Phosphinic Acid Pseudopeptides Analogous to Glutamyl-γ-glutamate:  Synthesis and Coupling to Pteroyl Azides Leads to Potent Inhibitors of Folylpoly-γ-glutamate Synthetase

Abstract

Several routes to a complex phosphinate phosphapeptide analogous to the gamma-glutamyl peptide Glu-gamma-Glu have been investigated. Formation of gamma-phosphono glutamate derivatives via addition of a phosphorus-based radical to protected vinylglycine was found to be of limited value because of the elevated temperatures required. Alkylation and conjugate addition reactions of trivalent phosphorus (P(III)) species were investigated. In situ generation of bis-trimethylsilyl esters of phosphinous acids proved to be an effective route to phosphinates of modest structural complexity. However, this chemistry could not be extended to the incorporation of an amino acid moiety at the N-terminal side of the desired phosphinate. A successful synthesis of the target phosphinate phosphapeptide was effected using P(III) chemistry and dehydrohalogenation to yield an alpha,beta-unsaturated phosphinic acid ester, following which conjugate addition of diethylacetamido malonate and acid-mediated hydrolysis afforded the desired phosphinate phosphapeptide. Coupling of the unprotected phosphinate phosphapeptide with two acyl azides derived from folic acid and methotrexate led to the corresponding pteroylphosphapeptides of interest as possible mimics of tetrahedral intermediates in the reaction catalyzed by folylpolyglutamate synthetase.

Phosphinic peptides as zinc metalloproteinase inhibitors

“…Only studies on phosphinic peptides published after the year 2000 are considered, as surveys of the literature before this date are available [4,5], and only results dealing with phosphinic peptides meeting the definition given above are discussed. The phosphinic moiety (PO 2 CH 2 ) appears in various non-peptide structures, but this topic is outside the scope of the present review [9,10].…”

Synthesis and Biological Applications of Phosphinates and Derivatives

“…Because of the high dividing rate of cancer cells, FPGS has been considered as a potential target in cancer chemotherapy [84,85]. In this context, Coward et al elaborated various phosphorus-containing pseudopeptides as FPGS inhibitors, such as diastereomerically pure phosphonate 89 [86] or biologically preferred phosphinates 90 and 91 (mixture of four diastereomers) [87,88] (90a and 91a), the nature of the heterocyclic R-group 92a and the number of glutamate motifs 93a (Fig. 16).…”

“…For the preparation of targeted molecules, each phosphinate diastereomer has been prepared individually and was coupled with three different heterocycles: 4-amino-4-deoxy-10-methylpteroate [89], pteroate [90] and 5,10-dideazatetrahydropteroate [90]. For example, both diastereomers under salt form 90a1 and 90a2 (Scheme 21) [89] were prepared by coupling pure diastereomer pseudopeptide 94a or 94b with acyl azide 95, AMPte-N 3 , derived from 4-amino-4-deoxy-10-methylpteroic acid [91], using the strategy described [87]. Both pseudopeptides 94a and 94b were obtained according a multistep sequence from the corresponding protected phenyl selenide 96 (Scheme 21) [89].…”

An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate‐specific membrane antigen small molecule derivatives

“…Formic acid 99% for analysis was purchased from Acros Organic (Geel, Belgium). Guilford 11245-36 (GPI; 2[((3-amino-3-carboxypropyl)(hydroxy) (phosphinyl)-methyl]pentane-1,5-dioic acid) was synthesized as described previously [11]. The perchlorate salt of IR-786 was purchased from Sigma-Aldrich (St. Louis, MO).…”