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Cyclometallated complexes for cancer chemotherapy

Pell, Thomas

[Thesis]. Manchester, UK: The University of Manchester; 2011.

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Abstract

A number of palladium (II) cyclometallated complexes of the general molecular formula [({η2-C,N-C6H4-2-(CH2NMe2)}Pd)nXn(L)] are prepared and characterized (where L represents a mono- or bi-dentate phosphine, X represents either chloro or acetate ligands and n = 1 or 2 for mono- or bidentate phosphines respectively). All of the compounds prepared, including the analogous platinacycles and the phosphite palladacycles of Bedford et al., are tested in vitro against the two human breast cancer cell lines MDA-NQ01 and MDA-MB-468 using MTT assays. MDA-NQ01 over-expresses DT-diaphorase which is a two electron reductase enzyme, and MDA-MB-468 is the corresponding cell line which does not express DT-diaphorase. The results from these tests showed that most of the compounds have good or excellent cytotoxic activity however, only 11 [{η2-C,N-C6H4-2-(CH2NMe2)}PdCl(PPh3)] showed a large enough differential between the two cell lines for it to be considered as possibly activated by DT-diaphorase. All the other drugs exhibited very similar activity in both cell lines. 25 and 26 which are platinum dinuclear bridge-split complexes had IC50 values above 12.8 μM.The complex with the best anti-cancer activity is tested for its ability to perform the Heck reaction. The turnover numbers of this compound is compared to one of the best known palladium catalysts of Bedford et al. and the results show that the Pd(0) oxidation state is accessible for these complexes.Control (untreated) cells and cells treated a with range of drugs (Cisplatin, RH1, mitomycin C, [{η2-C,N-C6H4-2-(CH2NMe2)PtCl}2{μ-4,4'-(PPh2)2-(C6H4-O-C6H4)}] 26, [{η2-C,N-C6H4-2-(CH2NMe2)PdCl}2{μ-4,4'-(PPh2)2-(C6H4-O-C6H4)}] 23, and [1-Br-2 -{Pd(PEt3)2Br}-C6H4] 29a) are analysed using SR-IRMS (synchrotron radiation infrared microspectroscopy) to look for differences in biochemical responses to the drugs in an attempt to elucidate differences in each drug‟s mode of action. After careful analysis, the data show that the drugs act in different phases of the cell cycle and operate with different mechanisms, a result that is consistent with literature precedents.

Additional content not available electronically

Electronic Supplementary Information

Bibliographic metadata

Type of resource:
Content type:
Administered thesis
Form of thesis:
PhD by published work
Type of submission:
Doctoral level ETD - final
Thesis title:
Cyclometallated complexes for cancer chemotherapy
Degree type:
Master of Philosophy
Degree programme:
MPhil Chemistry
Publication date:
2011-10-22T09:54:26
Institution:
The University of Manchester
Location:
Manchester, UK
Total pages:
101
Abstract:
A number of palladium (II) cyclometallated complexes of the general molecular formula [({η2-C,N-C6H4-2-(CH2NMe2)}Pd)nXn(L)] are prepared and characterized (where L represents a mono- or bi-dentate phosphine, X represents either chloro or acetate ligands and n = 1 or 2 for mono- or bidentate phosphines respectively). All of the compounds prepared, including the analogous platinacycles and the phosphite palladacycles of Bedford et al., are tested in vitro against the two human breast cancer cell lines MDA-NQ01 and MDA-MB-468 using MTT assays. MDA-NQ01 over-expresses DT-diaphorase which is a two electron reductase enzyme, and MDA-MB-468 is the corresponding cell line which does not express DT-diaphorase. The results from these tests showed that most of the compounds have good or excellent cytotoxic activity however, only 11 [{η2-C,N-C6H4-2-(CH2NMe2)}PdCl(PPh3)] showed a large enough differential between the two cell lines for it to be considered as possibly activated by DT-diaphorase. All the other drugs exhibited very similar activity in both cell lines. 25 and 26 which are platinum dinuclear bridge-split complexes had IC50 values above 12.8 μM.The complex with the best anti-cancer activity is tested for its ability to perform the Heck reaction. The turnover numbers of this compound is compared to one of the best known palladium catalysts of Bedford et al. and the results show that the Pd(0) oxidation state is accessible for these complexes.Control (untreated) cells and cells treated a with range of drugs (Cisplatin, RH1, mitomycin C, [{η2-C,N-C6H4-2-(CH2NMe2)PtCl}2{μ-4,4'-(PPh2)2-(C6H4-O-C6H4)}] 26, [{η2-C,N-C6H4-2-(CH2NMe2)PdCl}2{μ-4,4'-(PPh2)2-(C6H4-O-C6H4)}] 23, and [1-Br-2 -{Pd(PEt3)2Br}-C6H4] 29a) are analysed using SR-IRMS (synchrotron radiation infrared microspectroscopy) to look for differences in biochemical responses to the drugs in an attempt to elucidate differences in each drug‟s mode of action. After careful analysis, the data show that the drugs act in different phases of the cell cycle and operate with different mechanisms, a result that is consistent with literature precedents.
Additional digital content not deposited electronically:
Electronic Supplementary Information
Keyword(s):
Thesis co-supervisor(s):
Degree grantor:
Language:
en

Institutional metadata

University researcher(s):
Academic department(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:134072
Created by:
Pell, Thomas
Created:
22nd October, 2011, 08:54:26
Last modified by:
Pell, Thomas
Last modified:
13th April, 2012, 11:00:17

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