Synthesis of Phosphinic Analogue of Alanylleucine
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Synthesis of Phosphinic Analogue of Alanylleucine S. R. Golovasha, O. S. Grigorkevichb, G. S. Tsebrikovac, M. E. Dmitrieva, and V. V. Ragulina,* a
Institute of Physiologically Active Substances of the Russian Academy of Sciences, Chernogolovka, 142432 Russia b V.V. Zakusov Research Institute of Pharmacology of the Russian Academy of Sciences, Moscow, 125315 Russia c A.N. Frumkin Institute of Physical Chemistry and Electrochemistry of the Russian Academy of Sciences, Moscow, 119071 Russia *e-mail: [email protected] Received September 27, 2019; revised September 27, 2019; accepted October 5, 2019
Abstract—The amidoalkylation reactions of a phosphonous acid containing a structural isostere of leucine in acetyl chloride and(or) acetic anhydride were studied under conditions of acid catalysis. A two-component method for the synthesis of a phosphinic analogue of alanylleucine using ethylidenebis(benzylcarbamate) was proposed. Keywords: pseudo-alanylleucine, matrix metalloproteinases (MMPs), zinc metalloproteinase inhibitors, amidoalkylation, phosphinic structural isosteres
DOI: 10.1134/S1070363220040313 Phosphinic structural analogues of natural peptides are included in promising radiopharmaceuticals as ligand components [1]. They are also inhibitors of matrix metalloproteinases (MMPs), which are a family of zinc-containing endoproteases involved into various biological processes [2, 3]. Metalloproteinases of types 2 and 9 (MMP-2 and MMP-9), called gelatinases, play an important role in post-infarction myocardial remodeling [4]. Undesirable activity of gelatinases, which manifests itself in a negative effect on the tissues of the cardiovascular system, can be reduced or eliminated using inhibitors containing function that chelates zinc cation [5, 6]. Effective inhibitors of zinc-metalloproteinases are phosphinic pseudopeptides, structural isosteres of peptides in the molecule of which two amino acid components of the dipeptide are linked by a zinc chelating phosphinic fragment [2, 7]. In this case, methylenephosphorylic CH2P(O)(OH) fragment imitates a natural peptide bond with a tetra-coordinated carbon atom in the transition state of peptide hydrolysis (Scheme 1). A widely used approach to the phosphinic modification of the peptide bond is the synthesis of the N,P-protected derivative 1, the phosphorous isoster of the corresponding amino acid, developed by Ciba-Geigy company [8, 9] with its subsequent conversion to the silylic ether of the PIII-phosphonous analog of the amino acid and addition to corresponding α-substituted acrylates 2 (Scheme 2) [2, 7].
We have proposed a shorter synthesis with the reverse construction of the desired pseudopeptide 3 molecule. It consists in the initial addition of the in situ generated hypophosphite 4 to the corresponding α-R2-substituted acrylates 2 with the formation of phosphonous acids 5 containing a structural isostere fragment of the corresponding amino acid, which is determined by the corresponding substituent (R2) in the α-position of the acrylic system [10–13
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