Analysis of the DNA binding of pixantrone

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Copyright: Adnan, Najia
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Abstract
The binding of the anti-cancer drug pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate) to the oligonucleotide duplexes d(ACGATCGT)2 and the corresponding 5MeC analogue d(A5MeCGAT5MeCGT)2 has been studied by 1H NMR spectroscopy and molecular modelling. The large upfield shifts observed for the resonances from the aromatic protons of pixantrone upon addition to either d(ACGATCGT)2 or the corresponding 5MeC analogue is consistent with the drug binding the octanucleotides by intercalation. The selective reduction in the sequential NOEs between the C2-G3 and C6-G7 nucleotides in NOESY spectra of either octanucleotide with added pixantrone confirms an intercalative binding mechanism. Strong NOEs from the side-chain ethylene protons of pixantrone to the H5 protons and the 5-CH3 protons of the C2 and C6 residues of d(ACGATCGT)2 and d(A5MeCGAT5MeCGT)2, respectively, indicate that pixantrone predominantly intercalates from the DNA major groove at the 5'-CG and 5'-5MeCG sites. Simple molecular models based on the conclusions from the NMR experiments indicated that the 5MeC groups do not represent a steric barrier to intercalation from the major groove. However, the observation of weak NOEs from the ethylene protons to a variety of minor groove protons from either of the octanucleotide studied also suggests that the drug can associate in the minor groove. The binding of pixantrone to the oligonucleotide d(CCGAGAATTCCGG)2 that contain an adenine bulge site was studied by 1H NMR spectroscopy. The oligonucleotide was chosen to determine if the pixantrone would exhibit any binding specificity to an A-bulge site in an oligonucleotide. NMR results shows that pixantrone binds at the expected 5'-CG site, however, some NOEs were observed from pixantrone to minor groove protons at the bulge site of the oligonucleotide, indicating that additional binding is possible in the minor groove. Finally, a study of the encapsulation of pixantrone within cucurbit[7,8]uril as a means of increasing the aqueous solubility of pixantrone was made. 1H NMR spectroscopy studies and molecular modelling of pixantrone with cucurbit[7]uril showed that pixantrone is not encapsulated inside the cucurbit[7]uril cavity, however, it does interact with the cucurbit[7]uril portals. Comparatively, encapsulation of pixantrone within cucurbit[8]uril induced significant shifting and splitting of the pixantrone 1H NMR peaks. This indicated pixantrone can be encapsulated in cucurbit[8]uril.
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Author(s)
Adnan, Najia
Supervisor(s)
Collins, Grant
Day, Anthony
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Publication Year
2010
Resource Type
Thesis
Degree Type
Masters Thesis
UNSW Faculty
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