Study of physico-chemical properties of novel highly sulfated, aromatic, mimetics of heparin and heparan sulfate.
Heparin (H) and heparan sulfate (HS) play major roles in a number of biological processes. Yet, H/HS-based pharmaceutical agents are also associated with multiple adverse effects. This has led to the concept of designing noncarbohydrate, aromatic mimetics that modulate H/HS function. In this work, we study a library of synthetic, aromatic H/HS mimetics for their capillary electrophoretic profiles, the acid and base stability, and aqueous-organic partitioning property. The nonsugar H/HS mimetics exhibit electrophoretic properties similar to sulfated oligosaccharides suggesting that the mimetics can be rapidly and quantitatively analyzed. Stability studies show that the mimetics are essentially stable under neutral and basic conditions in a manner similar to the heparins, but are considerably unstable under acidic conditions in contrast to heparins. The measurement of partition coefficients show major differences within the sulfated mimetics as well as between the measured and calculated log P values. Understanding these physico-chemical properties is expected to have significant implications in the pharmaceutical development of this growing class of molecules.
Liang
Aiye
A
Department of Medicinal Chemistry, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23219, USA.
Thakkar
Jay N
JN
Desai
Umesh R
UR
D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry*; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004355:Drug Stability; D019075:Electrophoresis, Capillary / Q000379:methods; D006493:Heparin / Q000031:analogs & derivatives / Q000737:chemistry*; D006497:Heparan Sulfate / Q000737:chemistry*; D015394:Molecular Structure; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility
D000925:Anticoagulants; D006493:Heparin; D006497:Heparan Sulfate; D011084:Polycyclic Aromatic Hydrocarbons