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Alice Dawson

Publications and source records attributed to Alice Dawson.

11 recordsLinked to original sources
PubMed2006

Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands.

We report structure-activity relationships for organometallic RuII complexes of the type [(eta6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- (e.g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY=ethylenediamine (en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY=bipyridyl derivatives exhibited reduced activity. The activity of the O,O-chelated complexes depended strongly on the substituents and on the arene. For arene=p-cymene, XY=amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY=en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

2,2'-Dipyridyl↗
PubMed2006

The nucleotide-binding site of Aquifex aeolicus LpxC.

The structure of recombinant Aquifex aeolicus UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) in complex with UDP has been determined to a resolution of 2.2 A. Previous studies have characterized the binding sites of the fatty-acid and sugar moieties of the substrate, UDP-(3-O-hydroxymyristoyl)-N-acetylglucosamine, but not that of the nucleotide. The uracil-binding site is constructed from amino acids that are highly conserved across species. Hydrophobic associations with the Phe155 and Arg250 side chains in combination with hydrogen-bonding interactions with the main chain of Glu154 and the side chains of Tyr151 and Lys227 position the base. The phosphate and ribose groups are directed away from the active site and interact with Arg137, Lys156, Glu186 and Arg250. The orientation of the phosphate-ribose tail is not conducive to catalysis, perhaps owing to the position of an inhibitory Zn(2+). However, based on the position of uracil revealed in this study and on the previously reported complex of LpxC with an inhibitor, a model is proposed for substrate binding.

Amidohydrolases↗
PubMed2006

Models of the cytochromes: crystal structures and EPR spectral characterization of low-spin bis-imidazole complexes of (OETPP)Fe(III) having intermediate ligand plane dihedral angles.

The preparation, EPR spectra, and crystal structures of octaethyltetraphenylporphyrinatoiron(III) having two imidazole, N-benzylimidazole, and N-methylimidazole axial ligands are reported, [(OETPP)Fe(HIm)2]Cl, [(OETPP)Fe(N-BzIm)2]Cl, and [(OETPP)Fe(N-MeIm)2]Cl. Despite large variation in axial ligand size, the unit cell parameters for all complexes are very similar; each structure has the same basic motif, with large voids formed by the extended porphyrin framework (filled by ordered or disordered axial ligands and disordered solvent), which allows differently sized ligands to fit within the same cell dimensions. Each porphyrin core adopts a saddled conformation with absolute value(deltaC(beta)) = 1.13-1.15 A. The dihedral angles between axial ligand planes, delta phi, are far from being either ideal parallel or perpendicular: 30.1 degrees, 57.2 degrees for [(OETPP)Fe(HIm)2]Cl (molecules 1 and 2), 56.8 degrees for [(OETPP)Fe(N-BzIm)(2)]Cl, and 16.0 degrees, 44.6 degrees, 59.6 degrees, and 88.1 degrees for [(OETPP)Fe(N-MeIm)2]Cl, which has disordered axial ligands. Among the complexes of this study, an axial ligand delta phi of 56.8 degrees is found to be the largest "parallel" angle (as defined by the observation of a normal rhombic or Type II EPR signal (N-BzIm, g = 3.08, 2.19, 1.31)), while 57.2 degrees is found to be the smallest "perpendicular" delta phi (as defined by the observation of a "large gmax" or Type I EPR signal (HIm, gmax = 3.24)). From the results of this study, it is clear that the size of the largest g for Types I and II complexes varies continuously, with no break between the two. While the switch in EPR signal type, from Type II to Type I, appears to be very sharp in this study, this may be somewhat artificial based upon limited numbers of examples and the required saddle distortion of the (OETPP)Fe(III) complexes. However, in comparison to several proteins with dihedral angles near 60 degrees and Type II EPR spectra, we may conclude that the switch in EPR signal type occurs near 57 degrees +/- 3-5 degrees.

Crystallography, X-Ray↗
PubMed2006

A photoactivated trans-diammine platinum complex as cytotoxic as cisplatin.

The synthesis and X-ray structure (as the tetrahydrate) of the platinum(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 3 are described and its photochemistry and photobiology are compared with those of the cis isomer cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 4. Complexes 4 and 3 are potential precursors of the anticancer drug cisplatin and its inactive trans isomer transplatin, respectively. The trans complex 3 is octahedral, contains almost linear azide ligands, and adopts a layer structure with extensive intermolecular hydrogen bonding. The intense azide-to-platinum(IV) charge-transfer band of complex 3 (285 nm; epsilon=19 500 M(-1) cm(-1)) is more intense and bathochromically shifted relative to that of the cis isomer 4. In contrast to transplatin, complex 3 rapidly formed a platinum(II) bis(5'-guanosine monophosphate) (5'-GMP) adduct when irradiated with UVA light, and did not react in the dark. Complexes 3 and 4 were non-toxic to human skin cells (keratinocytes) in the dark, but were as cytotoxic as cisplatin on irradiation for a short time (50 min). Damage to the DNA of these cells was detected by using the "comet" assay. Both trans- and cis-diammine platinum(IV) diazide complexes therefore have potential as photochemotherapeutic agents.

Antineoplastic Agents↗
PubMed2006

Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate.

The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP+ and the inhibitor determined at 2.2 A resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the beta6-alpha6 loop and alpha6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis.

Amino Acid Sequence↗
PubMed2005

Barriers to racemization in C3-symmetric complexes containing the hydrotris(2-mercapto-1-ethylimidazolyl)borate (Tm(Et)) ligand.

The tripodal ligands hydrotris(N-ethyl-2-mercaptoimidazol-1-yl)borate (NaTm(Et)) (1) and hydrotris(N-benzyl-2-mercaptoimidazol-1-yl)borate (NaTm(Bn)) (2), analogues of the hydrotris(N-methyl-2-mercaptoimidazol-1-yl)borate ligand (Tm) containing alternative nitrogen substituents, have been employed to examine the racemization of their C3-symmetric complexes with both four- and six-coordinate metals. The ligands react at room temperature with metal halides to provide C3-symmetric metal complexes. The syntheses of the four-coordinate complexes [Tm(Et)ZnCl] (3), [Tm(Et)CdBr] (4), [Tm(Et)HgCl] (5), [Tm(Et)CuPPh3] (6), [Tm(Et)AgPPh3] (7), and [Tm(Bn)ZnCl] (8) are reported. The six-coordinate complexes [Tm(Et)Ru(p-cymene)]Cl (9), [Tm(Et)Ru(p-cymene)]PF(6) (10), and [Tm(Et)Mn(CO)3] (11) were also synthesized. The X-ray crystal structures of 3, 4, 6, and 9 are reported. The diastereotopic nature of the ethyl and benzyl hydrogen atoms in the ligands allows the enantiomeric forms of these complexes to be distinguished by 1H NMR spectroscopy. Variable-temperature (VT) 1H NMR spectra have thus been used to investigate the energies of the racemization processes occurring in these chiral complexes. In solvents the activation energies to racemization for the four-coordinate complexes lay in the range of 53-77 kJ mol(-1). In non-donor solvents the energies are reduced and a dissociative mechanism is therefore implicated. No interconversion could be observed by VT NMR for the six-coordinate complexes in any solvent. To further explore the racemization mechanisms ab initio density functional theory calculations have been conducted on the ground- and transition-state structures of representative six-coordinate [Mn(I)] and four-coordinate [Zn(II)] complexes following a proposed nondissociative mechanism of racemization. The calculated energy barriers to racemization are 163 and 121 kJ mol(-1), respectively. It is concluded that the low-energy racemization of substitution-labile four-coordinate complexes occurs via a dissociative mechanism, while substitution-inert six-coordinate complexes experience a significantly higher barrier to racemization. Whether this is due to the operation of a dissociative mechanism with a higher activation barrier or to a nondissociative mechanism remains unknown.

Journal Article↗
PubMed2005

Synthesis, structure and reactivity of 5-pyranosyl-1,3,4-oxathiazol-2-ones.

5-(1,2,3,4-tetra-O-acetyl-alpha-D-xylopyranos-5S-C-yl)-1,3,4-oxathiazol-2-one (8) has been prepared from glucuronamide in two steps and 73% overall yield by conversion to the tetra-O-acetyl derivative 7 followed by reaction with chlorocarbonylsulfenyl chloride. 5-(2,3,4-Tri-O-acetyl-beta-D-xylopyranosyl)-1,3,4-oxathiazol-2-one (12) was synthesised from D-xylose by a four-step sequence involving conversion to the xylopyranosylnitromethane derivative 9, reaction with PCl3 to afford nitrile 10, hydrolysis to amide 11, and finally treatment with ClCOSCl. D-glucose-derived analogue 13 was prepared similarly. The structure of oxathiazolone 8 was established by X-ray crystallography. Thermolysis of the oxathiazolones 8 and 12 at 130-160 degrees C resulted in decarboxylation and desulfuration to yield the corresponding nitriles. Attempts to trap the putative nitrile sulfide intermediates by repeating the thermolysis in the presence of dipolarophiles, such as ethyl cyanoformate, afforded only traces of the 1,3-dipolar cycloadducts; however, under microwave irradiation oxathiazolone 8 and ethyl cyanoformate afforded ethyl 3-(1,2,3,4-tetra-O-acetyl-alpha-D-xylopyranos-5S-C-yl)-1,2,4-thiadiazole-5-carboxylate 22 in good yield.

Crystallography, X-Ray↗
PubMed2003

Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers.

Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by eta 6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((eta 6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(eta 6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated RRu*RN* and SRu*RN* diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t(1/2) approximately 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the RRu*RN* configurations are more stable than SRu*RN* (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to SRu*RN* diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31 degrees) of plasmid DNA, twice that of mononuclear 2 (14 degrees), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.

Antineoplastic Agents↗
PubMed2002

Pressure-induced polymorphism in phenol.

The high-pressure crystal structure of phenol (C(6)H(5)OH), including the positions of the H atoms, has been determined using a combination of single-crystal X-ray diffraction techniques and ab initio density-functional calculations. It is found that at a pressure of 0.16 GPa, which is just sufficient to cause crystallization of a sample held at a temperature just above its ambient-pressure melting point (313 K), a previously unobserved monoclinic structure with P2(1) symmetry is formed. The structure is characterized by the formation of hydrogen-bonded molecular chains, and the molecules within each chain adopt a coplanar arrangement so that they are ordered in an alternating 1-1-1 sequence. Although the crystal structure of the ambient-pressure P112(1) phase is also characterized by the formation of molecular chains, the molecules adopt an approximate threefold arrangement. A series of ab initio calculations indicates that the rearrangement of the molecules from helical to coplanar results in an energy difference of only 0.162 eV molecule(-1) (15.6 kJ mole(-1)) at 0.16 GPa. The calculations also indicate that there is a slight increase in the dipole moment of the molecules, but, as the high-pressure phase has longer hydrogen-bond distances, it is found that, on average, the hydrogen bonds in the ambient-pressure phase are stronger.

Journal Article↗