Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.666219
Title: Platinum picoline anticancer complexes
Author: McGowan, Geraldine
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
Availability of Full Text:
Access through EThOS:
Full text unavailable from EThOS. Please try the link below.
Access through Institution:
Abstract:
The 2-picoline (2-methylpyridine) complex, cis-[PtCl2(NH3)(2-pic)] (AMD473), is promising new generation platinum antitumour agent currently in clinical trials and highly active cisplatin resistant cell-lines. The antitumour activity of trans platinum complexes has attracted renewed interest since it has been shown that some trans compounds, in particular those possessing planar amine ligands, are anticancer-active. Therefore, three trans isomers, trans-[PtCl2(NH­3)(2-pic)] (1), trans-[PtCl2(NH3)(3-pic)] (2) and trans-[PtCl2(NH3)(4-pic)] (3), were synthesised and characterised. The crystal structure of 1 shows steric hindrance induced by the 2-methyl group towards an axial approach to Pt, while its 3-pic (2) and 4-pic (3) analogues are less sterically hindered. Notable however, is that in the solid state complex 1 is less sterically-hindered than its cis isomer. 15N-labelling of complexes 1-3 allowed both the hydrolysis rates and pKa values of the complexes to be determined using 2D[1H, 15N] NMR spectroscopy. Adducts of cis- and trans-(PtCl2(NH3)(2-pic)] with neutral 9-ethylguanine (9-EtGH) and anionic (N1-deprotonated) 9-ethylguanine (9-EtG) were prepared and their structures determined by X-ray crystallography. Platinum is coordinated at the guanine N7 position with a head-to-tail arrangement of the bases in all cases. Two of the complexes exhibited intermolecular triple hydrogen bonding between neutral and deprotonated guanine ligands. In addition, adducts of cis- and trans-[PtCl­2(NH3)(2-pic)] with guanosine and 2’-deoxyguanosine were prepared and characterised in solution by NMR spectroscopy and ESI mass spectrometry. The complexes cis-[Pt(NH3)(2-pic)(Guo)2]2+, and cis- and trans-(Pt(NH3)(2-pic)(2’-dGuo)2]2+ were assigned as head-to-tail conformations, on the basis of their NOE cross-peaks. The reaction of cis-[Pt(15NH3)(2-pic)(OH2)2]2+ and guanosine (Guo) was followed by 2D [1H, 15N] NMR spectroscopy and was found to proceed through two mono(guanosine) intermediate species to yield the dominant product cis-[Pt(15NH3)(2-pic)(Guo)2]2+. Initial guanosine substitution trans to 2-picoline was faster than substitution cis to 2-picoline due to steric hindrance, but the rates of the second guanosine substitution were similar. The binding of 15N-labelled-1 to a self-complementary DNA duplex, d(TATGGTACCATA)2, was investigated using 1D 1H and 2D [1H, 15H] NMR spectroscopy. The first aquation step appeared to be the rate-limiting step in the formation of the monofunctional adducts. Several DNA products were observed but could not be identified unambiguously. The rate constants for reactions between 15N-laabelled 1 and guanosine 5’-monophosphate (5’-GMP) were determined via 2D NMR studies, and compared to those previously reported for cis-[PtCl2(NH3)(2-pic)].
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.666219  DOI: Not available
Share: