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Copper(II) complexes of substituted salicylaldehyde semicarbazones : synthesis, cytotoxicity and interaction with quadruplex DNA
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Type
Thesis
Author
Siti Munira Haidad Ali
Supervisor
Yan, Yaw Kai
Lee, Peter Peng Foo
Abstract
A series of substituted salicylaldehyde dibenzyl semicarbazones [RC6H3(OH)CH=N-NHCON(CH2Ph)2] and their copper(II) complexes were synthesized and characterized. The chloridocopper(II) complexes of the 4-OH and 5-OH substituted ligands (complexes CuBZ9 and CuBZ7) show modest affinity and good selectivity (over duplex DNA) for the quadruplex formed from the 22AG human telomeric (HTelo) DNA sequence. Substitution of the chlorido ligands of these two complexes with pyridine yielded derivatives (C7-py and C9-py) with increased affinity for HTelo. These derivatives also show good selectivity for HTelo over calf-thymus DNA (170- and 211-fold, respectively).
The X-ray crystal structures of CuBZ9 and C9-py were determined. Molecular docking studies based on these structures show that the complexes stack on the 5'-end of the HTelo quadruplex, with the hydroxyl group forming a hydrogen bond with a guanine residue. Complexes CuBZ7, CuBZ9, C7-py and C9-py display significant cytotoxicity against MOLT-4 human leukaemia cells. Interestingly, they have low to negligible cytotoxicity against the non-cancerous IMR-90 human fibroblasts.
Another series of copper(II) 2,4-dihydroxybenzaldehyde N,N-dibenzyl semicarbazone complexes with substituted pyridine ligands were further synthesized and characterized. The copper(II) complex with the 4-bromopyridine substituent shows very high selectivity for the quadruplex formed from the 22AG human telomeric (HTelo) DNA sequence over calfthymus DNA (293-fold). All the complexes are also strongly cytotoxic against MOLT-4 human leukaemia cells. Complexes C9-pyBr, C9-pyOH, C9-pyPh, C9-py(CH3) and C9-py(OCH3) inhibit MOLT-4 human leukaemia cells selectively over non-cancerous IMR-90 human fibroblasts and are effective in inhibiting proteasome activity.
The X-ray crystal structures of CuBZ9 and C9-py were determined. Molecular docking studies based on these structures show that the complexes stack on the 5'-end of the HTelo quadruplex, with the hydroxyl group forming a hydrogen bond with a guanine residue. Complexes CuBZ7, CuBZ9, C7-py and C9-py display significant cytotoxicity against MOLT-4 human leukaemia cells. Interestingly, they have low to negligible cytotoxicity against the non-cancerous IMR-90 human fibroblasts.
Another series of copper(II) 2,4-dihydroxybenzaldehyde N,N-dibenzyl semicarbazone complexes with substituted pyridine ligands were further synthesized and characterized. The copper(II) complex with the 4-bromopyridine substituent shows very high selectivity for the quadruplex formed from the 22AG human telomeric (HTelo) DNA sequence over calfthymus DNA (293-fold). All the complexes are also strongly cytotoxic against MOLT-4 human leukaemia cells. Complexes C9-pyBr, C9-pyOH, C9-pyPh, C9-py(CH3) and C9-py(OCH3) inhibit MOLT-4 human leukaemia cells selectively over non-cancerous IMR-90 human fibroblasts and are effective in inhibiting proteasome activity.
Date Issued
2014
Call Number
QD474 Sit
Date Submitted
2014