The long-term goal of this project is to develop methods of synthesis which will make available cyclic phosphonic or phospinic anhydrides which are close analogs of cyclic nucleotides such as cyclic 3'5'-adenosine monophosphate, or the cyclic 2' 3' nucleotides. The synthetic cyclic phosphate analogs resemble in shape and polarity the natural cyclic nucleotides. According to well-known principles of drug design, the synthetic analogs may either block or be competitive with the natural nucleotides, and may thus possess biochemical or biological activity. Initially the research will focus on the preparation of simple phosphonic anhydrides, (-(CH2P(O)0))20, which contain a 5-membered ring, and the 6-membered ring analog, with an extra methylene group. Methods of synthesis of these compounds from available diphosphonic acids, or diphosphonous dichlorides, are proposed which follow established precedents, and should lead to the desired target molecules. The chemistry of the cyclic compounds will be explored, with emphasis on the products, kinetics, and mechanisms of their reactions with nucleophiles, which should lead to interesting analogs of biologically significant polyphosphates, and phosphoramidates. The action of the anhydrides, their precursor acids, and their esters as chelating agents for metal ions will be studied. Similar synthetic schemes, and exploratory chemistry, will be initiated for cyclic phosphinic anhydrides.
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