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Synthesis, characterisation and in vitro cytotoxic studies of some metal surface functionalised PAMAM dendrimers
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Type
Thesis
Author
Zhao, Xinxin
Supervisor
Chu, Chit Kay
Abstract
A series of zero, first and second generation polyamidoamine (PAMAM) dendrimers have been synthesized with improved yields and characterized spectroscopically. The full generation PAMAM dendrimers were prepared and subsequently functionalized using excess pyridine-2-carboxaldehyde to give the corresponding terminally modified PAMAM Schiff bases. Those pyridylimine ligands were finally obtained as light yellow solids but turned oily when exposed to air, probably due to the absorption of moisture.
A series of new metallodendrimers were prepared by reacting these Schiff bases with [ReBr(CO)5], [PtC12(coe)]2, CuC12, and HgCI2. The spectral and physical properties of these new complexes were studied.
Among these metallodendrimers, the rhenium derivatives were found to display fluorescence and possess liquid crystal properties. The linear relationship between the molar extinction coefficient and the number of chromophores present suggests little or no metal-metal interactions at least up to the second generation for rhenium complexes; It was found that [G2-Py16-{ReBr(CO)3}16] (16C) forms a columnar mesophase during the slow cooling from 120oC. Apparently, the mesophase transition is independent of the dendrimer generation due to the similarities in temperature and enthalpy of the solid-to-mesophase transition obtained from DSC study. The aggregation properties of rhenium complexes in DMF/H2O (1:10 v/v) were also investigated by transmission electron microscopy (TEM). The introduction of heavy atoms (Re, Br) enables the imaging of the molecules by TEM without staining procedures. The dendritic complexes [G0-Py4-{ReBr(CO)3}4] (4C), [G1-Py8-{ReBr(CO)3}8] (8C), and 16C tend to self-assemble into small vesicles of sizes between 20-50 nm with a membrane thickness of 2-5 nm. The size of these vesicles is independent of the generation of dendrimers. However, it was found that the particles of lower generation 4C tend to coalesce into bigger particles comparing with 8C and 16C.
The corresponding metal moiety containing reference compounds [fac-[MeCONHCH2CH2N=CHPy]ReBr(CO)3] (1C), (MeCONHCH2CH2N=CHPy)(PtC12)] (1D), [(MeCONHCH2CH2N=CHPy)(CuC12)] (1E), and [(MeCONHCH2CH2N=CHPy)(HgC12)]2 (1F) were prepared and characterized by single crystal X-ray diffraction. Single crystal X-ray diffraction studies showed that the Pt center of compound 1D has a planar configuration with an N-Pt-N angle of 79.8o. The shorter N-Pt bond length as compared to cisplatin suggests increased trans influence on the chloride ligands rendering them more labile. Compound 1E shows that the copper center has a distorted tetrahedral environment with a rather long Cu-C1 intermolecular distance precluding dinner formation.
The MALDI-TOF mass spectrum suggests the structure of [G0-Py4-(CuC12)7] (4E) is different from that of other metal complexes. Ligand G0-Py4 does not coordinate with four copper chloride moieties as we expected, but rather coordinate with seven CuC12 by using three different copper coordinations. The v(C=O) stretching absorption of 4B at 1649 cm-1 shifts to lower frequency at 1635 cm-1 after complexing with CuC12, which suggests the coordination of CuC12 with the ketonic oxygen of 4B.
The anticancer potential of both the dendrimer ligands and their corresponding metal derivatives were investigated by in vitro cytotoxic studies against human cancer cell lines (MOLT-4 and MCF-7) and compared with the benign origin Chang Liver cell line. Results from cytotoxic essays on these three cell lines showed that some of the complexes prepared are very cytotoxic. The copper complexes 1E and 4E are found to be the most cytotoxic. Coordinating with more CuC12, 4E shows even higher cytotoxic activity against the three cell lines but at the expanse of losing cell selectivity. The rhenium dendritic derivatives 8C are cell selective, which shows no cytotoxicty to MOLT-4 cells. However, the higher generation rhenium complex 16C shows no such selectivity. In this study, some of the ligands and their metal complexes showed significant potential anticancer activities. This preliminary study provides a strong platform for further investigations into this class of metallodendrimers as anticancer drug carriers.
A series of new metallodendrimers were prepared by reacting these Schiff bases with [ReBr(CO)5], [PtC12(coe)]2, CuC12, and HgCI2. The spectral and physical properties of these new complexes were studied.
Among these metallodendrimers, the rhenium derivatives were found to display fluorescence and possess liquid crystal properties. The linear relationship between the molar extinction coefficient and the number of chromophores present suggests little or no metal-metal interactions at least up to the second generation for rhenium complexes; It was found that [G2-Py16-{ReBr(CO)3}16] (16C) forms a columnar mesophase during the slow cooling from 120oC. Apparently, the mesophase transition is independent of the dendrimer generation due to the similarities in temperature and enthalpy of the solid-to-mesophase transition obtained from DSC study. The aggregation properties of rhenium complexes in DMF/H2O (1:10 v/v) were also investigated by transmission electron microscopy (TEM). The introduction of heavy atoms (Re, Br) enables the imaging of the molecules by TEM without staining procedures. The dendritic complexes [G0-Py4-{ReBr(CO)3}4] (4C), [G1-Py8-{ReBr(CO)3}8] (8C), and 16C tend to self-assemble into small vesicles of sizes between 20-50 nm with a membrane thickness of 2-5 nm. The size of these vesicles is independent of the generation of dendrimers. However, it was found that the particles of lower generation 4C tend to coalesce into bigger particles comparing with 8C and 16C.
The corresponding metal moiety containing reference compounds [fac-[MeCONHCH2CH2N=CHPy]ReBr(CO)3] (1C), (MeCONHCH2CH2N=CHPy)(PtC12)] (1D), [(MeCONHCH2CH2N=CHPy)(CuC12)] (1E), and [(MeCONHCH2CH2N=CHPy)(HgC12)]2 (1F) were prepared and characterized by single crystal X-ray diffraction. Single crystal X-ray diffraction studies showed that the Pt center of compound 1D has a planar configuration with an N-Pt-N angle of 79.8o. The shorter N-Pt bond length as compared to cisplatin suggests increased trans influence on the chloride ligands rendering them more labile. Compound 1E shows that the copper center has a distorted tetrahedral environment with a rather long Cu-C1 intermolecular distance precluding dinner formation.
The MALDI-TOF mass spectrum suggests the structure of [G0-Py4-(CuC12)7] (4E) is different from that of other metal complexes. Ligand G0-Py4 does not coordinate with four copper chloride moieties as we expected, but rather coordinate with seven CuC12 by using three different copper coordinations. The v(C=O) stretching absorption of 4B at 1649 cm-1 shifts to lower frequency at 1635 cm-1 after complexing with CuC12, which suggests the coordination of CuC12 with the ketonic oxygen of 4B.
The anticancer potential of both the dendrimer ligands and their corresponding metal derivatives were investigated by in vitro cytotoxic studies against human cancer cell lines (MOLT-4 and MCF-7) and compared with the benign origin Chang Liver cell line. Results from cytotoxic essays on these three cell lines showed that some of the complexes prepared are very cytotoxic. The copper complexes 1E and 4E are found to be the most cytotoxic. Coordinating with more CuC12, 4E shows even higher cytotoxic activity against the three cell lines but at the expanse of losing cell selectivity. The rhenium dendritic derivatives 8C are cell selective, which shows no cytotoxicty to MOLT-4 cells. However, the higher generation rhenium complex 16C shows no such selectivity. In this study, some of the ligands and their metal complexes showed significant potential anticancer activities. This preliminary study provides a strong platform for further investigations into this class of metallodendrimers as anticancer drug carriers.
Date Issued
2007
Call Number
TP1180.D45 Zha
Date Submitted
2007