New Synthetic Isoxazole Derivatives Acting As Potent Inducers of Fetal Hemoglobin in Erythroid Precursor Cells Isolated from β-Thalassemic Patients

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Jan 11

PMID 38202591

Authors

Cristina Zuccato

Lucia Carmela Cosenza

Chiara Tupini

Alessia Finotti

Gianni Sacchetti

Daniele Simoni

Roberto Gambari

Ilaria Lampronti

Affiliations

Soon will be listed here.

Abstract

Induction of fetal hemoglobin (HbF) is highly beneficial for patients carrying β-thalassemia, and novel HbF inducers are highly needed. Here, we describe a new class of promising HbF inducers characterized by an isoxazole chemical skeleton and obtained through modification of two natural molecules, geldanamycin and radicicol. After preliminary biological assays based on benzidine staining and RT-qPCR conducted on human erythroleukemic K562 cells, we employed erythroid precursors cells (ErPCs) isolated from β-thalassemic patients. ErPCs weretreated with appropriate concentrations of isoxazole derivatives. The accumulation of globin mRNAs was studied by RT-qPCR, and hemoglobin production by HPLC. We demonstrated the high efficacy of isozaxoles in inducing HbF. Most of these derivatives displayed an activity similar to that observed using known HbF inducers, such as hydroxyurea (HU) or rapamycin; some of the analyzed compounds were able to induce HbF with more efficiency than HU. All the compounds were active in reducing the excess of free α-globin in treated ErPCs. All the compounds displayed a lack of genotoxicity. These novel isoxazoles deserve further pre-clinical study aimed at verifying whether they are suitable for the development of therapeutic protocols for β-thalassemia.

Citing Articles

A β-Thalassemia Cell Biobank: Updates, Further Validation in Genetic and Therapeutic Research and Opportunities During (and After) the COVID-19 Pandemic.

Gambari R, Gamberini M, Cosenza L, Zuccato C, Finotti A J Clin Med. 2025; 14(1.

PMID: 39797371 PMC: 11722022. DOI: 10.3390/jcm14010289.

Therapeutic Relevance of Inducing Autophagy in β-Thalassemia.

Gambari R, Finotti A Cells. 2024; 13(11.

PMID: 38891049 PMC: 11171814. DOI: 10.3390/cells13110918.

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