High-resolution NMR spectroscopic analysis of anticancer drugs, DNA and their interactions: 1. Platinum anticancer compounds - DNA interactions. 2. Anthracycline drugs - DNA interactions and modified DNA.

摘要

Chemotherapy with anticancer drugs is one of the main method of cancer treatment. The exploitation of the stereochemical interactions between anticancer drugs and DNA is of great importance for the ultimate clinical advances of cancer chemotherapy, which needs the detailed structural knowledge of DNA, drugs, and their interactions. Cisplatin is one of the most effecient and widely used anticancer drugs in the world. Extensive effort has been devoted to designing the new better anticancer platinum compounds. The structural studies on interactions of two anticancer platinum compounds, cisplatin and the third-generation bisplatinum compound 1,1/t,t, with DNA are described in this thesis. The structure of an intrastrand cisplatin-crosslinked didentate DNA duplex consisting of d(CCTG{dollar}rmsp*Gsp*{dollar}TCC) and its complement d(GGACCAGG) is determined by NMR spectroscopy. The refined duplex is unwound ({dollar}sim{lcub}-{rcub}21spcirc{dollar}) and kinked ({dollar}{lcub}sim{rcub}58spcirc{dollar}) toward the major groove at the {dollar}rm Gsp*Gsp*{dollar} site and the minor groove is significantly widened. The stability of the major intrastrand cisplatin-G{dollar}rmsp*pGsp*{dollar} adduct has been studied and this intrastrand cisplatin-crosslinked adduct appears to be converted into an interstrand crosslink adduct. Three palindromic DNA oligonucleotides, each having a single intrastrand cisplatin crosslinked at GpG site, have also been studied by NMR spectroscopy. The structural consequence of the incorporation of the {dollar}rm Gsp*Gsp*{dollar} lesions into palindromic sequences is dependent on the location of the lesion sites in the sequence. Such alternative structural distortions may be relevant in understanding the protein recognition of the cisplatin-induced lesions. A new anticancer bisplatinum compound 1,1/t,t exhibits excellent cytotoxicity towards cisplatin-resistant cancer cells. The structure of the interstrand adduct of 1,1/t,t with a palindromic DNA oligomer CATGCATG has been determined by NMR spectroscopy. Upon platination by 1,1/t,t, the DNA octamer forms a novel hairpin structure with the platinated G{dollar}sb4{dollar} residue adopting a syn conformation and with the guanine base in the minor groove. Two such hairpins stack end-over-end and are linked together by the butanediamine tether to form a dumbbell structure. Such unusual structural distortion induced by the bisplatinum compound is completely different from that of the anticancer drug cisplatin-DNA adduct and may provide clues to explain the distinct biological activities of the two compounds.; Anthracycline antibiotics are important anticancer intercalative drugs. The solution structures of anticancer anthracycline drugs aclacinomycin A and B, nogalamycin and disnogalamycin, complexed to a DNA hexamer have all been determined by high resolution NMR spectroscopy. Structural modification of DNA through covalent interactions have significant functional consequences and/or anticancer activities. Structural analysis of the C{dollar}sp2{dollar}-methyl-hypoxanthine:Cytosine base pair and O{dollar}sp6{dollar}-ethyl-Guanine:Cytosine base pair in B-DNA help understand their biological functions.