Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics.
Anthracycline antibiotics such as daunomycin (Dauno) and doxorubicin (Dox) are well-known clinically used cancer chemotherapeutics, which, among other mechanisms, bind to DNA, thereby triggering a cascade of biological responses leading to cell death. However, anthracyclines are cardiotoxic, and drug resistance develops rapidly, thus limiting their clinical use. We report here the synthesis and DNA-binding affinity of a novel class of functional anthracycline mimetics consisting of an aromatic moiety linked to a carbohydrate (1-12). In the targets, the aromatic core consists of a 2-phenylbenzo[b]furan-3-yl, 2-phenylbenzo[b]thiophen-3-yl, 1-tosyl-2-phenylindol-3-yl, or 2-phenylindol-3-yl group that is bound to one of three aminosugars (daunosamine, acosamine, or 4-amino-2,3,4,6-tetradeoxy-alpha-l-hexopyranoside) via a propargyl linker. The DNA binding affinity of these twelve compounds has been evaluated by using both direct and indirect fluorescence measurements. Compared to Dauno and Dox, the DNA binding affinity of these analogues is weaker. However, both aromatic and aminosugar motifs are critical to DNA binding, with more influence coming from the structural features of the aromatic portion.
Shi
Wei
W
Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada.
Coleman
Robert S
RS
Lowary
Todd L
TL
D000818:Animals; D018943:Anthracyclines / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D015195:Drug Design; D006027:Glycosides / Q000737:chemistry; D006031:Glycosylation; D006595:Hexosamines / Q000737:chemistry; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D007455:Iodine / Q000737:chemistry; D013050:Spectrometry, Fluorescence
D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D006027:Glycosides; D006595:Hexosamines; D007364:Intercalating Agents; C007217:daunosamine; C010669:acosamine; D004247:DNA; D007455:Iodine
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