Hoppe A, McKenna C E, Harutunian V, Levy J N, Dousa T P
Nephrology Research Unit, Mayo Clinic and Foundation, Rochester, MN 55905.
Biochem Biophys Res Commun. 1988 Jun 30;153(3):1152-8. doi: 10.1016/s0006-291x(88)81348-2.
We found that alpha-Cl-alpha-Br-phosphonoacetate (ClBrPAA) is a competitive, solute-specific inhibitor of Na+/Pi cotransport across renal cortical brush border membrane. Inhibition by ClBrPAA (Ki = 62 microM) is more than three times more effective than inhibition by phosphonoformate (PFA), the most potent Na+/Pi cotransport inhibitor known to date, and 26 times more effective than the parent compound, phosphonoacetate (PAA). These observations indicate that substitution of bromine and chlorine atoms at the alpha-carbon of PAA greatly enhances its efficacy as a competitive inhibitor of Na+/Pi cotransport. As ClBrPAA is much less inhibitory than PAA and PFA towards viral DNA polymerases and did not inhibit human alpha-DNA polymerase (ref. 10), the results also demonstrate that Na+/Pi cotransport inhibition can be dissociated from inhibition of DNA polymerases by phosphonocarboxylate compounds.
我们发现α-氯-α-溴膦酰基乙酸酯（ClBrPAA）是一种竞争性的、溶质特异性的抑制剂，可抑制肾皮质刷状缘膜上的Na⁺/Pi共转运。ClBrPAA（Ki = 62 μM）的抑制作用比膦甲酸盐（PFA）的抑制作用有效三倍以上，膦甲酸盐是迄今为止已知的最有效的Na⁺/Pi共转运抑制剂，并且比母体化合物膦酰基乙酸酯（PAA）有效26倍。这些观察结果表明，在PAA的α-碳上取代溴和氯原子大大增强了其作为Na⁺/Pi共转运竞争性抑制剂的效力。由于ClBrPAA对病毒DNA聚合酶的抑制作用远小于PAA和PFA，并且不抑制人α-DNA聚合酶（参考文献10），结果还表明，膦酰基羧酸盐化合物对Na⁺/Pi共转运的抑制作用可与对DNA聚合酶的抑制作用分离。
