Novel chemo-enzymatic oligomers of cinnamic acids as direct and indirect inhibitors of coagulation proteinases

Monien, Bernhard H.; Henry, Brian L.; Raghuraman, Arjun; Hindle, Michael; Desai, Umesh R.

doi:10.1016/j.bmc.2006.07.066

Cited by 63 publications

(147 citation statements)

References 36 publications

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“…The molecular weight values suggest that an average of 12.7, 15.5, and 14.4 monomer units are present in CD, FD, and SD, respectively. Sulfate composition of the sulfated DHPs was determined by elemental analysis and found to be 0.40, 0.30, and 0.38 sulfate groups per monomer unit (16). This implies that an average of 5.1, 4.7, and 5.5 sulfate groups per average DHP chain are present in CDSO3, FDSO3, and SDSO3, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Physicochemical Properties of CDSO3, FDSO3, and SDSO3-The weight average molecular weight of the unsulfated parent dehydropolymers CD, FD, and SD were determined by Monien et al (16) using nonaqueous size-exclusion chromatography ( Table 1). The molecular weight values suggest that an average of 12.7, 15.5, and 14.4 monomer units are present in CD, FD, and SD, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…1B). Horseradish peroxidase-catalyzed oxidative coupling followed by sulfation of the available hydroxyl and phenolic groups gives the corresponding sulfated DHPs, CDSO3, FDSO3, and SDSO3, in reproducibly good yields (16). Overall, these sulfated DHPs are a mixture of many oligomeric species that range in size from 4 to 15 monomer units and contain several intermonomer linkages, including ␤-O-4, ␤-5, ␤-␤, and 5-5.…”

Section: Structure Of Sulfated Dehydropolymers (Dhps)-mentioning

confidence: 99%

“…The sulfated DHPs prolonged activated partial thromboplastin time and prothrombin time at concentrations equivalent to LMWH. Interestingly, although being designed as heparin mimics, CDSO3, FDSO3 and SDSO3 were found to inhibit factor Xa and thrombin in an antithrombin-independent (direct) manner suggesting a potentially novel mode of inhibition (16).…”

mentioning

confidence: 99%

“…1B). Three sulfated DHPs, CDSO3, FDSO3, and SDSO3, were prepared in a simple two-step chemo-enzymatic process involving horseradish peroxidase-catalyzed oligomerization of 4-hydroxycinnamic acid monomers followed by the chemical sulfation of the resulting DHPs with triethylamine-sulfur trioxide complex (16). Preliminary studies suggested that the chemo-enzymatic sulfated DHPs were potent anticoagulants in vitro.…”

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confidence: 99%

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A Novel Allosteric Pathway of Thrombin Inhibition

Henry

Monien

Bock

et al. 2007

Journal of Biological Chemistry

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118

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Thrombin and factor Xa, two important pro-coagulant proteinases, can be regulated through direct and indirect inhibition mechanisms. Recently, we designed sulfated dehydropolymers (DHPs) of 4-hydroxycinnamic acids that displayed interesting anticoagulant properties (Monien, B. H., Henry, B. L., Raghuraman, A., Hindle, M., and Desai, U. R. (2006) Bioorg. Med. Chem. 14, 7988 -7998). To better understand their mechanism of action, we studied the direct inhibition of thrombin, factor Xa, factor IXa, and factor VIIa by CDSO3, FDSO3, and SDSO3, three analogs of sulfated DHPs. All three sulfated DHPs displayed a 2-3-fold preference for direct inhibition of thrombin over factor Xa, whereas this preference for inhibiting thrombin over factor IXa and factor VIIa increased to 17-300-fold, suggesting a high level of selectivity. Competitive binding studies with a thrombin-specific chromogenic substrate, a fluorescein-labeled hirudin peptide, bovine heparin, enoxaparin, and a heparin octasaccharide suggest that CDSO3 preferentially binds in or near anion-binding exosite II of thrombin. Studies of the hydrolysis of H-D-hexahydrotyrosol-Ala-Arg-p-nitroanilide indicate that CDSO3 inhibits thrombin through allosteric disruption of the catalytic apparatus, specifically through the catalytic step. Overall, designed sulfated DHPs appear to be the first molecules that bind primarily in the region defined by exosite II and allosterically induce thrombin inhibition. The molecules are radically different in structure from all the current clinically used anticoagulants and thus represent a novel class of potent dual thrombin and factor Xa inhibitors.The coagulation cascade is composed of two intertwined pathways, called the extrinsic and the intrinsic pathways, that operate in a highly complex, but tightly regulated, manner to bring about controlled formation of the fibrin polymer. Several enzymes participate in this process, including factor IXa and factor VIIa, which belong to the intrinsic and extrinsic pathways, respectively, and thrombin and factor Xa, which belong to the common pathway (1, 2). The cascade is regulated by several proteins present naturally in the plasma, of which antithrombin is a major regulator (3, 4).Antithrombin, a member of the serpin (serine proteinase inhibitor) family of proteins, primarily inhibits thrombin, factor Xa, and factor IXa and also possibly inhibits several other enzymes to a lesser extent. Yet antithrombin is a rather poor inhibitor of these pro-coagulant enzymes and requires the presence of heparin to exhibit its anticoagulant potential (3, 4). Heparin is a highly sulfated polysaccharide that greatly enhances the rate of antithrombin inhibition of thrombin, factor Xa, and factor IXa under physiological conditions (5). This acceleration is the primary reason for the continued use of heparin as an effective anticoagulant for the past 8 decades. Yet heparin suffers from several limitations, including enhanced risk for bleeding, variable patient response, heparin-induced thrombocytopenia, and the ...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Structure Of Sulfated Dehydropolymers (Dhps)-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Allosteric Pathway of Thrombin Inhibition

Henry

Monien

Bock

et al. 2007

Journal of Biological Chemistry

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118

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Anticoagulants

Henry

Desai

2010

Burger's Medicinal Chemistry and Drug Discovery

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Thrombotic disorders are a major cause of morbidity and mortality in humans. Examples of thrombotic disorders include pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, acute myocardial infarction, unstable angina, and cerebrovascular thrombosis. Anticoagulants are the mainstay of treatment and prevention of these disorders. The most widely used anticoagulants include unfractionated heparin, low molecular weight heparins and warfarin. Newer agents introduced in the past decade include bivalirudin, fondaparinux, and argatroban. Mechanistically, these anticoagulants either directly inhibit thrombin or indirectly reduce the activity of thrombin and factor Xa. Several new molecules have been recently designed to directly inhibit thrombin and factor Xa with high potency and considerable selectivity, of which dabigatran and rivaroxaban were approved for clinical use in few countries in 2008. Molecules being pursued in clinical trials include AZD0837, LB‐30870, otamixaban, apixaban, YM‐150, and others. Ximelagatran, which was introduced in 2004 as a direct thrombin inhibitor, was taken off the market within 20 months due to significant hepatotoxicity. Indirect anticoagulants utilize the antithrombin‐mediated conformational activation and bridging mechanisms for inhibiting coagulation enzymes. Among the indirect anticoagulants that are currently being investigated in clinical trials are a biotinylated idraparinux and SR123781. Over the last two decades, major conceptual strides have been made including the design of the first anticoagulant based solely on factor Xa inhibition (fondaparinux) and the establishment of the paradigm that anticoagulation is possible without frequent laboratory monitoring (ximelagatran). Current work attempts to establish other concepts such as the dual inhibition of free and clot‐bound thrombin by a heparin‐based molecule (ORG42675) and the applicability of neutral P1‐group containing active site‐directed molecules as effective inhibitors of coagulation enzymes (rivaroxaban). To date, no molecule has been designed that satisfies all the properties of an ideal anticoagulant including a broad therapeutic window, absence of bleeding risk, no requirement for frequent coagulation monitoring, oral bioavailability, availability of an effective antidote, lack of hepatoxicity and absence other adverse effects. Yet, the newer agents are likely to be more attractive than the heparin‐ and coumarin‐based therapy. In this chapter, we review the structure, design, and mechanism of action of clinically used and new potential anticoagulants. Special emphasis is placed on the molecular interaction of anticoagulants with their targets.

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