Judy Coates

Gold-phosphine binding to de novo designed coiled coil peptides.

The coordination of the therapeutically interesting [AuCl(PEt(3))] to the de novo designed peptide, TRIL23C, under aqueous conditions, is reported here. TRIL23C represents an ideal model to investigate the binding of [AuCl(PEt(3))] to small proteins in an effort to develop novel gold(I) phosphine peptide adducts capable of mimicking biological recognition and targeting. This is due to the small size of TRIL23C (30 amino acids), yet stable secondary and tertiary fold, symmetric nature and the availability of only one thiol binding site. [AuCl(PEt(3))] was found to react readily with the Cys side chain in a 1:1 ratio as confirmed by UV-visible, (31)P NMR and mass spectrometry. Circular dichroism confirmed that the coiled coil structure was retained on coordination of the {Au(PEt(3))}(+) unit. Redesign of the exterior of TRIL23C based on a biologically relevant recognition sequence found in GCN4, did not alter the coordination chemistry of [AuCl(PEt(3))]. To the best of our knowledge, this represents the first report on the coordination of gold(I) phosphine compounds to de novo designed peptides, and could lead to the generation of novel gold(I) phosphine peptide therapeutics in the future.

Modification of HIV-1 reverse transcriptase and integrase activity by gold(III) complexes in direct biochemical assays.

Gold(I) and gold(III) complexes have been previously investigated for potential biomedical applications including as anti-HIV agents. The oxidising nature of some gold(III) complexes yields well-documented cellular toxicity in cell-based assays but the effect in direct biochemical assays has not been fully investigated. In this study, gold(III) complexes were evaluated in HIV-1 reverse transcriptase and HIV-1 integrase biochemical assays. The gold(III) tetrachlorides KAuCl(4) and HAuCl(4) yielded sub-micromolar IC(50)s of 0.947 and 0.983μM in the direct HIV-1 RT assay, respectively, while IC(50)s ranging from 0.461 to 8.796μM were obtained for seven selected gold(III) complexes. The gold(III) tetrachlorides were also effective inhibitors of integrase enzymatic activity with >80% inhibition obtained at a single dose evaluation of 10μM. RT inhibition was decreased in the presence of a reducing agent (10mM DTT) and against the M184V HIV-1 RT mutant, while none of the gold(III) complexes were effective inhibitors in cell-based antiviral assays (SI values <5.95). Taken together, the findings of this study demonstrate that gold(III) complexes modify HIV-1 enzyme activity in direct biochemical assays, most likely through protein oxidation.

Novel furocoumarins as potential HIV-1 integrase inhibitors.

A series of seven novel, rationally designed N-substituted 3-{3,5-dimethylfuro[3,2-g]coumarin-6-yl}propanamides have been prepared as potential HIV-1 integrase (IN) inhibitors via a five-step pathway commencing with resorcinol and diethyl 2-acetylglutarate, and the HIV-1 IN inhibition potential of these compounds has been examined relative to raltegravir, a known HIV-1 IN inhibitor.

Heteroditopic P,N ligands in gold(I) complexes: synthesis, structure and cytotoxicity.

New heteroditopic, bi- and multidentate imino- and aminophosphine ligands were synthesised and complexed to [AuCl(THT)] (THT=tetrahydrothiophene). X-ray crystallography confirmed Schiff base formation in three products, the successful reduction of the imino-group to the sp(3)-hybridised amine in several instances, and confirmed the formation of mono-gold(I) imino- and aminophosphine complexes for four Au-complexes. Cytotoxicity studies in cancerous and non-cancerous cell lines showed a marked increase in cytotoxicity upon ligand complexation to gold(I). These findings were supported by results from the 60-cell line fingerprint screen of the Developmental Therapeutics Programme of the National Institutes of Health for two promising compounds. The cytotoxicity of some of these ligands and gold(I)complexes is due to the induction of apoptosis. The ligands and gold(I)complexes demonstrated selective toxicity towards specific cell lines, with Jurkat T cells being more sensitive to the cytotoxic effects of these compounds, while the non-cancerous human cell line KMST6 proved more resistant when compared to the cancerous cell lines. Results from the NIH DTP 60 cell-line fingerprint screen support the observed enhancement of cytotoxicity upon gold(I) complexation. One gold(I)complex induced high levels of apoptosis at concentrations of 50 μM in all the cell lines screened in this study, while some of the other compounds selectively induced apoptosis in the cell lines. These results point towards the potential for selective toxicity to cancerous cells through the induction of apoptosis.

Application of the Morita-Baylis-Hillman reaction in the synthesis of 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones as potential HIV-1 integrase inhibitors

A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.

[μ-1,2-Bis(diphenyl­phosphan­yl)-1,2-dimethyl­hydrazine-κ2P:P′]bis­[chlorido­gold(I)]

The title compound, [Au2Cl2(C26H26N2P2)], is formed from a bidentate phosphine ligand complexed to two linearly coordinated gold(I) atoms. The gold(I) atoms are 3.4873 (7) Å apart. The molecule exhibits a crystallographic twofold rotation axis.

[μ-1,2-Bis(diphenyl-phosphan-yl)-1,2-diethyl-hydrazine-κP:P']bis-[chlorido-gold(I)] tetra-hydro-furan disolvate.

The title compound, [Au(2)Cl(2)(C(28)H(30)N(2)P(2))]·2C(4)H(8)O, was synthesized from a bidentate phosphine ligand complexed to two linear gold(I) chloride moieties. The Au(I) atom is in an almost linear coordination with a P-Au-Cl angle of 179.22 (4)°. The complex molecules reside on a twofold rotation axis.

Random and Rational Approaches to HIV Drug Discovery in Africa

The development of therapeutic agents to inhibit human immunodeficiency virus (HIV) replication began soon after the isolation and identification of the virus as the causative agent of the acquired immune deficiency syndrome (AIDS). Within a short period of time thereafter, azidothymidine (AZT) was found to inhibit viral replication and became the first FDA-approved drug for the treatment of HIV/AIDS in 1987. Since then, continual and substantial progress has been made. To date, 35 drugs have been clinically approved, and with treatment, HIV infection has been transformed from a life-threatening disease with a short survival rate into a chronic manageable condition. Furthermore, several drugs are currently under investigation in various stages of clinical and preclinical development. Despite this remarkable success, there is continued global effort directed towards the design, discovery and development of novel inhibitors that may improve treatment strategies and overcome new challenges that have arisen. This chapter focuses on the discovery phase of the HIV drug discovery and development pipeline and describes the contribution and progress made by African scientists and research laboratories. Review of the period 1990 to present day reveals considerable African research describing anti-HIV inhibitors, derived from natural sources or through synthetic means, and identified through both rational and random drug discovery approaches. Several challenges facing HIV researchers on the continent disproportionately affected by HIV/AIDS are also described.

{μ-1,2-Bis[bis(4-meth­oxy­phen­yl)phosphan­yl]-1,2-dimethyl­hydrazine-κ2 P:P′}bis­[chloridogold(I)] tetra­hydro­furan disolvate

The title compound, [Au2Cl2(C30H34N2O4P2)]·2C4H8O, is formed from a bidentate phosphine ligand complexed to two almost linearly coordinated gold(I) atoms [P—Au—Cl = 175.68 (3) Å]. The nuclei are 3.122 (2) Å apart. The molecule exhibits a twofold rotation axis.

{μ-1,2-Bis[bis­(4-meth­oxy­phen­yl)phosphan­yl]-1,2-diethyl­hydrazine-κ2P:P′}bis­[chloridogold(I)] tetra­hydro­furan disolvate

The title compound, [Au2Cl2(C32H38N2O4P2)]·2C4H8O, is formed from a bidentate phosphine ligand complexed to two linear gold(I) nuclei [P—Au—Cl = 175.98 (3)°]. The nuclei are 3.1414 (2) Å apart. The molecule exhibits a twofold symmetry axis. Stacks of the compound are formed through intermolecular C—H⋯Cl interactions, while the tetrahydrofuran (THF) solvate is further attached to the stacks through weak C—H⋯O hydrogen bonding from the THF O atom to two separate H atoms on the complex.