Preparation, crystal and molecular structure, and evaluation of plant growth regulating activity of guanidinoalkanephosphinates and phosphonates
A series of previously unknown α-guanidinoalkanephosphonous, α- and β-guanidinoalkanephosphonic acids has been prepared in order to study their structures and biological activity. Aminoalkanephosphonous and phosphonic acids have been converted into their guanidino derivatives by means of S-methylisothiourea hydroiodide or cyanamide amidination. The crystal and molecular structures of three guanidino acids have been determined by single-crystal X-ray diffraction. The plant growth regulating activity of all synthesized guanidinoalkanephosphinates and phosphonates has been evaluated on Lepidium sativum. © 1995 John Wiley & Sons, Inc.
A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases
Abstract N′-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., K i = 65 nM of 1u for Hs APN). Two structures of an M1 representative (APN from Neisser…
A three-component Mannich-type condensation leading to phosphinic dipeptides—extended transition state analogue inhibitors of aminopeptidases
Abstract N-Protected α-aminoalkylphosphinic acids bearing a P–H function were found to be novel practical building blocks in three-component condensations with formaldehyde and secondary amines (amino acids). Such Mannich-type N -phosphonomethylation is a common approach for phosphorus acid derived substrates and leads to multifunctional (phosphonic/amino/carboxylic) compounds of diverse relevance. The utility of this reaction was examined for construction, in a single synthetic step, of advanced phosphinic pseudodipeptides designed to act as extended transition state analogue inhibitors of selected aminopeptidases. Phosphinomethylation of primary amino acids was less efficient and yielded …
Unusual activity pattern of leucine aminopeptidase inhibitors based on phosphorus containing derivatives of methionine and norleucine
Ligands containing bulky aliphatic P1 residues exhibit a high affinity towards cytosolic leucine aminopeptidase, a bizinc protease of biomedical significance. According to this specificity, a series of phosphonic and phosphinic compounds have been put forward as novel putative inhibitors of the enzyme. These phosphonic and phosphinic compounds were derivatives of methionine and norleucine as both single amino acids and dipeptides. The designed inhibitors were synthesised and tested towards the peptidase isolated from porcine kidneys using an improved separation procedure affording superior homogeneity. Unexpectedly, organophosphorus derivatives of methionine and norleucine exhibited moderat…
Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases
Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor–enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side…
A synthetic method for diversification of the P1′ substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1′ binding pockets of leucine aminopeptidases
Abstract A novel, general, and versatile method of diversification of the P1′ position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, was elaborated. The procedure was based on parallel derivatization of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. This synthetic strategy represents an original approach to phosphinic dipeptide chemistry. Its usefulness was confirmed by obtaining a series of P1′ modified phosphinic dipeptides, inhibitors of cytosolic leucine aminopeptidase, through computer-aided design basing on the structure of homophenylalanyl-phenylalanine analogue (hPheP[CH 2 ]Phe) bound in …
Individual stereoisomers of phosphinic dipeptide inhibitor of leucine aminopeptidase
Abstract Individual stereoisomers of the phosphinic pseudodipeptide hPheψ[P(O)(OH)CH2]Phe were obtained by stereoselective liquid chromatographic separation as N- and C-terminally protected derivative on quinidine carbamate modified silica stationary phase. The stereoisomeric purity, exceeding 95% for each fraction, was determined before and after deprotection using two independent methods. The absolute configuration was rationally assigned by application of enantiomerically pure phosphinic acid substrates in the synthetic procedure and correlation with biological activity of the products. Substantial differences in inhibition of leucine aminopeptidase by the individual isomers revealed nov…
Enantiodifferentiation of N-benzyloxycarbonylaminophosphonic and phosphinic acids and their esters using cyclodextrins by means of capillary electrophoresis
Capillary electrophoresis was successfully applied for separation of the enantiomers of N-benzyloxycarbonyl-alpha-aminophosphonic and alpha-aminophosphinic acids as well as their ethyl and phenyl monoesters with the use of a range of commercially available cyclodextrins (alpha, beta and hydroxypropyl-gamma-cyclodextrins) as chiral selectors. The dependence of effectiveness of separation on type and concentration of these chiral selectors as well as on pH of background electrolyte was examined in some detail.
High-performance liquid chromatographic enantiomer separation and determination of absolute configurations of phosphinic acid analogues of dipeptides and their α-aminophosphinic acid precursors
The enantiomers of N-benzyloxycarbonyl-phosphinic pseudodipeptides and their N-benzyloxycarbonyl-α-aminophosphinic acid precursors as well as various other structural analogues were separated on a set of cinchona alkaloid-derived chiral anion-exchangers by HPLC in the reversed-phase mode. Semi-preparative scale chromatography provided single enantiomers in 100 mg quantities. The configurations of the enantiomers were assigned indirectly by enantioselective chromatography on the basis of the elution order and was confirmed by enantiomeric reference compounds.
Synthesis and activity of phosphinic tripeptide inhibitors of cathepsin C
Phosphinic tripeptide analogues Gly-Xaaψ[P(O)(OH)CH2]-Gly have been developed as inhibitors of cathepsin C (DPP I), a lysosomal, papain-like cysteine protease. The target compounds were synthesised by addition of methyl acrylate to the appropriate phosphinic acids followed by the N-terminus elongation using mixed anhydride procedure. The latter step has been demonstrated to be a suitable method for N-terminal extension of the phosphinic pseudopeptide analogues without requirement of hydroxyphosphinyl protection. The title compounds appeared to be moderate inhibitors of the cathepsin C. However, although designed as transition state analogues, they surprisingly exhibited noncompetitive mode …