Pyrazole and pyrazolyl palladium(II) and platinum(II) complexes: synthesis and in vitro evaluation as anticancer agents

Magister Scientiae - MScThe use of metallo-pharmaceuticals, such as the platinum drugs, for cancer treatment illustrates the utility of metal complexes as therapeutic agents. Platinum group metal complexes therefore offer potential as anti-tumour agents to fight cancer. This study was aimed at synthesizing and evaluating the effects of palladium(II) and platinum(II) complexes as anticancer agents.South Afric

Initiatives to support local pharmaceutical production of quality essential medicines in East Africa

This policy brief provides a road map towards a better functioning, more stable, and sustainable pharmaceutical industry in Economic Community of West African States (ECOWAS) countries. Based on country studies and detailed analysis of data, a risk categorization model has been derived which includes product quality and Good Manufacturing Practices (GMP) compliance of local pharmaceutical producers (LPP). A means of structured incentives can be used for different levels of categorisation to drive compliance. Since 2002, an annual amount of more than US$4 billion has been invested in the purchase of fixed dose combinations in anti-retroviral (ARV) and anti-malarial drugs

Improving access to essential medicines through public-private partnerships in East Africa

The policy brief recommends that East African Community (EAC) partner states should stimulate Public Private Partnerships (PPPs) by directing the R&D agenda, funding pharmaceutical research and formulating policies that encourage product development. As in the US, India’s pharmaceutical industry experienced phenomenal growth when the government proactively crafted policy interventions like tax, partnerships, technology, and legal provisions for the manufacturing sector, which has made their pharma industry the largest provider of generic medicines globally. There are approximately 60 pharmaceutical manufacturers in EAC and Ethiopia. The policy brief covers University-Industry-Government partnerships and linkages

New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations : potential for incorporation into virostatic cocktails

Four bis(thiosemicarbazonate)gold(III) complexes (1–4) with a general formula [Au(L)]Cl {L=L1, glyoxal-bis (N4-methylthiosemicarbazone); L2, glyoxal-bis(N4-ethylthiosemicarbazone); L3, diacetyl-bis(N4- methylthiosemicarbazone); L4, diacetyl-bis(N4-ethylthiosemicarbazone)} were synthesised and screened for activity against the human immunodeficiency virus (HIV). Complexes 1–4 were characterised using 1H-NMR and IR spectroscopy; and their purity established by micronanalysis. Complex 3 inhibited viral infection of TZM-bl cells by 98% (IC50=6.8±0.6 μM) at a non toxic concentration of 12.5 μM while complex 4 inhibited infection of these cells by 72 and 98% (IC50=5.3±0.4 μM) at concentrations of 6.25 and 12.5 μMrespectively. Themechanism of inhibition of infection in TZM-bl cells is presumably as a result of the cytostatic or anti-proliferative activity that was observed for complex 4 in real time cell electronic sensing (RT-CES) and carboxyflourescein succinimidyl ester (CFSE) analysis. Treatment of T lymphocytes from HIV infected individuals with 4 decreased CD4+ T cell expression (p=0.0049) as demonstrated by multi-parametric flow cytometry without suppressing cytokine production. None of the ligands (L1–L4) demonstrated anti-viral activity, supporting the importance of metal (gold) complexation in these potential drugs. Complexes 3 and 4were shown to have ideal lipophilicity values thatwere similarwhenshake flask (0.97±0.5 and 2.42±0.6) and in silico prediction (0.8 and 1.5) methods were compared. The activity and drug-like properties of complexes 3 and 4 suggests that these novel metal-based compounds could be combined with virus inhibitory drugs to work as cytostatic agents in the emerging class of anti-HIV drugs known as virostatics.The South African National Research Foundationhttp://www.elsevier.com/locate/jinorgbionf201

Pharmaceutical partnerships for increased access to quality essential medicines in the East Africa region

The study investigated innovation capacity of the Eastern Africa pharmaceutical manufacturing industry, identified barriers to Public/Private Partnerships (PPP) and established a framework for an impactful pharmaceutical cross-sector partnership system. Findings reveal industry’s view: that there are no adequate incentives to catalyze investing in facility upgrading and quality improvement programs, especially in the production of donor funded products such as antiretrovirals and antimalarials. Government policies, training, good manufacturing practices (GMP) compliance, manufacturing and financing/markets are important factors towards ensuring success

Phosphinogold(I) dithiocarbamate complexes : effect of the nature of phosphine ligand on anticancer properties

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Palladium, platinum and gold complexes: a synthetic approach towards the discovery of anticancer agents

Ph.D.Ligands bis(pyrazolyl)acetic acid (L1) and bis(3,5-dimethylpyrazolyl)acetic acid (L2) were synthesised by reacting pyrazoles and dibromoacetic acid under phase transfer conditions, by using benzyltriethylammonium chloride as the catalyst. Ligands L1 and L2 were characterised by a combination of 1H, 13C{1H} NMR, IR spectroscopy and microanalysis. Esterification of L1 and L2 led to formation of bis(pyrazolyl)ethyl acetate (L3) and bis(3,5-dimethylpyrazolyl)ethyl acetate (L4). Ligands L3 and L4 were also characterised by a combination of 1H, 13C{1H} NMR, IR spectroscopy and microanalysis. Subsequently, new pyrazolyl palladium(II) and platinum(II) compounds, [PdCl2(L1)] (1), [PdCl2(L2)] (2), [PtCl2(L1)] (3a) and [PtCl2(L2)] (4) were prepared by reacting bis(pyrazolyl)acetic acid ligands (L1-L2) with K2[PdCl4] or K2[PtCl4] respectively. The structures of complex 1 and 2 reveal distorted square planar geometries. The bond angles of N-Pd-N, N-Pd-Cl, N-Pd-Cl, for 1 and 2 are between 85.8(3)o and 90.81(4)o). The platinum compound, K2[Pt4Cl8(L1)2(deprotonated-L1)2].2H2O (3b), crystallised from aqueous solutions containing 3a when such solutions were left to stand overnight. Each platinum coordination environment consists of two cis-Cl ligands and one K2-N^N(L1) unit (L1 = bis(pyrazolyl)acetic acid), with two ligand moieties in 3b that are deprotonated with two K+ counter ions. Reaction of bis(pyrazolyl)acetic acid ligands (L1-L2) with [HAuCl4].4H2O gave gold(III) complexes [AuCl2(L1)]Cl (5a) and [AuCl2(L2)]Cl (6a). The spectroscopic, mass spectroscopy and microanalysis data were used to confirm the formation of the desired complexes. However, attempts to crystallise 5a and 6a led to formation of [AuCl2(pz)(pzH)] (5b) and [AuCl2(3,5-Me2pz)(3,5-Me2pzH)] (6b). This was confirmed by the structural characterisation of 5b, which has a distorted square-planar geometry. When complexes 1-6a were screened for their anti-tumour activity against CHO-22 cells, they showed no appreciable biological activities against CHO-22 cells. Substitution reactions of complexes 1-6a with L-cysteine performed to probe any relationship between the observed antitumour activities and the rates of ligand substitution of these complexes were inconclusive. Dithiocarbamate ligands L5-L8 were synthesised as potassium salts by introducing a CS2 group in positions 1 of pyrazole, 3,5-dimethylpyrazole, indazole and imidazole. The reaction of L5-L8 with [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)] and [Au2Cl2(dpph)], led to isolation of complexes [Au(L)(PPh3)] (13-16), [Au2(L)2(dppe)] (17a-19), [Au2(L)2(dppp)] (20-22) and [Au2(L)2(dpph)] (23-25) (dppe = bis(diphenylphosphino)ethane, dppp = bis(diphenylphosphino)propane, dpph = bis(diphenylphosphino)hexane; L = anions of L5-L8). The mononuclear molecular structure of 15 features a near linear geometry with a P(1)-Au(1)-S(1) angle of 175.36(2) o. The binuclear gold(I) complexes 20-22 and 23-25 have two P-Au-S moieties as evident in the solid state structure of 25. Attempts to crystallise complex 17a led to the formation of a gold(I) cluster complex [Au18S8(dppe)6]2+ (17b) as confirmed by X-ray crystallography. Cluster 17b features weak Au···Au interactions (2.9263(7)-3.1395(7) Å). Complexes 13-16 and 20-25 were tested in vitro for anticancer activity on HeLa cells. The activities of gold(I) complexes 13-16 were comparable to that of cisplatin. Dinuclear gold(I) complexes 20-25 also showed appreciable antitumour activity against HeLa cells. However, the dpph gold(I) compounds (23-25) were highly active, with 24 showing the highest activity against HeLa cells (IC50 = 0.1 μM). The tumour specificity (TS) factors for 23 and 24 were 31.0 and 70.5, respectively

Pharmaceutical partnerships for increased access to quality essential medicines in the East Africa region

The study assesses the capability/capacity of local manufacturers in the East Africa Community (EAC) region (Kenya, Tanzania, Uganda and Ethiopia) to produce essential medicines. As well, it explores how partnerships can be leveraged to expand the range of essential medicines that are manufactured in order to improve access to quality medicines through local production. The Science Granting Councils Initiative (SGCI) objective is to enhance knowledge exchange between academia and industry and stimulate private sector investments into research and innovation

HIV therapeutic possibilities of gold compounds

Highly active antiretroviral therapy (HAART) has resulted in decreased mortality and morbidity from the acquired immune deficiency syndrome caused by the human immunodeficiency virus (HIV). Drug resistance and toxicity of HAART has led to the search for novel inhibitors of HIV infection. Gold-based compounds have shown promising activity against a wide range of clinical conditions and microorganism infections including HIV-1. A typical example is auranofin which resulted in an elevated CD4? T-cell count in an HIV patient being treated for psoriatic arthritis. In addition, reports exist on gold-based inhibitors of reverse transcriptase (RT), protease (PR) and viral entry of host cells. These and other characteristics of goldbased HIV drugs are reviewed here

Facile Attachment of TAT Peptide on Gold Monolayer Protected Clusters: Synthesis and Characterization

High affinity thiolate-based polymeric capping ligands are known to impart stability onto nanosized gold nanoparticles. Due to the stable gold-sulfur bond, the ligand forms a protective layer around the gold core and subsequently controls the physicochemical properties of the resultant nanogold mononuclear protected clusters (AuMPCs). The choice of ligands to use as surfactants for AuMPCs largely depends on the desired degree of hydrophilicity and biocompatibility of the MPCs, normally dictated by the intended application. Subsequent surface modification of AuMPCs allows further conjugation of additional biomolecules yielding bilayer or multilayered clusters suitable for bioanalytical applications ranging from targeted drug delivery to diagnostics. In this study, we discuss our recent laboratory findings on a simple route for the introduction of Trans-Activator of Transcription (TAT) peptide onto the surface of biotin-derivatised gold MPCs via the biotin-strepavidin interaction. By changing the surface loading of biotin, controlled amounts of TAT could be attached. This bioconjugate system is very attractive as a carrier in intercellular delivery of various delivery cargoes such as antibodies, proteins and oligonucleotides