Gold(III) Complexes of Pyridyl- and Isoquinolylamido Ligands: Structural, Spectroscopic, and Biological Studies of a New Class of Dual Topoisomerase I and II Inhibitors

Abstract

The structures, spectroscopy, and cytotoxicity of four novel nominally square-planar gold(III) chelates 1-4 with the general formula cis-AuCl2(X), where the ligand X is an anionic bidentate pyridyl- or isoquinolylamido chelating agent, are described. The Au-N(amido), Au-N(pyridyl), and Au-N(isoquinolyl) distances are 2.002(9)-2.016(3), 2.01(1)-2.037(3), and 2.037(3) Å, respectively. Density functional theory simulations afforded accurate gold(III) coordination geometries for 1-4 (bond distances and angles to within 5% of the X-ray values), while accurate transition energies were limited to those calculated in the UV spectral region. The complexes had variable stability in dimethyl sulfoxide: compound 3 (relatively rigid) was indefinitely stable, compounds 1 and 2 (conformationally flexible) slowly demetalated over 30 days, and 4 (extensively aromatic) formed an insoluble precipitate after 10 days (72 h in an aqueous buffer). The isoquinolylamido derivative 4 was sufficiently cytotoxic in the NCI-60 screen to undergo full five-dose testing. Notably low GI50 (1.8, 2.3, and 3.2 μM) and IC50 (4.0, 9.8, and 15 μM) values were recorded for the OVCAR-3, IGROV1, and SW-620 cell lines, respectively. Hierarchical cluster analysis employing the National Cancer Institute (NCI) data for known anticancer drugs and 4 revealed that compound 4 is mechanistically identical with the topoisomerase IIα (Top2) poison zorubicin and statistically similar to the topoisomerase IB (Top1) poisons camptothecin and 9-methoxycamptothecin. The Top2-catalyzed decatenation reaction of kinetoplast DNA was studied as a function of the concentration of 4: the compound acts as an interfacial poison of Top2 at low concentrations (<1 μM) and a catalytic inhibitor of the enzyme above 5 μM. Gel mobility shift assays (plasmid DNA substrate) showed that the catalytic inhibition of Top2 likely correlates with DNA binding by 4 at concentrations >5 μM. Compound 4 is also a catalytic inhibitor of Top1 at higher concentrations, consistent with DNA binding by the complex.

Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I

“…67 Mechanistically, a large association constant, K A1 , exists for formation of the ternary drug·DNA–enzyme covalent cleavage complex, while a smaller association constant, K A2 , exists for intercalation of the enzyme’s DNA substrate. 65 Because the two assays used here each permit a distinction to be made between Top1 IFPs and catalytic inhibitors in a single experiment, they are ideal for detecting dual-mode inhibitors. Consequently, 1 can be firmly assigned as a dual-mode (IFP-CIC) Top1 inhibitor.…”

Linked Picolinamide Nickel Complexes as Redox Carriers for Nonaqueous Flow Batteries

“…Three variants of the ligand motif were examined; the −CH 2 CH 2 − bridged (bpen 2− ), −CH 2 CH 2 CH 2 − bridged (bppn 2− ), and the −C 6 H 4 − bridged (bpb 2− ) derivatives. Metal complexes of bpen 2− , bppn 2− , and bpb 2− have been used previously as catalysts and anticancer metallodrugs, but not examined for RFB applications. The nickel complexes Ni(bpen)⋅H 2 O, Ni(bppn)⋅H 2 O, and Ni(bpb)⋅H 2 O (Figure ) were synthesized in moderate yield by using a variation of the literature procedure …”

“…[16] An examination of the literature pointedt oo ne ligand motif that might be less expensive than cyclam yet embody other desirable characteristics:t he pyridinecarboxamido group linked by an alkyl or aryl group.T hree variants of the ligand motif were examined;t he ÀCH 2 CH 2 À bridged (bpen 2À ), [17] ÀCH 2 CH 2 CH 2 À bridged (bppn 2À ), [18] and the ÀC 6 H 4 À bridged (bpb 2À ) [19] derivatives. Metal complexes of bpen 2À ,b ppn 2À ,a nd bpb 2À have been used previously as catalysts [20] and anticancer metallodrugs, [21] but not examined for RFB applications.T he nickel complexes Ni(bpen)·H 2 O, Ni(bppn)·H 2 O, and Ni(bpb)·H 2 O ( Figure 2) were synthesized in moderate yield by using av ariation of the literature procedure. [22] Althought he diamagnetic 1 HNMR spectra (Figures S1-S3 in the Supporting Information) strongly suggested as quareplanar coordination environment, consistent with the reported structure, we crystallizedN i(bppn)·H 2 Ot om aximize purity and verify the correct material was obtained.…”

A “Golden Age” for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system

“…Most of the inhibitors, as camptothecin, present a planar structure formed by fused heterocycles. Several Au III ‐macrocyclic [168] and Au III ‐complexes [169–171] showed to inhibit TopIB and less importantly some Au I complexes [172,173] . For Au III complexes, polydentate ligands containing planar aromatic moieties show low micromolar inhibition of TopIB [168,174] .…”