A mechanistic approach for the DNA binding of chiral enantiomeric L‐ and D‐tryptophan‐derived metal complexes of 1,2‐DACH: Cleavage and antitumor activity

Abstract

A new chiral series of potential antitumor metal-based complexes 1-3(a and b) of L- and D-tryptophan have been synthesized and thoroughly characterized. Both enantiomers of 1-3 bind DNA noncovalently via phosphate interaction with slight preference of metal center for covalent coordination to nucleobases. The K(b) values of L-enantiomer, however, possess higher propensity for DNA binding in comparison with the D-enantiomeric analogs. The relative trend in K(b) values is as follows: 2(a) > 2(b) > 3(a) > 1(a) > 3(b) > 1(b). These observations together with the findings of circular dichoric and fluorescence studies reveal maximal potential of L-enantiomeric form of copper complex to bind DNA, thereby exerting its therapeutic effect. The complex 2a exhibits a remarkable DNA cleavage activity with pBR322DNA in the presence of different activators such as H(2) O(2) , ascorbic acid, 3-mercaptopropionic acid, and glutathione, suggesting the involvement of active oxygen species for the DNA scission. In vitro anticancer activity of complexes 1-3(a) were screened against 14 different human carcinoma cell lines of different histological origin, and the results reveal that 2a shows significant antitumor activity in comparison with both 1a and 3a and is particularly selective for MIAPACA2 (pancreatic cancer cell line).

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

“…The intercalative mode of binding will be sensitive to ligand characteristics such as planarity of ligand, extent of aromatic π system available for stacking, and depth of ligand, which can penetrate into the double helix. On the other hand, electrostatic interaction would be more sensitive to the charge of the metal ion, ligand hydrophobicity, and size of the complex 54. An observed increase in emission intensity is associated with electrostatic interaction.…”

Zinc(II)‐N2O2ligation complex‐based DNA/protein binder and cleaver having enhanced cytotoxic and phosphatase activity

“…Absorption titration study was used to study the conformational change of BSA after complex formation with compounds. In the absorption spectra of BSA, the peak at 278 nm originates from the phenyl rings in aromatic acid residues (Trp, Tyr, and Phe) (Figure S6) . After the addition of 1 and 2 , the emission intensity of the peak increased, suggesting that an interaction between the metal complexes with BSA protein.…”

“…In the absorption spectra of BSA, the peak at 278 nm originates from the phenyl rings in aromatic acid residues (Trp, Tyr, and Phe) ( Figure S6). [30] After the addition of 1 and 2, the emission intensity of the peak increased, suggesting that an interaction between the metal complexes with BSA protein. Also, there is a change in the microenvironment surrounded the aromatic amino acid residues of BSA.…”

Nutritional and medicinal aspects of d-amino acids

“…The L-enantiomeric form exhibited greater binding affinity than did the D-form (Arjmand and Muddassir 2011). The aryl hydrocarbon receptor (AHR) mediates toxic and adaptive responses to xenobiotic compounds.…”