The synthesis of amino acid analogs wherein an acidic phosphorus unit replaces the carboxylic acid group has been an area of investigation for more than twenty years. These analogs, and the derived peptides incorporating them, exhibit a variety of biological effects such as enzyme inhibition, herbicidal activity and antibacterial action. While the majority of these compounds are analogs of the naturally occurring alpha- amino acids found in peptides and proteins, there has been some interest in beta and gamma analogs as well. To a large extent, analog development has focused on the dibasic phosphonic acids [RP(O)(OH)2]. Until recently, there had been less interest in analogs derived from the monobasic phosphinic acids [R2P(O)OH], even though these compounds would seem to be structurally more similar to the naturally occurring amino acids. In those cases which have been investigated, several aminoalkylphosphinic acids and peptides incorporating them do show antibacterial and other biological activity. Thus, the longterm objective of this project is the synthesis of additional aminoalkylphosphinic acids as well as the di- and tripeptides containing these phosphorous-based amino acid analogs. This project will focus on modifications of existing synthetic methods for application to phosphorus amides which have not previously been used as substrates in analog development. specifically, the amides to be employed are the trivalent amidoesters [alkyl alkylphosphonamidites, RP(OR')NR112], which will be prepared using established methods from commercially available precursors. These amidoesters will be combined with N- haloalkylphthalimides in an Arbuzov reaction to afford the corresponding phthalimidophosphinamides. Removal of the phthaloyl group with hydrazine and acetic acid should also cleave the acid sensitive P-N linkage of the phosphinamide moiety, thereby generating the desired aminoalkylphosphinic acids. Depending on the specific phthalimide derivative used, alpha, beta or gamma-amino acid analogs are obtained. Coupling of these analogs with suitably protected aminocarboxylic acids and related dipeptides by use of a coupling agent such as dicyclohexylcarbodiimide will afford the respective di- and tripeptide analogs. The aminoalkylphosphinic acids as well as the phosphorus-containing peptide analogs will be tested to ascertain the nature and degree of anticipated biological activity that these compounds exhibit.
| Dorsey, Charles H; Cousin, Carolyn E; Lewis, Fred A et al. (2002) Ultrastructure of the Schistosoma mansoni cercaria. Micron 33:279-323 |
