A series of PtIV anticancer complexes with chloro leaving groups have been investigated for the effects of axial and carrier ligands on the reduction and cytotoxicity. The reduction rates of the PtIV complexes such as Pt(d,l)(1,2-(NH2)2C6H10)Cl4 (tetraplatin, Pt(dach)Cl4; dach = diaminocyclohexane), cis,trans,cis-[Pt((CH3)2CHNH2)2(OH)2Cl2] (iproplatin, Pt(ipa)(OH)2Cl2; ipa = isopropylamine), cis,trans,cis-[Pt(NH3)(C6H11NH2)(OCOCH3)2Cl2] (JM-216, Pt(a,cha)(OCOCH3)2Cl2; a = ammine, cha = cyclohexylamine), cis,trans,cis-[Pt(NH3)(C6H11NH2)(OCOC3H7)2Cl2] (JM-221, Pt(a,cha)(OCOC3H7)2Cl2), cis,trans,cis-[Pt(en)(OH)2Cl2], Pt(en)Cl4 (en = ethylenediamine), cis,trans,cis-[Pt(en)(OCOCH3)2Cl2], and cis,trans,cis-[Pt(en)(OCOCF3)2Cl2] by ascorbate and cathodic reduction potentials strongly depend on the electron-withdrawing power and the steric hindrance of the axial and carrier ligands. Beginning with PtIV complexes bearing en carrier ligands, reduction rates and reduction potentials increase in the following order of axial ligand substitutions:  OH < OCOCH3 < Cl < OCOCF3, coinciding with increasing electron-withdrawing power of the axial ligand. PtIV complexes with en carrier ligands tend to show slower reduction rates than the corresponding complexes with ipa or cha carrier ligands. Ascorbic acid does not reduce Pt(en)(OH)2Cl2, but reduces Pt(ipa)(OH)2Cl2. The reduction rate of Pt(a,cha)(OCOCH3)2Cl2 is about 12 times higher than that of Pt(en)(OCOCH3)2Cl2. Overall, there is no strong correlation between reduction rate and cytotoxicity toward cisplatin-sensitive L1210/0 cells among the eight complexes studied. However, when the four compounds with en carrier ligands were compared with one another, the one with the fastest reduction rate exhibited the highest cytotoxicity. The cytotoxicity increases with axial ligand substitution in the order OH < OCOCH3 < Cl < OCOCF3, following the same trend as reduction rate. Comparing complexes having different carrier ligands but the same axial ligands reveals that the compound with the faster reduction rate exhibits the higher cytotoxicity. Reduction rate and cytotoxicity increase in the order Pt(en)(OH)2Cl2 < Pt(ipa)(OH)2Cl2, Pt(en)(OCOCH3)2Cl2 < Pt(a,cha)(OCOCH3)2Cl2, Pt(en)Cl4 < Pt(dach)Cl4.

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The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the c-secretase complex in the generation of b-amyloid (Ab), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased Ab production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which Ab is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr 354 and that this phosphorylation increases c-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphosphorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the Ab pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.

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