Design, synthesis and evaluation of Fe-S targeted adenosine 5'-phosphosulfate reductase inhibitors.

Abstract

Adenosine 5'-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of Mycobacterium tuberculosis during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5'-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of N(6)-substituted adenosine analogues and their 5'-phosphates as well as adenosine 5'-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5'-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors.

• Authors: Hanumantharao Paritala, Yuta Suzuki, Kate S Carroll
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 34 Issue 3 Pg. 199-220 ( 2015) ISSN: 1532-2335 [Electronic] United States
• PMID: 25710356 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Sulfur
• Iron
• Oxidoreductases Acting on Sulfur Group Donors
• adenylylsulfate reductase

Topics

• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry)
• Iron (chemistry)
• Models, Molecular
• Molecular Conformation
• Oxidoreductases Acting on Sulfur Group Donors (antagonists & inhibitors)
• Solid-Phase Synthesis Techniques
• Sulfur (chemistry)