Issue 22, 2015

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

Abstract

Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on the ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds – designated as KAUS (imidazolylacryloyl derivatives) – that we hypothesized would bind covalently to βCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition between the β-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with βCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, but showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation for the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.

Graphical abstract: Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

Supplementary files

Article information

Article type
Paper
Submitted
23 Feb 2015
Accepted
16 Apr 2015
First published
17 Apr 2015

Org. Biomol. Chem., 2015,13, 6353-6370

Author version available

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

A. M. Omar, M. A. Mahran, M. S. Ghatge, N. Chowdhury, F. H. A. Bamane, M. E. El-Araby, O. Abdulmalik and M. K. Safo, Org. Biomol. Chem., 2015, 13, 6353 DOI: 10.1039/C5OB00367A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements