Synthesis and enantiopreferential DNA‐binding profile of late 3d transition metal R‐ and S‐enantiomeric complexes derived from N,N‐bis‐(1‐benzyl‐2‐ethoxyethane): Validation of R‐enantiomer of copper(II) complex as a human topoisomerase II inhibitor

Abstract

To evaluate the biological preference of chiral drug candidates for molecular target DNA, new potential metal-based chemotherapeutic agents 1-3 (a and b) of late 3d transition metals Ni(II), Cu(II), and Zn(II), respectively, derived from (R)- and (S)-2-amino-2-phenylethanol with CH(2) CH(2)  linker were synthesized and thoroughly characterized. Interaction studies of 1-3 (a and b) with calf thymus DNA in Tris buffer were studied by electronic absorption titrations, luminescence titrations, cyclic voltammetry, and circular dichroism. The results reveal that the extent of DNA binding of R-enantiomer of copper 1a was highest in comparison to rest of the complexes via electrostatic interaction mode. The nuclease activity of 1(a and b) with supercoiled pBR322 DNA was further examined by gel electrophoresis, which reveals that complex 1a exhibits a remarkable DNA cleavage activity (concentration dependent) with pBR322DNA, and the cleavage activity of both enantiomers of complex 1 was significantly enhanced in the presence of activators. The activating efficiency follows the order Asc > H(2) O(2) > MPA for 1a, and reverse order was observed for 1b, because of the differences in enantioselectivity and conformation. Further, it was observed that cleavage reaction involves singlet oxygen species and superoxide radicals via oxidative cleavage mechanism. In addition, complex 1a exhibits significant inhibitory effects on the topoisomerase II (topo II) activity at a very low concentration ∼24 μM, which suggest that complex 1a is indeed catalytic inhibitor or (poison) of human topo II.

Enantiomeric Specificity of Biologically Significant Cu(II) and Zn(II) Chromone Complexes Towards DNA

“…Upon addition of increasing amounts of CT-DNA (0-0.2 Â 10 À4 M) to complexes (0.066 Â 10 À3 M), there was an increase in the absorbance (hyperchromism) of intraligand (IL) bands with a moderate red shift of 2-4 nm (Figs. 26,33 Interaction with Guanosine-5 0 -monophosphate disodium salt and Thymidine-5 0 -monophosphate disodium salt These spectral changes were indicative of the stabilization of DNA helix.…”

“…The results presented here are in accordance to our previous reports on chiral discrimination of metal complexes with DNA. 26,33 Interaction with Guanosine-5 0 -monophosphate disodium salt and Thymidine-5 0 -monophosphate disodium salt…”

A novel copper(II) complex identified as a potent drug against colorectal and breast cancer cells and as a poison inhibitor for human topoisomerase IIα

“…[18] There have been many reports of metal-based complexes inhibiting human topoisomerase IIα, including some platinum complexes and other copper complexes as well, as mentioned above. [13, 14, 19, 20] However, many of these previous findings with copper(II) complexes have not shown poison inhibition of hTop2α, but rather catalytic inhibition, or have not determined the mechanism of topoisomerase inhibition at all. The identification of a novel poison inhibitor is significant, because topoisomerase poisons are highly effective anti-cancer agents.…”

“…These results are significant, because a quantitative increase in linear DNA cleavage product was not observed for other copper(II)-containing complexes reported in previous studies, for example, 1-((5(or 6)-carboxy-1 H -benzo[ d ]imidazol-2-yl)methyl)pyridinium copper(II) chloride hydrate,[13] copper(II) complexes with α-heterocyclic thiosemicarbazones as ligands,[14] and an R - and S -enantiomeric copper(II) complex derived from N , N -bis(1-benzyl-2-ethoxyethane),[19] all of which showed either little or no poisoning effect. In our study, this novel effect is significant, since the accumulation of topoisomerase cleavage intermediates would be an important mode of action for anti-cancer activity.…”

Drug Candidate Discovery: Targeting Bacterial Topoisomerase I Enzymes for Novel Antibiotic Leads

“…Several copper(II) complexes have been shown to inhibit human topoisomerase IIα (Arjmand et al, 2011;Das et al, 2014;Duff et al, 2012). As human topoisomerase IIα is overexpressed in many cancer cells, it is an attractive anticancer target, with existing drugs such as etoposide and doxorubicin (Jarvinen and Liu, 2006).…”