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

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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.