Simon M. Pyke

In vitro antiviral activity of the anthraquinone chrysophanic acid against poliovirus.

Chrysophanic acid (1,8-dihydroxy-3-methylanthraquinone), isolated from the Australian Aboriginal medicinal plant Dianella longifolia, has been found to inhibit the replication of poliovirus types 2 and 3 (Picornaviridae) in vitro. The compound inhibited poliovirus-induced cytopathic effects in BGM (Buffalo green monkey) kidney cells at a 50% effective concentration of 0.21 and 0.02 microgram/ml for poliovirus types 2 and 3, respectively. The compound inhibited an early stage in the viral replication cycle, but did not have an irreversible virucidal effect on poliovirus particles. Chrysophanic acid did not have significant antiviral activity against five other viruses tested: Coxsackievirus types A21 and B4, human rhinovirus type 2 (Picornaviridae), and the enveloped viruses Ross River virus (Togaviridae) and herpes simplex virus type 1 (Herpesviridae). Four structurally-related anthraquinones--rhein, 1,8-dihydroxyanthraquinone, emodin and aloe-emodin were also tested for activity against poliovirus type 3. None of the four compounds was as active as chrysophanic acid against the virus. The results suggested that two hydrophobic positions on the chrysophanic acid molecule (C-6 and the methyl group attached to C-3) were important for the compounds activity against poliovirus.

Synthesis and characterization of triorganotin(IV) complexes of 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acids. - Crystal and molecular structures of a series of triphenyltin 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoates (aryl=phenyl, 2-methylphenyl, 3-methylphenyl and 4-methoxyphenyl)

Abstract The triphenyltin and tri-n-butyltin complexes of some 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acids have been synthesized and characterized by 1H-, 13C-, 119Sn-NMR, IR and 119mSn Mossbauer spectroscopic techniques in combination with elemental analysis. The crystal structures of triphenyltin 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoates (aryl=phenyl, 2-methylphenyl, 3-methylphenyl and 4-methoxyphenyl) are reported. Both X-ray and 119Sn Mossbauer data indicate that the triphenyltin complexes adopt a monomeric distorted tetrahedral configuration with the carboxylate ligand coordinating in a monodentate mode. By contrast, 119Sn Mossbauer spectroscopy shows that each tributyltin complex is polymeric and features a trans-trigonal bipyramidal geometry with a planar SnBu3 unit and two apical carboxylate oxygen atoms derived from bidentate bridging carboxylate ligands. This is a solid-state effect, as both 119Sn-NMR and 1J(13C–119/117Sn) coupling constant data indicate tetrahedral geometries in solution for the triphenyl and tri-n-butyl complexes.

A new and highly efficient synthesis of hydroxyporphyrins

Abstract A new synthesis of hydroxyporphyrins is reported. The method involves nucleophilic displacement of a nitro group using the sodium salt of E-benzaldoxime and is a general process allowing the synthesis of both β-hydroxyporphyrins and meso-hydroxyporphyrins. Activation of the porphyrin system towards nucleophilic attack is achieved by complexation of the macrocycle with the relatively electronegative nickel(II) or copper(II) ions. Thus, treatment of either the copper(II) or the nickel(II) chelates of 2-nitro-5, 10,15,20-tetraphenylporphyrin with the sodium salt of E-benzaldoxime gave the corresponding 2-hydroxyporphyrin in high yield. Similar treatment of the copper(II) or the nickel(II) chelates of 5-nitro-2, 3,7,8,12,13,17,18-octaethylporphyrin gave the corresponding 5-hydroxyporphyrin, again in high yield. These reactions show that metallo-nitroporphyrins display similar electrophilic properties to much simpler nitro-arene systems. The nickel(II) 5-hydroxyporphyrin 10 was cleanly demetallated on treatment with concentrated sulfuric acid to give the corresponding free-base oxophlorin thereby greatly increasing the general utility of the hydroxylation methodology. Conversion of (5-methoxy-15-nitro-2,3,7,8,12,13,17,18-octaethylporphyrinato) nickel(II) 16 into (5-acetoxy-15-methoxy-2,3,7,8,12,13,17,18-octaethyl-porphyrinato) nickel(II) 18 established that the reaction mechanism involves regiospecific replacement (i.e., ipso-substitution) of the nitro group by the oxygen nucleophile.

A new method for the synthesis of porphyrin-α-diones that is applicable to the synthesis of trans-annular extended porphyrin systems

Porphyrin-α-diones can be prepared by photooxidation or SeO2-oxidation of β-hydroxyporphyrins, which are in turn readily synthesized from the corresponding copper(II) or nickel(II) 2-halo- and 2-sulphinyl-porphyrins by reaction with the anion of E-benzaldoxime; the efficient conversion of the porphyrinoquinoxaline 6 into the diquinoxalino[2,3-g, 2,3-q] porphyrin 9 illustrates the usefulness of the new methodology for the synthesis of trans-annular extended porphyrin systems.

Reactivity of hydrazinophthalazine drugs with the lipid peroxidation products acrolein and crotonaldehyde

The nucleophilic drug hydralazine strongly inhibits cell toxicity mediated by acrolein, a short chain 2-alkenal formed during lipid peroxidation. We here report the chemistry of acrolein-trapping by hydralazine, and show that together with its structural analogue dihydralazine, it also readily traps crotonaldehyde. Isolable reaction products included (1E)-acrylaldehyde phthalazin-1-ylhydrazone (E-APH), (1Z)-acrylaldehyde phthalazin-1-ylhydrazone (Z-APH), (1E,2E)-but-2-enal phthalazin-1-ylhydrazone (E-BPH) and (1Z,2E)-but-2-enal phthalazin-1-ylhydrazone (Z-BPH). Concentration-dependent formation of (1E)-acrylaldehyde phthalazin-1-ylhydrazone was observed in the culture media of cells co-exposed to hydralazine and the acrolein precursor allyl alcohol. These aldehyde-sequestering properties of hydrazinophthalazine drugs may contribute to the protection they provide against 2-alkenal-mediated toxicity.

Sequential and Selective Buchwald−Hartwig Amination Reactions for the Controlled Functionalization of 6-Bromo-2-chloroquinoline: Synthesis of Ligands for the Tec Src Homology 3 Domain

Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate important biological processes and are considered valuable targets for the development of therapeutic agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted 2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-aminoquinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date. The key step in the synthesis of these compounds required a selective Buchwald-Hartwig amination of an aryl bromide in the presence of an activated heteroaryl chloride. The optimization of reaction conditions to achieve the selective amination is discussed and has allowed for cross-coupling with a range of cyclic amines. Introduction of the amino functionality of the 6-heterocyclic 2-aminoquinolines involved additional Buchwald-Hartwig chemistry utilizing lithium bis(trimethylsilyl)amide as an ammonia equivalent.

Characterisation and in vitro cytotoxicity of triorganophosphinegold(i) 2-mercaptobenzoate complexes.

The preparation and full NMR (1H, 13C and 31P) characterisation of three [R3PAu(2mba)] complexes, Where R = Et, Ph and Cy, and 2mba is the anion derived from 2-mercaptobenzoic acid is reported. An interesting solvent dependence in the 1H spectra is rationalised in terms of competing intra- and inter-molecular hydrogen bonding. An X-ray analysis of the [Ph3 PAu(2mba)] species reveals a linear P—Au—S arrangement and association in the lattice via the familar carboxylic acid dimer motif. The in Vitro cytotoxicity against seven human tumout lines is also described. The complexes display moderate to very high activity. Particularly noteworthy is their greater activity against the H226 cell line (non-small cell lung cancer) compared with that displayed by a range of cytotoxic drugs.

In Vivo Activity of Benzoyl Ester Clerodane Diterpenoid Derivatives from Dodonaea polyandra

Four new benzoyl ester clerodane diterpenoids, 15,16-epoxy-8α-(benzoyloxy)methylcleroda-3,13(16),14-trien-18-oic acid (1), 15,16-epoxy-8α-(benzoyloxy)methyl-2α-hydroxycleroda-3,13(16),14-trien-18-oic acid (2), 15,16-epoxy-8α-(benzoyloxy)methyl-2-oxocleroda-3,13(16),14-trien-18-oic acid (3), and 15,16-epoxy-2α-benzoyloxycleroda-3,13(16),14-trien-18-oic acid (4), have been isolated from the leaves and stems of Dodonaea polyandra. The anti-inflammatory activities of compounds 1, 2, and 4 were evaluated by means of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. Compounds 2 and 4 exhibited maximum inhibition of inflammation (70-76%) at doses of 0.22 and 0.9 μmol/ear, respectively. Modest activity (~45% inhibition) was maintained at nanomole/ear doses.

Crystal and molecular structure of aquatriphenyltin 2-(3-formyl-4-hydroxyphenylazo) benzoate

The crystal structure of the title compound, {Ph3Sn[C>2CC6H4(N=N(C6H3-4-OH-5CHO))-o]OH2}, reveals the carboxylate group to coordinate the tin atom via one oxygen atom only [Sn-0 2.161(5) A], The tin atom is also coordinated by a water molecule [SnO 2.527(5) Ä] and exists in a trigonal bipyramidal geometry with the three phenyl groups in equatorial positions; the O-Sn-O axial angle is 176.3(2)°. The lattice is stabilised by Η-bonding contacts as well as charge-transfer interactions. I n t r o d u c t i o n . The chemistry of organotin carboxylates is of importance owing to the wide use of such compounds in a variety of applications [1-4]. For example, organotin carboxylates have been used as homogeneous catalysts and as biocides. More recently, the anti-tumour properties of this class of compound have been investigated [5]. Crucial to the understanding of how these compounds function is a knowledge of their structure and, as a consequence, a large number of crystal structure determinations of organotin carboxylates have been reported for which a rich diversity of structural motifs exist [6, 7], An additional donor atom(s) resident on the carboxylate residue also increases the range of structural possibilities and it has been noted that frequently Sn-N and Sn-0 interactions of this type may be found, in addition to the Sn-O(carboxylate) connectivities [6, 7]. As a part of a wider study designed to ascertain the reason(s) for the structural variat ion found in these systems, the t i t le compound, { P h 3 S n [ 0 2 C C 6 H 4 ( N = N (C 6 H3-4 -OH-5 -CHO) ) -o ]OH2} , has been prepared and characterised. The crystal and molecular structure of {Ph3Sn[0 2 CC6H 4 (N=N(C6H3-4-0H-5-CH0)) o]} as the unsolvated [8] and solvated [9] forms have been reported. In each of these

Reaction of 5-nitro-octaethylporphyrins with nucleophiles

An investigation of the reactions of metallo-5-nitro-2,3,7,8,12,13,17,18-octaethylporphyrins with Grignard reagents, benzyl oxide, phenoxide and benzenethiolate nucleophiles shows that, except for benzenethiolate reactions, they are less efficient than related reactions of metallo-2-nitro-5,10,15,20-tetraarylporphyrins. Treatment of free-base and nickel(II) 5-nitro-octaethylporphyrin with the “soft” nucleophile benzenethiolate in DMF affords the corresponding 5-phenylthioporphyrins in 61 and 72% yield, respectively, by ipso-substitution of the nitro group. In contrast, with methylmagnesium iodide and benzyl oxide, “hard” nucleophiles, attack is at the diagonally opposite 15-position of the ring to give 15-substituted 5-nitroporphyrin while with phenoxide and more substituted Grignard reagents, electron-transfer reactions lead to denitration to (metallo)-octaethylporphyrin or reduction to the corresponding 5-aminoporphyrin. The lower efficiency of the latter reactions, compared to those on 2-nitro-tetraarylporphyrin analogues, is a consequence of two factors, higher energies being required for initial nucleophilic attack as macrocyclic aromaticity is lost in intermediates and the susceptibility of the resultant “non-aromatic” intermediates to further attack.