Abstract
Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections.
Highlights
The development of peptidyl fluoromethyl ketones (PFMKs) has received over the last few decades a growing interest in drug discovery, since these types of compounds may be employed as substrates for a wide variety of biological targets [1]
Structures and activity of the t-PFMKs developed as Histone deacetylases (HDACs) inhibitors
D-PFMKsare andgaining t-PFMKs are gainingattention considerable attention within the pharmaceutical d-PFMKs and t-PFMKs considerable within the pharmaceutical research area, area, as both and di-fluorinated and tri-fluorinated methyl ketoneare moieties recognized as research both di-fluorinated tri-fluorinated methyl ketone moieties are recognized as valid as valid electrophilic pharmacophores for the design of therapeutic agents
Summary
The development of peptidyl fluoromethyl ketones (PFMKs) has received over the last few decades a growing interest in drug discovery, since these types of compounds may be employed as substrates for a wide variety of biological targets [1]. As a matter of fact, various peptides bearing a C-terminal mono-fluoromethyl ketone (m-FMK) warhead have been used as selective activity-based probes for important druggable enzymatic targets, e.g., cathepsins (Cats), caspases (Casps), calpain I, SENPs, and N-glycanase Their development as drugs has been compromised by the in vivo metabolic conversion of the m-FMK moiety into the highly toxic fluoroacetate [3]. 2 of 2 of the C–F bond was expected to lead a slow-binding reversible competitive inhibition of these nucleophilic enzymes) by electrophiles forming hemi(thio)ketal adducts (Figure 1). Theseimportant two fluorinated moieties exhibit another important characteristic; they of can the amino acids they are bound to, forming very stable gem-diols which mimic the tetrahedral adduct of hydrate, depending on the nature of the amino acids they are bound to, forming very stable the transition-state the enzyme-substrate (Figure 1).of. Design is becoming notable in view of their ability to selectively inhibit specific hydrolytic enzymes
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