Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents

Abstract

In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB.

Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?

“…cisplatin), ( 1 ) is effective at overcoming cisplatin resistance in ovarian cancer cells [ 179 , 183 ]. The inhibition of Trx correlates with the downregulation of the apoptosis signal-regulating kinase (ASK-1) and further regulation of the Bcl-2:Bax ratio (in particular, the inhibition of Bcl-2 gene and activation and further increased activity of the Bax gene) so as to induce an apoptotic cell death pathway via MAP kinase [ 160 , 184 , 185 , 186 ].…”

In vitro antibacterial and time kill evaluation of mononuclear phosphanegold(I) dithiocarbamates

“…While 1 and 2, with hydroxyethyl functionalized dithiocarbamate ligands and 4 are new, 3 is a known compound [35] and the crystal structure of 3 is available [47]. A number of studies are now available suggesting that dithiocarbamate ligands with hydroxyethyl groups possess biological activity [43,44,48,49] and therefore it was thought of interest to extend the studies to 1 and 2, given the anti-bacterial activity of R3PAu[S2CN(iPr)CH2CH2OH] for R = Et, Cy and Ph [42]. Compounds 3 and 4 were included in the present study as they contain Et3P, as in Auranofin®, and have conventional dithiocarbamate ligands which have demonstrated biological activity when complexed to metals [36].…”

Exploring the Topological Landscape Exhibited by Binary Zinc-triad 1,1-dithiolates

“…This structure is a methanol solvate [83]. The same binuclear molecule is found in a di-hydrate (75) and is centrosymmetric [96]. The persistence of the centrosymmetric motif is also seen in the structures of {Zn[S 2 CN(CH 2 CH 2 ) 2 NPh] 2 } 2 (67) [92] and {Zn[S 2 CN(Me)Et] 2 } 2 (70) [94] for each of which there are two crystallographically independent binuclear molecules, each disposed about a centre of inversion.…”