Terence G. Collins Responds to Ira Schor

Collins, Terence

doi:10.37514/jbw-j.1997.16.2.08

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“…The resonances in the 1 H NMR spectra of the free and WEHI-150-bound oligonucleotide were assigned by standard techniques. [33][34][35] Consistent with many NMR studies of oligonucleotides, [33][34][35][36] the analysis of short mixing-time NOESY and DQFCOSY spectra indicated that the octanucleotide adopted a B-type conformation in the aqueous buffer. Fig.…”

Section: Wehi-150 Binding To D(acggccgt)supporting

confidence: 71%

Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA

et al. 2016

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Collins, J. (2016). Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA. Organic and Biomolecular Chemistry, 14 (20), 4728-4738. Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA AbstractThe ability of a bis-amino mitoxantrone anticancer drug (named WEHI-150) to form covalent adducts with DNA, after activation by formaldehyde, has been studied by electrospray ionisation mass spectrometry and HPLC. Mass spectrometry results showed that WEHI-150 could form covalent adducts with d(ACGCGCGT)2 that contained one, two or three covalent links to the octanucleotide, whereas the control drugs (daunorubicin and the anthracenediones mitoxantrone and pixantrone) only formed adducts with one covalent link to the octanucleotide. HPLC was used to examine the extent of covalent bond formation of WEHI-150 with d(CGCGCG)2 and d(CG5MeCGCG)2. Incubation of WEHI-150 with d(CG5MeCGCG)2 in the presence of formaldehyde resulted in the formation of significantly greater amounts of covalent adducts than was observed with d(CGCGCG)2. In order to understand the observed increase of covalent adducts with d(CG5MeCGCG)2, an NMR study of the reversible interaction of WEHI-150 at both CpG and 5MeCpG sites was undertaken. Intermolecular NOEs were observed in the NOESY spectra of d(ACGGCCGT)2 with added WEHI-150 that indicated that the drug selectively intercalated at the CpG sites and from the major groove. In particular, NOEs were observed from the WEHI-150 H2,3 protons to the H1′ protons of G3 and G7 and from the H6,7 protons to the H5 protons of C2 and C6. By contrast, intermolecular NOEs were observed between the WEHI-150 H2,3 protons to the H2′′ proton of the 5MeC3 in d(CG5MeCGCG)2, and between the drug aliphatic protons and the H1′ proton of G4. This demonstrated that WEHI-150 preferentially intercalates at 5MeCpG sites, compared to CpG sequences, and predominantly via the minor groove at the 5MeCpG site. The results of this study demonstrate that WEHI-150 is likely to form interstrand DNA cross-links, upon activation by formaldehyde, and consequently exhibit greater cytotoxicity than other current anthracenedione drugs. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsKonda, S., Kelso, C., Pumuye, P. P., Medan, J., Sleebs, B. E., Cutts, S. M., Phillips, D. R. & Collins, J. (2016

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