Study of physico-chemical properties of novel highly sulfated, aromatic, mimetics of heparin and heparan sulfate

Liang, Aiye; Thakkar, Jay N.; Desai, Umesh R.

doi:10.1002/jps.21908

Cited by 22 publications

(27 citation statements)

References 29 publications

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“…These small sulfated NSGMs offer many advantages including i) adequate aqueous solubility (>25 mg/mL), which is expected to help antifibrinolytic use during surgeries, ii) limited cellular and central nervous system toxicity arising from their highly charged nature, iii) reasonable chemical stability, particularly under neutral and basic conditions [45], and iv) ease of chemical synthesis [41,46,47]. Further efforts are necessary to develop these sulfated NSGMs into clinically relevant molecules.…”

Section: Discussionmentioning

confidence: 99%

“…The monomeric scaffolds included chalcones (compounds 1-10), flavonoids (11)(12)(13)(14)(15)(16) [30][31][32], sucrose octasulfate (17) [40], quinazolinones (18 and 19) [37], and tetrahydro-isoquinolines (20)(21)(22)(23)(24)(25)(26)(27) [36], whereas the dimeric scaffolds comprised flavonoid-quinazolinone heterodimers (28)(29)(30)(31)(32)(33)(34) [37], bis-quinazolinones homodimers (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47) [37], and bis-flavonoid homodimers (48-55). In addition to the inherent diversity of the scaffolds in this library, NSGMs also differed in the number (1 to 8) and orientation of the sulfate groups.…”

Section: Chemical Synthesis Of the Library Of Nsgmsmentioning

confidence: 99%

“…New NSGMs synthesized for the first time included 10 sulfated chalcones (1-10), six sulfated bis-quinazolinones homodimers (42)(43)(44)(45)(46)(47), four sulfated flavonoid-quinazolinone heterodimers (31)(32)(33)(34), and eight sulfated bis-flavonoid homodimers (48-55). The synthesis of the new NSGMs is described in detail in Supplementary Information (Schemes S1-S6).…”

Section: Chemical Synthesis Of the Library Of Nsgmsmentioning

confidence: 99%

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Plasmin Regulation through Allosteric, Sulfated, Small Molecules

et al. 2015

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Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%-100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.

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Section: Discussionmentioning

confidence: 99%

Section: Chemical Synthesis Of the Library Of Nsgmsmentioning

confidence: 99%

Section: Chemical Synthesis Of the Library Of Nsgmsmentioning

confidence: 99%

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Plasmin Regulation through Allosteric, Sulfated, Small Molecules

et al. 2015

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“…Further, whereas sulfated LMWLs contain an average of one negatively charged group for every three monomers [4], LMWHs contain nearly 3 – 3.5 anionic groups for every three monosaccharides [7,8]. The combination of an aromatic scaffold with a limited number of carboxylate and sulfate groups appears to be responsible for interesting physico-chemical properties [9]. In addition, sulfated LMWLs have been found to exhibit novel protein recognition properties [10,11].…”

Section: Introductionmentioning

confidence: 99%

Sulfated, low molecular weight lignins inhibit a select group of heparin-binding serine proteases

Henry

Thakkar

Liang

et al. 2012

Biochemical and Biophysical Research Communications

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Sulfated low molecular weight lignins (LMWLs), designed as oligomeric mimetics of low molecular weight heparins (LMWHs), have been found to bind in exosite II of thrombin (Abdel Aziz et al. Biochem. Biophys. Res. Commun. 413 (2011) 348–352). To assess whether sulfated LMWLs recognize other heparin-binding proteins, we studied their effect on serine proteases of the coagulation, inflammatory and digestive systems. Using chromogenic substrate hydrolysis assay, sulfated LMWLs were found to potently inhibit coagulation factor XIa and human leukocyte elastase, moderately inhibit cathepsin G and not inhibit coagulation factors VIIa, IXa, and XIIa, plasma kallikrein, activated protein C, trypsin, and chymotrypsin. Competition studies show that UFH competes with sulfated LMWLs for binding to factors Xa and XIa. These results further advance the heparin-mimicking property of sulfated LMWLs and will aid the design of anticoagulants based on their novel scaffold.

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“…The oligomers possess interesting dual physicochemical properties. Sulfated LMWLs are highly hydrophilic due to their multiple anionic (sulfate and carboxylate) groups, but possess some hydrophobicity because of the presence of aromatic rings along the chains [5]. …”

Section: Introductionmentioning

confidence: 99%

Dynamic affinity chromatography in the separation of sulfated lignins binding to thrombin

Liang

Thakkar

Hindle

et al. 2012

Journal of Chromatography B

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Sulfated low molecular weight lignins (LMWLs), a mixture of chemo-enzymatically prepared oligomers, have been found to be potent antagonists of coagulation. However, structures that induce anticoagulation remain unidentified. The highly polar sulfate groups on these molecules and the thousands of different structures present in these mixtures make traditional chromatographic resolution of sulfated LMWLs difficult. We performed dynamic thrombin affinity chromatography monitored using chromogenic substrate hydrolysis assay to isolate sulfated LMWL fractions that differed significantly in their biophysical and biochemical properties. Three fractions, I35, I55 and Peak II, were isolated from the starting complex mixture. Independent plasma clotting assays suggested that I35 possessed good anticoagulation potential (APTT = 4.2 μM; PT = 6.8 μM), while I55 and Peak II were approximately 10- and 100-fold less potent. The ESI-MS spectrum of this oligomeric fraction showed multiple peaks at 684.8, 610.6, 557.4, 541.4, 536.5, and 519.4 m/z, which most probably arise from variably functionalized (β-O4—β-β-linked trimers and/or a β-O4—β-O4-linked dimers. The first direct observation of these structures in sulfated LMWLs will greatly assist in the discovery of more potent sulfated LMWL-based anticoagulants.

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Study of physico-chemical properties of novel highly sulfated, aromatic, mimetics of heparin and heparan sulfate

Cited by 22 publications

References 29 publications

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Sulfated, low molecular weight lignins inhibit a select group of heparin-binding serine proteases

Dynamic affinity chromatography in the separation of sulfated lignins binding to thrombin

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