1994 Syntex Award Lecture: Anionic Electrophiles, Protein Modification, and Artificial Blood

Abstract

Monomethyl esters of acyl phosphates (mixed anhydrides of carboxylic and phosphoric acids) are being developed as site-directed acylating agents for amino groups in proteins. In an illustrative application, these anionic materials are shown to bind to a positively charged region of hemoglobin where they convert amino groups to amides. Bifunctional acyl methyl phosphates cross-link hemoglobin to give a variety of products, some of which have the oxygen-binding properties anticipated for materials that can serve as an alternative to red cells in transfusions. Higher yields of desired products result from the use of a trifunctional analogue. Kinetic patterns of the reactions of a series of alkyl amines and methyl aroyl phosphates indicate that the transition state for formation of the amide involves almost complete development of positive charge on nitrogen.

A Site-Specific Tetrafunctional Reagent for Protein Modification: Cross-Linked Hemoglobin with Two Sites for Further Reaction

“…This suggests that the additional anionic groups have a significant effect on reducing the oxygen affinity, beyond that of the cross-link. It is notable that the affinity is close to that considered ideal for a red cell substitute to be used for transfusions …”

2001 Lemieux Award Lecture Organic chemistry and hemoglobin: Benefits from controlled alteration

“…Since hemoglobin is a specific chemical entity, it is amenable to alteration through organic chemistry (5). Can hemoglobin be chemically altered so that it can effectively deliver oxygen and remain in circulation outside the red cell?…”

ChemInform Abstract: Acyl Phosphate Esters: Charge‐Directed Acylation and Artificial Blood

“…With a large variety of acyl phosphate esters available, we were able to use them to cross-link hemoglobin systematically, providing an array of oxygencarriers that can be substitutes for red blood cells. 11 Many acyl phosphates are metabolic acylating and/or phosphorylating agents that function with enzymes. For example, their acylation of nucleophiles leads to formation of acetogenins by Claisen condensations or to proteins by transacylation.…”