Development of zinc chelators with protein specificity aiming at molecular target therapy of cancer

本研究旨在通过锌络合剂和蛋白质识别部分相结合的方法设计锌蛋白抑制剂。我们感兴趣的是法尼基转移酶和ADAM家族蛋白水解酶作为锌蛋白的抑制物。法尼基转移酶抑制剂的合成研究一种锌蛋白法尼基转移酶催化癌基因产物RAS的法尼化，从而诱导RAS的致癌功能。本研究的目的是在含有吡啶和半胱胺侧链的锌络合剂中引入法尼基磷酸，以获得抑制剂。考虑到法尼基的不稳定性，首次合成了4-氨基吡啶螯合剂。然后通过4-氨基和法尼基磷酸之间的磷酸酰胺键成功地引入了法尼基部分。ADAM家族蛋白酶抑制剂的合成研究已知与癌细胞的增殖、侵袭和转移密切相关的黏附分子CD44。细胞黏附和细胞运动是由于ADAM家族的蛋白水解酶对CD44胞外区的裂解，导致肿瘤的转移和侵袭。本研究使用ADAM 30的抑制剂marimastat作为ADAM家族的蛋白酶识别部分。因此，(D)-酒石酸盐被转化为相应的依波糖苷，并引入异丁基，以获得关键中间体，即马拉马司他前体。尝试了这样得到的marimastat部分与锌络合剂的偶联。

The present research aims at the development of inhibitors of zinc proteins designed by combing a zinc chelator and a protein recognition moiety. We were interested farnesyltransferase and ADAM family protease as zinc proteins to be inhibited.Synthetic study of farnesyltransferase inhibitorsA zinc protein farnesyltransferase catalyzes the farnesylation of an oncogene product Ras to induce the oncogenic function of Ras. The objective of the present study is to obtain inhibitors by introducing a farnesyl phosphate, a farnesyltransferase-recognition moiety, into a zinc chelator comprising a pyridine and cysteamine side chains.Considering the instability of the farnesyl group, a 4-aminopyridine chelator was first synthesized. The farnesyl moiety was then successfully introduced by the formation of phosphoramide linkage between the 4-amino group and farnesyl phosphate.Synthetic study of ADAM family protease inhibitorsAdhesive molecule CD44 is known to be closely related to proliferation, invasion and metastasis of cancer cells. The cell adhesion and the cell movement are due to the cleavage of the extracellular domain of the CD44 by ADAM family proteases, resulting the cancer metastasis and invasion.The present study employed marimastat, an ADAM 30 inhibitor, as the ADAM family protease recognition moiety. Thus (D)-Tartrate was converted into the corresponding eposide and an isobutyl group was introduced to obtain a key intermediate, a marimastat precursor. The coupling of the marimastat moiety thus obtained and the zinc chelator was attempted.