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1.
Thromb Res ; 141 Suppl 2: S4-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27207422

RESUMO

Cancer is an established risk factor for venous thromboembolism (VTE) and VTE is the second leading cause of death in patients with cancer. The incidence of cancer-related thrombosis is rising and is associated with worse outcomes. Despite our growing understanding on tumor-driven procoagulant mechanisms including cancer-released procoagulant proteases, expression of tissue factor on cancer cells and derived microvesicles, as well as alterations in the extracellular matrix of the cancer cell milieu, anticoagulation therapy in cancer patients has remained challenging. This review comments on a newly discovered cancer-associated procoagulant pathway. Experimental VTE models in mice and studies on patient cancer material revealed that prostate cancer cells and associated exosomes display the inorganic polymer polyphosphate on their plasma membrane. Polyphosphate activates blood coagulation factor XII and initiates thrombus formation via the intrinsic pathway of coagulation. Pharmacologic inhibition of factor XII activity protects mice from VTE and reduces thrombin coagulant activity in plasma of prostate cancer patients. Factor XII inhibitors provide thrombo-protection without impairing hemostatic mechanisms and thus, unlike currently used anticoagulants, do not increase bleeding risk. Interference with the polyphosphate/factor XII pathway may provide the novel opportunity for safe anticoagulation therapy in patients with malignancies.


Assuntos
Anticoagulantes/uso terapêutico , Fator XII/metabolismo , Neoplasias/complicações , Polifosfatos/metabolismo , Trombose/complicações , Trombose/tratamento farmacológico , Animais , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fator XII/antagonistas & inibidores , Humanos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/metabolismo , Trombose/sangue , Trombose/metabolismo , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/metabolismo
2.
J Org Chem ; 72(17): 6454-8, 2007 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-17630801

RESUMO

The conformational interconversions of four [2]catenanes (1-4) containing a dibenzo-34-crown-10 ether (BPP34C10) interlocked with rings containing two 4,4'-dipyridiniums tethered by 1,3-bis(ethyloxy)phenyl and bis(p-benzyl)methyl spacers have been studied by VT 1H NMR spectroscopy. Symmetrically placed blocking groups on thickened tethers enabled either pathway for circumrotation of the BPP34C10 between isoenergetic sites to be blocked. On the basis of chemical shifts of the BPP34C10, its internal p-hydroquinone forms pi-pi-stacking interactions with only one 4,4'-dipyridinium ring at a time. The activation barrier for migration along either open tether was approximately 11.5 kcal/mol. This study demonstrates an ability to select the pathway for conformational interconversions in these [2]catenanes containing the rigid bis(p-benzyl)methyl tether and the lowering the barrier for interconversion through destabilization of the ground state structures.


Assuntos
Catenanos/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray
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