Enzyme inhibitors fluorine-containing

A number of protein structures determined by X-ray crystallography have been reported to date for the complexes of various enzymes with fluorine-containing substrate mimics or inhibitors bearing multiple fluorines. This strongly suggests that not only single fluorine displacement but also various fluorine-substitution patterns in substrate analogues... 

Examples of fluorine-containing imino sugars as partial structures of PNPs have been reported. The S -deoxy-S -fluoro compound 116 ( S -F-Imucillin H, Scheme 29) was found to be a nanomolar inhibitor of human PNP (1 nM) as well as that of Plasmodium falciparum (A) 60 nM).237 2,-Deoxy-2,2 -difluoro derivative 117 ( -diF-immucillin-H ) exhibited slightly more inhibitory power against the microbial enzyme and an enhanced selectivity of more than three orders of magnitude (ATj 1.4 nM vs. 15 pM).238 Another type of inhibitor, the 3-fluoro compound 118 ( F-DADMe-immucillin-H ) was shown a potent picomolar inhibitor of the human enzyme (Kf 32 pM), with some selectivity over the Plasmodium phos-phorylase (2.6 nM), whereas the enantiomer 119 was 50- to 100-fold less active 239,240... 

This chapter deals with fluorine-containing molecules that are currently clinically used as pharmaceuticals or are at an advanced stage of their development (i.e., registered by the administration or under clinical trials I, II, or III). These compounds are found in almost all therapeutic classes and stem from very diverse chemical families. In most cases, they are inhibitors of enzymes (anti-infectious, antitumor, antiviral drugs) or are ligands of various receptors (membraneous receptors coupled to protein G, ionic channels, or nuclear receptors). 

Fluorination of Aminoacids and Amines. Fluorinated analogs of naturally occurring aminoacids and amines exhibit unique physiological activities. A number of fluorine containing amino acids have been synthesized and studied as potential enzyme inhibitors and therapeutic agents... 

Among the most deadly of simple compounds is sodium fluoroacetate. The LD50 (the dose lethal for 50% of animals receiving it) is only 0.2 mg/kg for rats, over tenfold less than that of the nerve poison diisopropylphosphofluoridate (Chapter 12).a b Popular, but controversial, as the rodent poison "1080," fluoroacetate is also found in the leaves of several poisonous plants in Africa, Australia, and South America. Surprisingly, difluoroacetate HCF2-COO is nontoxic and biochemical studies reveal that monofluoroacetate has no toxic effect on cells until it is converted metabolically in a "lethal synthesis" to 2R,3R-2-fluorocitrate, which is a competitive inhibitor of aconitase (aconitate hydratase, Eq. 13-17).b This fact was difficult to understand since citrate formed by the reaction of fluorooxalo-acetate and acetyl-CoA has only weak inhibitory activity toward the same enzyme. Yet, it is the fluorocitrate formed from fluorooxaloacetate that contains a fluorine atom at a site that is attacked by aconitase in the citric acid cycle. 

Sulfonylureas are generally extremely potent inhibitors of ALS [181] the key enzyme within the biosynthesis of branched amino acids such as leucine, isoleucine or valine [181, 182] (for more details see Chapter 2.2). Approximately 57.5% of commercialized sulfonylureas or development products are halogen free. The remaining 42.5% (halogens/subclass a > b) launched so far contain halogen atoms such as fluorine ( 24%), chlorine ( 15%) or iodine ( 3%) (Fig. 35.21). 

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