Synthesis and Properties of Aminoacylamido-AMP:  Chemical Optimization for the Construction of an N-Acyl Phosphoramidate Linkage

Abstract

This paper describes the design and synthesis of a new type of aminoacyl-adenylate analogue (aa-AMPN) having an N-acyl phosphoramidate linkage where the oxygen atom of the mixed anhydride bond of aminoacyl-adenylate (aa-AMP) is replaced by an amino group. This new type of aa-AMP analogue is expected to be useful as material for studies on the recognition mechanism of the aminoacylation of tRNA and other biochemical reactions. The condensation of phosphoramidite derivatives of carboxamides with nucleoside derivatives failed, because the activated phosphoramidite derivatives reacted with not only the hydroxyl groups but also another reactive species. An alternative approach was examined by the reaction of 5'-O-phosphoramidite adenosine derivatives with carboxamide derivatives. The TBTr and TSE groups were chosen for protection of the amino group of amino acid amides and the phosphate group, respectively. Detailed studies revealed that the use of 5-(3,5-dinitrophenyl)-1H-tetrazole as an activating catalyst of phosphoramidites resulted in rapid condensation within 10 min to give fully protected aa-AMPN derivatives. No side reaction occurred. Deprotection of these products via a two-step procedure gave aa-AMPN derivatives in good yields. It also turned out that aa-AMPNs thus obtained are stable under both acidic and basic conditions, such as 0.1 M HCl (pH 1.0) and 0.1 M NaOH (pH 13.0).

Aspartyl-tRNA Synthetase Is the Target of Peptide Nucleotide Antibiotic Microcin C

“…The synthesis of aminoacyl adenylate analogs having N-acylphosphoramidate linkage has also been reported (25).…”

Asparagine Synthetase Chemotherapy

“…For example, the antibiotic mupirocin 3 ( Figure 6) exerts its action by selectively inhibiting prokaryotic isoleucyl-tRNA synthetases (145,146), and phosmidosine 4 ( Figure 6) (147, 148) likely inhibits prolyltRNA synthetase by effectively mimicking the acyladenylate intermediate formed by this enzyme. These findings therefore resulted in the development of efficient synthetic routes for preparing chemically stable analogs of acyladenylates (148)(149)(150) in the expectation that such compounds will exhibit antibacterial activity coupled with low mammalian toxicity (151,152). In light of these studies (145)(146)(147)(148)(149)(150), β-asparaginyladenylate 5 ( Figure 6) was synthesized (153) The relatively lengthy synthetic route to obtain this compound and the presence of a charged phosphoamidate functional group argue against its likely clinical utility.…”

“…These findings therefore resulted in the development of efficient synthetic routes for preparing chemically stable analogs of acyladenylates (148)(149)(150) in the expectation that such compounds will exhibit antibacterial activity coupled with low mammalian toxicity (151,152). In light of these studies (145)(146)(147)(148)(149)(150), β-asparaginyladenylate 5 ( Figure 6) was synthesized (153) The relatively lengthy synthetic route to obtain this compound and the presence of a charged phosphoamidate functional group argue against its likely clinical utility. In addition, the coupling reaction was insufficiently robust for use in constructing molecular libraries that could be assayed for ASNS inhibitory activity using modern highthroughput screening methods (154)(155)(156)(157).…”

Simulating Solid-Liquid Interfaces in Atomic Force Microscopy

“…However, the complexities are significantly increased when the solvent itself is ionic. Ionic liquids (IL), originally discovered in the 1930s, are room-temperature molten salts, often composed of organic molecules, commonly used in synthesis [96,97] and catalysis [98,99]. Their popularity among synthetic chemists stems from the need to constantly replace solvents that are labelled too toxic or dangerous and banned by the authorities.…”