手性 α-甲基化聚胺类似物的 DNA 凝聚作用和保护细胞 DNA 免受氧化损伤。

DNA condensation by chiral alpha-methylated polyamine analogues and protection of cellular DNA from oxidative damage.

机构信息

University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.

出版信息

Biomacromolecules. 2010 Jan 11;11(1):97-105. doi: 10.1021/bm900958c.

DOI:10.1021/bm900958c

PMID:19919070

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.

摘要

多胺是支持核酸和蛋白质结构、构象和功能的必需分子。我们研究了α，α'-二甲基化精脒的立体异构体[(R,R)-Me2Spm、(S,S)-Me2Spm、(R,S)-Me2Spm]，以研究它们诱导 DNA 凝聚和保护 DNA 免受损伤的能力。(R,R)-和(R,S)-Me2Spm 比精脒显示出更强的凝聚能力，EC50（50%压缩浓度）值显著降低（p≤0.01）。然而，精脒对双链体的稳定作用略高于 Me2Spm。凝聚导致水动力半径在 39.6nm 到 48.4nm 之间的纳米颗粒形成，电子显微镜显示存在环形体和球形体。天然多胺和 Me2Spm 的立体异构体在体外保护 DNA 免受 DNA 酶消化和氧化应激，以及在 DU145 细胞中免受依托泊苷和氧化应激的影响，但对 UV-C 照射的保护作用很小。我们的发现表明，Me2Spm 立体异构体是有效的 DNA 包装剂，具有在基因传递中应用的潜力。我们的研究还揭示了 DNA 相互作用和对细胞应激的立体特异性保护。