James Darkwa

Perspective: the potential of pyrazole-based compounds in medicine

Pyrazoles are widely used as core motifs for a large number of compounds for various applications such as catalysis, agro-chemicals, building blocks of other compounds and in medicine. The attractiveness of pyrazole and its derivatives is their versatility that allows for synthesis of a series of analogues with different moieties in them, thus affecting the electronics and by extension the properties of the resultant compounds. In medicine pyrazole is found as a pharmacophore in some of the active biological molecules. While pyrazole derivatives have been extensively studied for many applications including anticancer, antimicrobial, anti-inflammatory, antiglycemic, anti-allergy and antiviral, much less has been reported on their metal counterparts in spite of the fact that metals have been shown to impart activity to ligands. Thus this perspective is intended to demonstrate the potential of pyrazole and pyrazolyl metal complexes in the areas of drug discovery and development. Several examples, that include palladium, platinum, copper, gold, zinc, cobalt, nickel, iron, copper, silver and gallium complexes, are used to bolster the above point. For the purposes of this review three areas are discussed, that is pyrazole metal complexes as: (i) anticancer, (ii) antibacterial/parasitic and (iii) antiviral agents.

Synthesis and evaluation of substituted pyrazoles palladium(II) complexes as ethylene polymerization catalysts

Abstract The substituted pyrazole palladium complexes, (3,5- t Bu 2 pz) 2 PdCl 2 ( 1 ) (3,5-Me 2 pz) 2 PdCl 2 ( 2 ), (3-Mepz) 2 PdCl 2 ( 3 ) and (pz) 2 PdCl 2 ( 4 ) (pzH=pyrazole), can be prepared from the reaction of (COD)PdCl 2 with the appropriate pyrazole. The chloromethyl derivative, (3,5- t Bu 2 pz) 2 PdCl(Me) ( 5 ), was prepared from (COD)PdClMe and t Bu 2 pzH. X-ray crystal structure determination of 1 and 5 established their structures in the solid state to be the trans -isomer. After activation of 1 – 4 and 5 with methylaluminoxane (MAO) the resulting palladium complexes were used as catalysts in ethylene polymerization, yielding linear high-density polyethylene (HDPE). The highest activity was observed for (3,5- t Bu 2 pz)PdClMe.

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

The reactions of potassium salts of the dithiocarbamates L {where L = pyrazolyldithiocarbamate (L1), 3,5-dimethylpyrazolyldithiocarbamate (L2), or indazolyldithiocarbamate (L3)} with the gold precursors [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)], or [Au2Cl2(dpph)] lead to the new gold(I) complexes [AuL(PPh3)] (1–3), [Au2L2(dppe)] (4–6), [(Au2L2)(dppp)] (7–9), and [Au2(L)2(dpph)] (10–12) {where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, and dpph = 1,6-bis(diphenylphosphino)hexane}. These gold compounds were characterized by a combination of NMR and infrared spectroscopy, microanalysis, and mass spectrometry; and in selected cases by single-crystal X-ray crystallography. Compounds 4–6, which have dppe ligands, are unstable in solution for prolonged periods, with 4 readily transforming to the Au18 cluster [Au18S8(dppe)6]Cl2 (4a) in dichloromethane. Compounds 1–3 and 7–12 are all active against human cervical epithelioid carcinoma (HeLa) cells, but the most active compounds are 10 and 11, with IC50 values of 0.51 μM and 0.14 μM, respectively. Compounds 10 and 11 are more selective toward HeLa cells than they are toward normal cells, with selectivities of 25.0 and 70.5, respectively. Further tests, utilizing the 60-cell-line Developmental Therapeutics Program at the National Cancer Institute (U.S.A.), showed 10 and 11 to be active against nine other types of cancers.

Benzenedicarbonyl and benzenetricarbonyl linker pyrazolyl complexes of palladium(ii): synthesis, X-ray structures and evaluation as ethylene polymerisation catalystsElectronic supplementary information (ESI) available: molecular structures and bond lengths and angles for L2, L3, L6 and 2. See http://www.rsc.org/suppdata/dt/b2/b208376k/

A series of novel compounds with pyrazolyl rings (pz) linked by benzenedicarbonyl (L1–L4) and benzenetricarbonyl (L5, L6) have been prepared and structurally characterized. The mutual orientation of their rings was studied by molecular mechanics. These polydentate species react with PdCl2(NCMe)2 to yield dinuclear complexes in which the Pd centers coordinate to one or two pz units, a terminal chloride and two bridging chloride ligands. In complex [{(3,5-tBu2pzCO)3-1,3,5-C6H4}Pd2Cl2(µ-Cl)2]4 the pyrazolyl ligand L5 acts as a bidentate donor despite the presence of the third pz group. These Pd complexes, when activated with methylaluminoxide (MAO), exhibit activity in ethylene polymerization.

Tandem ethylene oligomerisation and Friedel–Crafts alkylation of toluene catalysed by bis-(3,5-dimethylpyrazol-1-ylmethyl)benzene nickel(II) complexes and ethylaluminium dichloride

Three ligands, 1,2-bis(3,5-dimethylpyrazol-1-ylmethyl)benzene (L1), 1,3-bis(3,5-dimethylpyrazol-1-ylmethyl)benzene (L2) and 1,4-bis(3,5-dimethylpyrazol-1-ylmethyl)benzene (L3), were reacted with either nickel(II) chloride or nickel(II) bromide to produce four nickel complexes, Ni(L1)Br2 (1), Ni(L1)Cl2 (2), Ni(L2)Br2 (3), and Ni(L1)Br2 (4). The complexes were either mononuclear, 1 and 2, or polymeric, 3 and 4, depending on the positions of the pyrazolyl units on the benzene linker in the ligand. This was established from the crystal structures of 1, 2 and 3. All four complexes upon activation with ethylaluminium dichloride produced a tandem catalyst system that oligomerised ethylene to mainly 1-butene and 1-hexene and subsequently used the olefins present in the reaction medium to alkylate toluene that was used as solvent in the reactions. This led to mono-, di- and tri-alkyltoluenes with ethylene, butene and hexene.

Bidentate aryldichalcogenide complexes of [(diphosphino)ferrocene]palladium(II) and [(diphosphino)ferrocene]platinum(II). Synthesis, molecular structures and electrochemistry

Abstract A series of homochalcogenide and mixed-chalcogenide ligand complexes of palladium and platinum have been prepared from the reactions of Pd(dppf)Cl2, (dppf=1,1′-bis(diphenylphosphino)ferrocene), Pd(dippf)Cl2 (1,1′-bis(diisopropylphosphino)ferrocene), and Pt(dppf)Cl2 with 1,2-benzenedithiol (HSC6H4SH) (a), 3,4-toluenedithiol (HSC6H3MeSH) (b), 3,6-dichloro-1,2-benzenedithiol (HSC6H2Cl2SH) (c), 2-mercaptophenol (HSC6H4OH) (d), thiosalicylic acid (HSC6H4CO2H) (e) and thionicotinic acid (HSC6H3NCO2H) (f). Single-crystal X-ray diffraction studies show that all complexes have distorted square-planar geometry. The complexes undergo two quasi-reversible or irreversible one-electron redox processes that involve the chalcogen ligands and diphosphinoferrocene ligands. The oxidation potentials of the chalcogen ligands increase when they bear electron-withdrawing substituents.

Synthesis and Evaluation of Glycopolymeric Decorated Gold Nanoparticles Functionalized with Gold-Triphenyl Phosphine as Anti- Cancer Agents

In this study, statistical glyco-dithiocarbamate (DTC) copolymers were synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT) and subsequently used to prepare glyconanoparticles and conjugated glyconanoparticles with the anticancer drug, gold(I) triphenylphosphine. These glyconanoparticles and the corresponding conjugates were then tested for their in vitro cytotoxicity in both normal and cancer cell lines using Neutral Red assay. The glyconanoparticles and their Au(I)PPh3 conjugates were all active against MCF7 and HepG2 cells, but galactose-functionalized glyconanoparticles {P(GMA-EDAdtc(AuPPh3)-st-LAEMA)AuNP} were found to be the most cytotoxic to HepG2 cells (IC50 ∼ 4.13 ± 0.73 μg/mL). The p(GMA-EDAdtc(AuPPh3)-st-LAEMA)AuNP was found to be a 4-fold more potent antitumor agent in HepG2 cells, and the overexpressed asialoglycoprotein (ASGPR) receptors revealed to play an important role in the cytotoxicity, presumably by the enhanced uptake. In addition, the glyconanoparticles Au(I) conjugates are found to be significantly more toxic as compared to the standard chemotherapeutic reagents such as cisplatin and cytarabine.

Tetra-chloro-(bis-(3,5-dimethylpyrazolyl)methane)gold(III) chloride: An HIV-1 reverse transcriptase and protease inhibitor

The title compound ([3,5-Me(2)bpzaH(2)][AuCl(4)]Cl, 1) (Me(2)bpza=bis(3,5-dimethylpyrazolyl)acetic acid), was prepared by reacting H[AuCl(4)] with 3,5-Me(2)bpza; and spectroscopically and structurally characterized. In the solid state structure of 1, the pyrazolyl ligand is doubly protonated to form two strong charge assisted hydrogen bonds of the type N(+)Hcdots, three dots, centeredCl(-) with the single chloride anion whilst the [AuCl(4)](-) anion remains discrete. The anti-HIV-1 activity of 1 was determined by a colorimetric direct enzyme reverse transcriptase (RT) assay and a fluorogenic protease (PR) assay. Compound 1 significantly (p<0.05) inhibited RT over a concentration range of 5-250muM and inhibited HIV-1 protease at 100muM. Compound 1 inhibited two very important HIV-1 enzymes (RT and PR) in direct enzyme assays and therefore warrants further evaluation.

Synthesis of bis (diphenylphosphino) ethanenickel(II) organodichalcogenide complexes and cyclotrimerisation reaction of dimethylacetylenedicarboxylate : structure of Ni(dppe) (SC6H4O)

Abstract Reaction of Ni(dppe)Cl2 (dppe = bis(diphenylphosphino)ethane) with organodichalcogenide ligands of the type 1,2-HSC6H4EH (E = CO2, O, NH) in the presence of triethylamine to give the products Ni(dppe)(SC6H4CO2) (1), Ni(dppe)(SC6H40) (2), and Ni(dppe)(SC6H4NH) (3). Complex 2 was characterised by single crystal X-ray diffraction, which shows a distorted geometry. Complexes 1–3 and the dithiolato analogues of 1,2-benzenedithiol, Ni(dppe)(SC6H3S) (4), and 3,4-toluendithiol, Ni(dppe)(SC6H3MeS) (5), upon reflux with dimethylacetylenedicarboxylate (DMAD) formed the cyclotrimeric product hexamethylbenzene hexacarboxylate (HMBC).

Therapeutic potential of carbohydrate-based polymeric and nanoparticle systems

Introduction: Carbohydrates are key participants in many biological processes including reproduction, inflammation, signal transmission and infection. Their biocompatibility and ability to be recognized by cell-surface receptors illustrate their potential therapeutic applications. αYet, they are not ideal candidates because they are complex and tedious to synthesize. However, recent advances in the field of polymer science and nanotechnology have led to the design of biologically relevant carbohydrate mimics for therapeutic uses. This review focuses mainly on the therapeutic potential of glycopolymers and glyconanoparticles (GNPs). Areas covered: The significance of engineered glycopolymers and GNPs as nanomedicine is highlighted in areas such as targeted drug delivery, gene therapy, signal transduction, vaccine development, protein stabilization and anti-adhesion therapy. Expert opinion: Major effort should be focused towards the design and synthesis of more complex and biologically relevant carbohydrate mimics in order to have a better understanding of the carbohydrate–carbohydrate and carbohydrate–protein interactions. The full therapeutic potential of these carbohydrate-based polymeric and nanoparticles systems can be achieved once the pivotal participation of the carbohydrates in biological systems is clarified.