Síntese de derivados do voxelotor como agentes ligantes covalentes irreversíveis de hemoglobina
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Data
2022-12-15
Autores
Rauber, Raquel dos Santos
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Universidade Estadual Paulista (Unesp)
Resumo
A anemia falciforme (AF) é uma doença hematológica de origem genética caracterizada por uma mutação pontual, em que o códon que codifica o ácido glutâmico na hemoglobina adulta normal (HbA) passa a codificar a valina, resultando na hemoglobina falciforme (HbS). Tal troca provoca alterações na estrutura da hemoglobina aumentando a capacidade de polimerização frente aos estágios de desoxigenação. Dentre os tratamentos disponíveis, o mais utilizado é a hidroxiureia (HU), entretanto esta possui alguns efeitos adversos graves e estima-se que em cerca de 1/3 dos pacientes não respondem adequadamente a HU. Uma opção recente aprovada pela agência norte-americana FDA é o voxelotor, capaz de se ligar covalentemente à cadeia alfa da HbS e modular sua afinidade ao oxigênio (O2). O análogo do voxelotor, composto VZHE-039, demonstrou ser capaz de inibir a polimerização tanto em situações de hipoxia como anoxia mostrando vantagens comparados ao voxelotor. Dessa forma, esse análogo se constitui como um importante protótipo para modificações moleculares. Nos últimos anos nosso grupo de pesquisa demonstrou a importância no oxido nítrico (NO) no tratamento da anemia falciforme, apresentando efeitos diretos como dilatadores nos vasos, além de induzir a produção de hemoglobina fetal via ativação da via NO/guanilato ciclase/GMPc. Frente aos efeitos benéficos dos furoxanos como doadores de óxido nítrico, neste trabalho realizamos o planejamento e a síntese de um novo derivado do VZHE-039 conjugado a um doador de óxido nítrico.
Sickle cell anemia (SCA) is a hematological disease of genetic origin characterized by a punctual mutation, in which the codon that encodes glutamic acid in normal adult hemoglobin (HbA) starts to encode valine, resulting in sickle cell hemoglobin (HbS). Such an exchange causes changes in the hemoglobin structure, increasing the polymerization capacity in the face of deoxygenation stages. Among the available treatments, the most used is hydroxyurea (HU), however it has some serious adverse effects and it is estimated that in about 1/3 of patients do not respond adequately to HU. A recent option approved by the US FDA is voxelotor, capable of covalently binding to the alpha chain of HbS and modulating its affinity for oxygen. The voxelotor analogue, compound VZHE-039, was shown to be able to inhibit polymerization in both hypoxia and anoxia, showing advantages compared to voxelotor. Thus, this analogue constitutes an important prototype for molecular modifications. In recent years, our research group has demonstrated the importance of nitric oxide (NO) in the treatment of sickle cell anemia, presenting direct effects as dilators in the vessels, in addition to inducing the production of fetal hemoglobin via activation of the NO/guanylate cyclase/cGMP pathway. In view of the beneficial effects of furoxanes as nitric oxide donors, in this work we carried out the planning and synthesis of a new derivative of VZHE-039 conjugated to a nitric oxide donor.
Sickle cell anemia (SCA) is a hematological disease of genetic origin characterized by a punctual mutation, in which the codon that encodes glutamic acid in normal adult hemoglobin (HbA) starts to encode valine, resulting in sickle cell hemoglobin (HbS). Such an exchange causes changes in the hemoglobin structure, increasing the polymerization capacity in the face of deoxygenation stages. Among the available treatments, the most used is hydroxyurea (HU), however it has some serious adverse effects and it is estimated that in about 1/3 of patients do not respond adequately to HU. A recent option approved by the US FDA is voxelotor, capable of covalently binding to the alpha chain of HbS and modulating its affinity for oxygen. The voxelotor analogue, compound VZHE-039, was shown to be able to inhibit polymerization in both hypoxia and anoxia, showing advantages compared to voxelotor. Thus, this analogue constitutes an important prototype for molecular modifications. In recent years, our research group has demonstrated the importance of nitric oxide (NO) in the treatment of sickle cell anemia, presenting direct effects as dilators in the vessels, in addition to inducing the production of fetal hemoglobin via activation of the NO/guanylate cyclase/cGMP pathway. In view of the beneficial effects of furoxanes as nitric oxide donors, in this work we carried out the planning and synthesis of a new derivative of VZHE-039 conjugated to a nitric oxide donor.
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Palavras-chave
Voxelotor, VZHE-039, Óxido nítrico, Novos fármacos, Anemia falciforme, Nitric oxide, New drugs, Sickle cell anemia