Development of biologically active compounds based on features of phosphonyl and phosphinyl functional groups

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9-(5', 5'-Difluoro-5'-phosphonopentyl)-9-deazaguanine(DFPP-DG) was designed as a multi-substrate analogue inhibitor against purine nucleoside phosphorylase(PNP) on the basis of X-ray crystallographic data obtained for a binary complex of 9-(5', 5'-difluoro-5'-phosphonopentyl) guanine(DFPP-G) with calf-spleen PNP. DFPP-DG and its analogous compounds were adjusted by length of the linker achieved by the Sonogashira coupling reaction between a 9-deaza-9-iodoguanine derivative andω-alkynyldifluoromethylene phosphonates as a key reaction. DFPP-DG is a very potent PNP inhibitor with apparent inhibition constants(in the presence of 1 mM phosphate) of 4.4 nM and 8.1 nM vs calf spleen and human erythrocyte PNPs, respectively. One of its analogues, homo-DFPP-DG, with longer chain linking phosphonate and 9-deazaguanine is even more potent vs human enzyme, with an apparent inhibition constant of 5.3 nM(in the presence of 1 mM phosphate). The inhibition constant at equilibrium(1 mM phosphate concentration) with calf spleen PNP was shown to be K_<eqi>=85±13pM(pH7.0, 25℃).In the research for developing phosphinyl dipeptide isostere(PDIs), we have found a new method for synthesis of optically active PDIs by using chemo-enzymatic processes. We also developed an efficient stereoselective synthesis of the Leu. Pro type PDI. In addition, we have also developed several new methods for synthesis of some new molecules having phosphonyl or phosphiniyl functional group.