2 research outputs found
Biophysical Characterization and Molecular Docking Studies of Imidazolium Based Polyelectrolytes–DNA Complexes: Role of Hydrophobicity
Nonviral gene delivery vectors are
acquiring greater attention
in the field of gene therapy by replacing the biological viral vectors.
DNA–cationic polymer complexes are one of the most promising
systems to find application in gene therapy. Hence, a complete insight
of their biophysical characterization and binding energy profile is
important in understanding the mechanism involved in nonviral gene
therapy. In this investigation, the interaction between calf thymus
DNA (ctDNA) and imidazolium-based polyÂ(ionic liquids) (PILs) also
known as polyelectrolytes with three different alkyl side chains (ethyl,
butyl, and hexyl) in physiological conditions using various spectroscopic
experiments with constant DNA concentration and varying polyelectrolyte
concentrations is reported. UV–visible absorption, fluorescence
quenching studies, gel electrophoresis, circular dichroism (CD), and
Fourier transform infrared spectroscopy (FTIR) have confirmed the
binding of polyelectrolytes with DNA. UV–vis absorption measurements
and fluorescence quenching revealed that the binding between DNA and
the polyelectrolyte is dominated by electrostatic interactions. Additionally,
CD and FTIR results indicated that the DNA retained its B-form with
minor perturbation in the phosphate backbone without significant change
in the conformation of its base pairs. Preference for alkyl side chains
(<i>K</i><sub>PIL‑Ethyl Br</sub> < <i>K</i><sub>PIL‑Butyl Br</sub> < <i>K</i><sub>PIL‑Hexyl Br</sub>) toward efficient binding between
the polyelectrolyte and DNA was inferred from the binding and quenching
constants calculated from the absorption and emission spectra, respectively.
Further, in silico molecular docking studies not only validated the
observed binding trend but also provided insight into the binding
mode of the polyelectrolyte–DNA complex
Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues
A series
of calothrixin B (<b>2</b>) analogues bearing substituents
at the ‘E’ ring and their corresponding deoxygenated
quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities
of calothrixins <b>1</b>, <b>2</b>, and <b>15b</b>–<b>p</b> and quinocarbazole analogues were investigated
against nine cancer cell lines. The quinocarbazoles <b>21a</b> and <b>25a</b> inhibited the catalytic activity of human topoisomerase
II. The plasmid DNA cleavage abilities of calothrixins <b>1</b>, <b>2</b>, and <b>15b</b>–<b>p</b> identified
compound <b>15h</b> causing DNA cleavage comparable to that
of calothrixin A (<b>1</b>). Calothrixin A (<b>1</b>),
3-fluorocalothrixin <b>15h</b> and 4-fluoroquinocarbazole <b>21b</b> induced extensive DNA damage followed by apoptotic cell
death. Spectral and plasmid unwinding studies demonstrated an intercalative
mode of binding for quinocarbazoles. We identified two promising drug
candidates, the 3-fluorocalothrixin B <b>15h</b> with low toxicity
in animal model and its deoxygenated derivative 4-fluoroquinocarbazole <b>21b</b> as having potent cytotoxicity against NCI-H460 cell line
with a GI<sub>50</sub> of 1 nM