Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Abstract

Copper-based antitumor drug entities 1-3 derived from substituted (F -, Br -, -CH 3 ) 3formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct-DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 >3. The structure of drug entities could facilitated strong halogen bonding interaction(in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Brelectron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity , the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form(Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies.The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC 50 value of 1.6μM. Highlights Substituted chromone Copper (II) complexes were synthesized and characterized.  DFT computational studies were also performed.  Electrophoretic studies revealed an oxidative cleavage pathway.  Cytotoxicity was evaluated against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines.  Copper (II) complex 2 exhibited selective cytotoxicity against DU-145 cell line at GI 50 =1.6μM.

Chromone‐Appended Zn(II) tRNA‐Targeted Potential Anticancer Chemotherapeutic Agent: Structural Details, in vitro ct‐DNA/tRNA Binding, Cytotoxicity Studies And Antioxidant Activity

“…Synthesis of complex 1. Experimental information such as FT-IR, 1 H and 13 C NMR, Hirshfeld surface and fingerprint plots.…”

“…[6,7] Moreover, chromone-based metallodrugs are known to inhibit various types of cancer targets viz., DNA, tRNAs, kinase inhibitor enzymes and topoisomerases. [8][9][10] Zn(II) in chromone-appended ligand framework can be explored as an antitumor agent due to its capability to mediate cleavage of the phosphate diester backbone, redox inertness, Lewis acidity, and rapid ligand exchange. [11] Chelation of Zn(II) to naturally occurring chromone improves the complex's planar functionality thereby, allowing the complex to insert and stack between base pairs of double-helical DNA more readily than the free ligand.…”

“…Therefore, it has been proven that halo-substituted complexes could enhance the pharmacological properties of these bioactive drug entities. [13] However, there are scarce reports on RNA-targeted Zn(II) complexes. RNA sequences represent an attractive therapeutic target for drug design (which was previously underexplored due to lack of characterization) unlike their passive role as a carrier of DNA sequence information.…”

Synthesis, structural insights, and biological screening of DNA targeted Ru(ii)(η6-p-cymene) complexes containing bioactive amino-benzothiazole ligand scaffolds

“…17,18 In this approach, biologically active pharmacophore fragments are tethered with a metal centre to enhance their biological activity. 19,20 Martı ´nez et al reported that upon coordination to an organo-ruthenium fragment, the activity of clotrimazole, an antifungal drug, increased by a factor of 110. 21 Biot et al conjugated a ferrocenyl derivative to chloroquine and demonstrated activity in the case of chloroquine-resistant P. falciparum.…”

Synthesis and Structural Characterization of CaO-P2O5-CaF:CuO Glasses with Antitumoral Effect on Skin Cancer Cells

“…As for copper [19][20][21]24,25] it is a bio-element necessity for the human body that occurs in calcium and phosphorus metabolism. It exhibits two different ionic oxidation states (Cu (II) or Cu (I)) [26], and copper-containing complexes have been identified as the best candidates for anticancer agents [27][28][29][30][31]. The mechanism underlying the anti-tumor activity of these Cu-based complexes is the increase of ROS production and oxidative stress which causes DNA damage, increased death receptor expression and ultimately apoptosis-mediated cell death.…”