3-Formylchromone based topoisomerase IIα inhibitors: discovery of potent leads

Singh, Satyajit; Baviskar, Ashish T.; Jain, Vaibhav; Mishra, Nidhi; Banerjee, Uttam Chand; Bharatam, Prasad V.; Tikoo, Kulbhushan; Ishar, M. P. S.

doi:10.1039/c3md00125c

Cited by 15 publications

(9 citation statements)

References 35 publications

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“…are considered to be privileged ligand scaffolds in medicinal chemistry that involve different types of cancer targets, viz. nucleic acids (DNA/RNA), 6 enzymes (kinase inhibitors and topoisomerases), 7,8 membrane receptors (dopamine D2 receptor agonists), 9 etc.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into a novel chromone-appended Cu(ii) anticancer drug entity: in vitro binding profile with DNA/RNA substrates and cytotoxic activity against MCF-7 and HepG2 cancer cells

et al. 2015

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A new chromone-appended Cu(ii) drug entity () was designed and synthesized as a potential anticancer chemotherapeutic agent. The structural elucidation was carried out thoroughly by elemental analysis, FT-IR, EPR, ESI-MS and single crystal X-ray crystallography. Complex resulted from the in situ methoxylation reaction of the 3-formylchromone ligand and its subsequent complexation with the copper nitrate salt in a 2 : 1 ratio, respectively. crystallized in the monoclinic P21/c space group possessing the lattice parameters, a = 8.75 Å, b = 5.07 Å, c = 26.22 Å, α = γ = 90°, β = 96.3° per unit cell. Furthermore, in vitro interaction studies of with ct-DNA and tRNA were carried out which suggested more avid binding propensity towards the RNA target via intercalative mode, which was reflected from its Kb, K and Ksv values. The gel electrophoretic mobility assay was carried out on the pBR322 plasmid DNA substrate, to ascertain the cleaving ability and the mechanistic pathway in the presence of additives, and the results revealed the efficient cleaving ability of via the oxidative pathway. In vitro cell growth inhibition via the MTT assay was carried out to evaluate the cytotoxicity of complex and IC50 values were found to be in the range of 5-10 μg mL(-1) in HepG2 and MCF-7 cancer cell lines, which were found to be much lower than the IC50 values of previously reported similar Cu(ii) complexes. Additionally, in the presence of , reactive oxygen species (ROS) and thiobarbituric acid reactive substance (TBARS) levels in the tested cancer cell lines increased significantly, coupled with reduced glutathione (GSH) levels. Thus, our results suggested that ROS plays an important role in cell apoptosis induced by the Cu(ii) complex and validates its potential to act as a robust anticancer drug entity.

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Section: Introductionmentioning

confidence: 99%

Mechanistic insights into a novel chromone-appended Cu(ii) anticancer drug entity: in vitro binding profile with DNA/RNA substrates and cytotoxic activity against MCF-7 and HepG2 cancer cells

et al. 2015

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“…In a rational structural modulation of a known hTopoIIα catalytic inhibitor class of compounds, imidazo-pyridines/pyrazines, , our initial docking studies revealed an astonishing important feature. The C2-biaryl and C6-aryl derivatizations implied the possibility of a switch in binding with hTopoIIα from the ATP-hydrolysis to DNA cleavage stage of the catalytic cycle.…”

mentioning

confidence: 99%

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

Baviskar¹,

Amrutkar²,

Trivedi³

et al. 2015

ACS Med. Chem. Lett.

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A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choicebased change" in target-specific mode of action for rapid drug discovery.

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“…Chromones have been demonstrated in the literature previously as privileged medicinal scaffold which have found application as an anti-inflammatory, antibacterial and anticancer agents. 9,10 Furthermore, chromone based drugs have been found to inhibit different types of cancer targets, 11 nucleic acids (DNA/RNA), 12,13 enzymes (kinase inhibitors and topoisomerases) 14 and other membrane receptors. 15 …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and characterization of novel chromone based-copper(ii) antitumor agents with N,N-donor ligands: comparative DNA/RNA binding profile and cytotoxicity

2018

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3-Formylchromone based topoisomerase IIα inhibitors: discovery of potent leads

Cited by 15 publications

References 35 publications

Mechanistic insights into a novel chromone-appended Cu(ii) anticancer drug entity: in vitro binding profile with DNA/RNA substrates and cytotoxic activity against MCF-7 and HepG2 cancer cells

Mechanistic insights into a novel chromone-appended Cu(ii) anticancer drug entity: in vitro binding profile with DNA/RNA substrates and cytotoxic activity against MCF-7 and HepG2 cancer cells

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

Design, synthesis and characterization of novel chromone based-copper(ii) antitumor agents with N,N-donor ligands: comparative DNA/RNA binding profile and cytotoxicity

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