Irreversible Inhibition of Serine Proteases – Design and In Vivo Activity of Diaryl α-Aminophosphonate Derivatives

Abstract

Diaryl esters of alpha-aminophosphonates are a group of low molecular weight inhibitors of serine proteases. For over 30 years these molecules have captured the attention of biochemists and medicinal chemists due to their similarity to the transition state of peptide bond cleavage observed in enzymatic reactions (transition state analogs) as well as their high potency of action. High reactivity toward serine proteases and complete lack of activity against cysteine or threonine proteases give alpha-aminophosphonates great advantage over other classes of inhibitors such as chloromethyl ketones or peptidyl derivatives of ketoesters and ketoamides, which are known to react with serine and cysteine proteases. Moreover, the selectivity of alpha-aminophosphonates' action can be easily adjusted - even for serine proteases with similar specificity a small modification in the inhibitor structure could lead to absolute selectivity towards a particular enzyme. Furthermore alpha-aminophosphonate derivatives are successfully used as the activity based probes (ABP) for serine protease-like activity screening and as covalently reactive antigens for the development of catalytic antibodies (CAbs). The design of alpha-aminophosphonate diaryl ester inhibitors focuses on enzymes involved in the development and progression of pathophysiological states in living organisms. Examples include cancer growth and metastasis (urokinase-type plasminogen activator, uPA), diabetes or transplant rejection (dipeptidyl peptidase IV, DPPIV), osteoarthritis and lung injury (elastase) or heart failure (mast cell chymase). This review article focuses on the design of new alpha-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.

New Selective Peptidyl Di(chlorophenyl) Phosphonate Esters for Visualizing and Blocking Neutrophil Proteinase 3 in Human Diseases

“…Peptidyldiphenyl phosphonate inhibitors are irreversible transition state inhibitors that form a tetrahedral adduct with the serine 195 residue (chymotrypsin numbering) of the catalytic triad (13,14). They selectively inhibit serine proteases, are chemically stable in several buffers and in the plasma under acidic and neutral conditions, and are effective at low concentrations (15).…”

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

“…The reaction of (1S,2S)-48 with oxalyl chloride and DMF in MeCN, afforded the phosphonomonochloridate (1S,2S)-49, that without additional purification was reacted with different organolithium or Grignard reagents, to obtain the α-amino-C-phosphinates (1S,2S)-50a-d in 37%-56% yield, which have been used in the design and synthesis of new enzyme inhibitors (Scheme 25). On the other hand, the reduction of the phosphonomonochloridate (1S,2S)-49 with LiAlH(Ot-Bu) 3 in THF at −78 • C, produced the H-phosphinate (1S,2S)-51 in 78% yield, which by alkylation either by activation with chlorotrimethylsilane (TMSCl) and diisopropyl ethylamine (DIPEA) followed by addition of an alkyl halide (method A), or using NaHMDS and subsequent addition of an alkyl halide (method B), furnished the P-alkylated α-amino-C-phosphinates (1S,2S)-50e-l in 27%-63% yield (Scheme 26) [65,66].…”

“…These classes of compounds are currently attracting great interest in organic and medicinal chemistry, as well as in agriculture, due to their important biological and pharmacological properties [1][2][3][4][5]. The great importance of this type of compounds has prompted organic chemists to report numerous procedures for their racemic or stereoselective synthesis [6][7][8][9][10][11].…”

Inhibitors of Proteinases as Potential Anti-Cancer Agents

“…15). Anyway, the mode of action of phosphonates towards serine proteinases is not yet fully elucidated and minor variations were observed, depending on the targeted enzyme and conditions (Grzywa et al 2007;Joossens et al, 2006;Sieńczyk et al, 2011;Sieńczyk & Oleksyszyn 2006;Sieńczyk & Oleksyszyn, 2009).…”