Synthesis and in vitro evaluation of aspartate transcarbamoylase inhibitors

Abstract

The design, synthesis, and evaluation of a series of novel inhibitors of aspartate transcarbamoylase (ATCase) are reported. Several submicromolar phosphorus-containing inhibitors are described, but all-carboxylate compounds are inactive. Compounds were synthesized to probe the postulated cyclic transition-state of the enzyme-catalyzed reaction. In addition, the associated role of the protonation state at the phosphorus acid moiety was evaluated using phosphinic and carboxylic acids. Although none of the synthesized inhibitors is more potent than N-phosphonacetyl-L-aspartate (PALA), the compounds provide useful mechanistic information, as well as the basis for the design of future inhibitors and/or prodrugs.

Modulating pyrimidine ribonucleotide levels for the treatment of cancer

“…Whether this is due to inhibition of CAD is unknown as PALA may not be specific and, for example, PALA is a potent inhibitor of human carbonic anhydrase IV [100]. To our knowledge, various modifications of PALA have not yet rendered more effective inhibitors [101] although encapsulating PALA into liposomes may improve delivery and efficacy according to tests in mice [102,103].…”

Phosphinate-containing heterocycles: A mini-review

“…This product was cyclized using Mitsunobu conditions and finally hydrogenolyzed to deliver the 6-membered heterocycle 29 in 12% overall yield (Scheme 12) [26]. …”

“…Montchamp and coworkers have achieved the synthesis of 5- and 6-membered rings “cyclo-PALA” analogs which are 1,3-azaphospholidine and 1,4-azaphosphorine derivatives 26 , 29 [ 26 ].…”

Cover Picture: Catalytic Molecular Logic Devices by DNAzyme Displacement (ChemBioChem 7/2014)

“…Two examples of Mitsunobu‐type reactions have been used to synthesize products 1,3‐azaphosphiridine 52a and 1,4‐azaphosphirinanes 52b 36 (Scheme ) and 1,3‐oxaphosphetane 55 (Scheme ). The syntheses of 52a and 52b proceeded under standard Mitsunobu conditions37 with yields of 44 and 33 %, respectively.…”

“…1,4‐Azaphosphirane 4‐oxide 107 (Scheme ) was synthesized from 106 by ozonolysis of the double bonds and subsequent double reductive amination 36…”