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

根据9-(5‘，5’-二氟-5‘-膦戊基)鸟嘌呤(5’-Difluoro-5‘-phosphonopentyl)-9-deazaguanine(DFPP-DG)-G)与小牛脾PNP形成的二元络合物的X-射线晶体结构数据，设计了9-(5’，5‘-DFPP-G)多底物类似物抑制剂。DFPP-DG及其类似物通过9-去氮基-9-碘鸟嘌呤衍生物与ω-炔基二氟亚甲基膦酸酯之间的索诺加希拉偶联反应得到的连接基长度作为关键反应进行调节。DFPP-DG是一种非常有效的PNP抑制剂，在1 mM磷酸盐存在下，对小牛脾和人红细胞PNPs的表观抑制常数分别为4.4 nM和8.1nM。它的一种类似物Homo-DFPP-DG具有更长的链连接磷酸盐和9-去氮鸟嘌呤，比人的酶更有效，在1 mM磷酸盐存在下的表观抑制常数为5.3 nM。在平衡条件下(1 mM磷酸盐浓度)，对牛脾PNP的抑制常数为K&lt；EQI&gt=85±13 Pm(pH=7.0，25℃)。在研制膦二肽异构体(PDIs)的研究中，我们找到了一种用化学-酶法合成光学活性PDIs的新方法。我们还开发了一种高效的亮氨酸的立体选择性合成方法。专业型PDI。此外，我们还开发了几种新的方法来合成一些具有膦酰基或膦酰基官能团的新分子。

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.