Biasone Alessandro, Tortorella Paolo, Campestre Cristina, Agamennone Mariangela, Preziuso Serena, Chiappini Marika, Nuti Elisa, Carelli Paolo, Rossello Armando, Mazza Fernando, Gallina Carlo
Dipartimento di Scienze del Farmaco, Università "G. d'Annunzio", Via dei Vestini 31, 66013 Chieti, Italy.
Bioorg Med Chem. 2007 Jan 15;15(2):791-9. doi: 10.1016/j.bmc.2006.10.047. Epub 2006 Oct 25.
(R)-alpha-Biphenylsulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are the most effective inhibitors based on phosphonate as zinc binding group. Since their preparation by direct N-acylation of expensive, enantiopure, alpha-aminophosphonic acids proceeds in low yields, we devised and evaluated a stereoselective and straightforward method of synthesis that avoids the unfavourable step of N-acylation. The key intermediate (R)-4-bromophenylsulfonylamino 2-methylpropyl phosphonate 9 was obtained by highly stereoselective addition of dibenzylphosphite to the enantiopure (S)-N-isobutylidene-p-bromobenzenesulfinamide 3, followed by oxidation with m-CPBA. Suzuki coupling of 9 with the desired arylboronic acids, gave the expected biphenylsulfonylamino derivatives in satisfactory yields. Liberation of the phosphonic group by hydrogenolysis led to the desired (R)-alpha-biphenylsulfonylamino 2-methylpropyl phosphonates 14a-i. Screening of the new compounds on MMP-1, -2, -3, -7, -8, -9, -13 and -14 showed IC(50) in the range of nM in most cases.
（R）-α-联苯磺酰氨基-2-甲基丙基膦酸酯对多种基质金属蛋白酶（MMP）具有纳摩尔级别的活性，是以膦酸酯作为锌结合基团的最有效抑制剂。由于通过对昂贵的对映体纯α-氨基膦酸进行直接N-酰化来制备它们的产率较低，我们设计并评估了一种立体选择性且直接的合成方法，该方法避免了不利的N-酰化步骤。关键中间体（R）-4-溴苯磺酰氨基-2-甲基丙基膦酸酯9是通过将亚磷酸二苄酯高度立体选择性地加成到对映体纯的（S）-N-异丁烯基对溴苯亚磺酰胺3上，然后用间氯过氧苯甲酸氧化而得到的。9与所需芳基硼酸的铃木偶联以令人满意的产率得到了预期的联苯磺酰氨基衍生物。通过氢解使膦酸基团游离得到所需的（R）-α-联苯磺酰氨基-2-甲基丙基膦酸酯14a-i。在MMP-1、-2、-3、-7、-8、-9、-13和-14上对新化合物进行筛选，在大多数情况下显示IC（50）在纳摩尔范围内。
