H.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Internal Medicine, Texas Health Science Center, McGovern Medical School, Houston, Texas (R.K.).
authors.forename: Reheman
authors.initials: R
authors.lastname: Adili
authors.affiliation: Department of Chemistry (J.R.), Division of Nutritional Sciences, Departments of Comparative Biosciences, Biochemistry, and Bioengineering, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science (A.D.), University of Illinois at Urbana-Champaign, Urbana, Illinois; Division of Cardiovascular Medicine (M.H.), Department of Pharmacology (R.A., M.H.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Internal Medicine, Texas Health Science Center, McGovern Medical School, Houston, Texas (R.K.).
authors.forename: Richard
authors.initials: R
authors.lastname: Kulmacz
authors.affiliation: Department of Chemistry (J.R.), Division of Nutritional Sciences, Departments of Comparative Biosciences, Biochemistry, and Bioengineering, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science (A.D.), University of Illinois at Urbana-Champaign, Urbana, Illinois; Division of Cardiovascular Medicine (M.H.), Department of Pharmacology (R.A., M.H.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Internal Medicine, Texas Health Science Center, McGovern Medical School, Houston, Texas (R.K.).
authors.forename: Michael
authors.initials: M
authors.lastname: Holinstat
authors.affiliation: Department of Chemistry (J.R.), Division of Nutritional Sciences, Departments of Comparative Biosciences, Biochemistry, and Bioengineering, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science (A.D.), University of Illinois at Urbana-Champaign, Urbana, Illinois; Division of Cardiovascular Medicine (M.H.), Department of Pharmacology (R.A., M.H.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Internal Medicine, Texas Health Science Center, McGovern Medical School, Houston, Texas (R.K.) aditidas@illinois.edu.
authors.forename: Aditi
authors.initials: A
authors.lastname: Das
mesh_terms: D000818:Animals; D001241:Aspirin / Q000737:chemistry* / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D015525:Fatty Acids, Omega-3 / Q000737:chemistry*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D061987:Sf9 Cells; D018411:Spodoptera; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D016861:Cyclooxygenase Inhibitors; D015525:Fatty Acids, Omega-3; D051545:Cyclooxygenase 1; D013930:Thromboxane-A Synthase; D001241:Aspirin