Nemorubicin and doxorubicin bind the G-quadruplex sequences of the human telomeres and of the c-MYC promoter element Pu22

• Published in: Biochimica et biophysica acta Vol. 1860; no. 6; pp. 1129 - 1138
• Main Authors: Scaglioni, Leonardo, Mondelli, Rosanna, Artali, Roberto, Sirtori, Federico Riccardi, Mazzini, Stefania
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2016
• Subjects: adenine; antineoplastic activity; Antineoplastic Agents - chemistry; c-MYC; Daunomycins; DNA; DNA-binding drugs; doxorubicin; Doxorubicin - analogs & derivatives; Doxorubicin - chemistry; electrospray ionization mass spectrometry; G-quadruplex; G-Quadruplexes; gene overexpression; Genes, myc; guanine; humans; ligands; Magnetic Resonance Spectroscopy; mechanism of action; Models, Molecular; Molecular modeling; NMR; nuclear magnetic resonance spectroscopy; oncogenes; promoter regions; Promoter Regions, Genetic; Spectrometry, Mass, Electrospray Ionization; Telomere; telomeres; transcription (genetics); A; DNA-binding drugs; c-MYC; G; G-quadruplex; nemo; TOCSY; doxo; daunomycins; DOSY; Q; NMR; R=[drug]/[DNA]; T; Molecular modeling; ESI–MS; NOESY; HSQC; Daunomycins
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.02.011

Intra-molecular G-quadruplex structures are present in the guanine rich regions of human telomeres and were found to be prevalent in gene promoters. More recently, the targeting of c-MYC transcriptional control has been suggested, because the over expression of the c-MYC oncogene is one of the most common aberration found in a wide range of human tumors. The interaction of nemorubicin and doxorubicin with DNA G-quadruplex structures has been studied by NMR, ESI–MS and molecular modelling, in order to obtain further information about the complex and the multiple mechanisms of action of these drugs. Nemorubicin intercalates between A3 and G4 of d(TTAGGGT)4 and form cap-complex at the G6pT7 site. The presence of the adenine in this sequence is important for the stabilization of the complex, as was shown by the interaction with d(TTGGGTT)4 and d(TTTGGGT)4, which form only a 1:1 complex. The interaction of doxorubicin with d(TTAGGGT)4 is similar, but the complex appears less stable. Nemorubicin also binds with high efficiency the c-MYC G-quadruplex sequence Pu22, to form a very well defined complex. Two nemorubicin molecules bind to the 3′-end and to the 5′-end, forming an additional plane of stacking over each external G-tetrad. The wild type c-MYCPu22 sequence forms with nemorubicin the same complex. Nemorubicin and doxorubicin, not only intercalate into the duplex DNA, but also result in significant ligands for G-quadruplex DNA segments, stabilizing their structure; this may in part explain the multiple mechanisms of action of their antitumor activity. [Display omitted] •NMR study on the interaction of nemorubicin to G-quadruplex of human telomeres and the c-MYC promoter element Pu22.