DNA Condensation by Chiral α-Methylated Polyamine Analogues and Protection of Cellular DNA from Oxidative Damage

Abstract

Polyamines are essential molecules supporting the structure, conformation, and function of nucleic acids and proteins. We studied stereoisomers of alpha,alpha'-dimethylated spermine [(R,R)-Me(2)Spm, (S,S)-Me(2)Spm, (R,S)-Me(2)Spm] for their ability to provoke DNA condensation and protect DNA from damage. (R,R)- and (R,S)-Me(2)Spm displayed more efficient condensing ability than spermine, with significantly lower EC(50) (concentration for 50% compaction) values (p < or = 0.01). However, spermine exerted slightly more duplex stabilization than Me(2)Spm. Condensation resulted in nanoparticles with hydrodynamic radii between 39.6 and 48.4 nm, and electron microscopy showed the presence of toroids and spheroids. Natural polyamines and stereoisomers of Me(2)Spm protected DNA against DNase digestion and oxidative stress in vitro and against etoposide and oxidative stress in DU145 cells but afforded little protection against UV-C irradiation. Our findings indicate that Me(2)Spm stereoisomers are efficient DNA packaging agents with potential applications in gene delivery. Our study also reveals stereospecificity in DNA interaction and protection against cellular stress.

Binding of the Biogenic Polyamines to Deoxyribonucleic Acids of Varying Base Composition: Base Specificity and the Associated Energetics of the Interaction

“…The effectiveness of polyamine analogs as antiproliferative agents against many tumor cell lines provides evidence for nucleic acid interaction [7]–[10]. Polyamines interaction with nucleic acids have also been shown to affect the stability of double and triple stranded DNA, protect DNA from oxidative stress, damaging agents, ionizing radiation, and endonuclease digestion etc [11]–[14].…”

Thermodynamics of the DNA binding of biogenic polyamines: Calorimetric and spectroscopic investigations

“…The effectiveness of polyamine analogues, as anti-proliferative agents against many tumour cell lines provide evidence for nucleic acid interaction of polyamines [17][18][19][20][21][22]. Structurally, polyamines have cationic groups (figure 1) with multiple positive charges (four for spermine, three for spermidine, two each for putrescine and cadaverine) that enable them to interact with anionic nucleic acids protecting the latter from damaging agents [23][24][25][26]. A number of studies have been performed to understand the in vitro interaction of polyamines and their derivatives with DNA and RNA by a variety of techniques, such as equilibrium dialysis, NMR imaging, circular dichroism, Raman spectroscopy, FT IR spectroscopy, X-ray crystallography and differential scanning calorimetry [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].…”

Current Status of the Polyamine Research Field

“…More recent studies, in which (S)- and (R)- isomers of α-methylspermidine and (S,S)-, (R,S)-, and (R,R)-diastereomers of α,α′-(dimethyl)spermine have been used, have confirmed and extended these important findings (67, 191–196). Such studies have shown the maintenance of nucleic acid structure (196, 197), the stereospecificity of oxidation reactions (192, 194), the ability of derivatives that can support hypusine synthesis to support growth (67, 188, 190), and the role of polyamines in other growth processes including hair synthesis (198), liver regeneration, and adipocyte differentiation (199). Of particular interest is the ability to overcome acute liver damage and pancreatitis related to polyamine depletion by provision of α-methylspermidine or α,α′-(dimethyl)spermine (168, 193, 195, 200, 201).…”