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Structure‐Based Design and Synthesis of the First Weak Non‐Phosphate Inhibitors for IspF, an Enzyme in the Non‐Mevalonate Pathway of Isoprenoid Biosynthesis
Author(s) -
Baumgartner Corinne,
Eberle Christian,
Diederich François,
Lauw Susan,
Rohdich Felix,
Eisenreich Wolfgang,
Bacher Adelbert
Publication year - 2007
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200790105
Subject(s) - chemistry , mevalonate pathway , stereochemistry , enzyme , biosynthesis , cytosine , terpenoid , moiety , biochemistry , substrate (aquarium) , ribose , active site , dna , biology , ecology
In this paper, we describe the structure‐based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non‐mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C 5 precursors to isoprenoids, isopentenyl diphosphate (IPP, 1 ) and dimethylallyl diphosphate (DMAPP, 2 ; Scheme 1 ). The non‐mevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non‐mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling ( cf. Figs. 2 and 3 ), new cytosine derivatives and analogues ( Fig. 1 ) were selected as potential drug‐like inhibitors of IspF protein, and synthesized ( Schemes 2–5 ). Determination of the enzyme activity by 13 C‐NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine‐2,5‐diamine derivatives in the upper micromolar range ( IC 50 values; Table ). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56′, which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub‐pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to ‘Pocket III’) and rings that occupy the flexible hydrophobic region of ‘Pocket II’. The proposed binding mode remains to be further validated by X‐ray crystallography.