Synthesis of isomeric polyacetylenes based on natural hydroxy matricaria esters

The construction of a library of natural and related polyacetylenes using a convergent synthetic strategy based on a palladium mediated cross-coupling reaction is described. The systematic synthetic study led to all possible alkene isomers of the hydroxy matricaria esters 29-32, and the corresponding tiglates 1-4. The synthesis of many of these compounds is described for the first time.

Antimicrobial activity of short, synthetic cationic lipopeptides.

The increasing emergence of multidrug-resistant micro-organisms presents one of the greatest challenges in the clinical management of infectious diseases. Therefore, novel antimicrobial agents are urgently required to address this issue. In this report, we describe the solid phase synthesis, characterization, microbiological and toxicological evaluation of a library of ultrashort cationic antimicrobial lipopeptides based on the previously described tetrapeptide amide H-Orn-Orn-Trp-Trp-NH2 conjugated with saturated fatty acids which have inherent antimicrobial activity. The microbiological activity of these ultrashort cationic lipopeptides, which exhibit excellent, broad-spectrum antimicrobial activity against a number of clinically important pathogenic bacteria and fungi, including multidrug resistant micro-organisms in both planktonic and sessile (biofilm) cultures is reported.

Development and characterization of 10 polymorphic microsatellite loci for the blue shark, Prionace glauca, and their cross shark-species amplification.

Ten polymorphic nuclear microsatellite loci were developed from a microsatellite enriched genomic library of the blue shark, Prionace glauca. The utility of these markers for genetic studies of this globally distributed, heavily exploited, oceanic predator was assessed by screening 120 specimens sampled from six locations throughout the species’ range. Both moderately and highly polymorphic marker loci were identified. Three to 35 alleles were found to be segregating per locus (mean 10.1) with observed heterozygosities ranging from 24 to 91%. Evaluation of the cross-species amplification of these markers across 18 additional shark species indicates that these microsatellites are potentially useful for genetic studies of other species of conservation concern.

Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes

Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds; and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.

Structure-based design of selective high-affinity telomeric quadruplex-binding ligands.

A library of triazole-based telomeric quadruplex-selective ligands has been developed that mimic an established family of tri-substituted acridine-based ligands, using crystal structure data as a starting-point for computer-based design. Binding affinities, estimated by electrospray mass spectrometry, are in accord with the design concept.

A novel small-molecule inhibitor of IL-6 signalling.

A small library of pyrrolidinesulphonylaryl molecules has been synthesized via an efficient 4-step route, and members evaluated for their ability to inhibit IL-6 signalling. One molecule (6a) was found to have promising activity against IL-6/STAT3 signalling at the low micromolar level, and to selectively inhibit phosphorylation of STAT3 (but not STAT1) in IL-6 stimulated MDA-MB-231 breast cancer and HeLa cell lines. It was also selectively cytostatic in MDA-MB-231 (STAT3-dependent) versus A4 (STAT3-null) cells suggesting STAT3-specific inhibitory properties.

Comprehensive Inhibitor Profiling Of The Proteus Mirabilis Metalloprotease Virulence Factor Zapa (Mirabilysin)

In this study we report for the first time the comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor, ZapA (mirabilysin) using a 160 compound focused library of N-alpha mercaptoamide dipeptides, in order to map the S1´ and S2´ binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in P1´ and aliphatic residues in P2´. From this library, six compounds were identified which exhibited sub- to low micromolar Ki values. The most potent inactivator, SH-CO2-Y-V-NH2 was capable of preventing ZapA-mediated hydrolysis of heat denatured IgA, indicating these inhibitors may be capable of protecting host proteins against ZapA during colonisation and infection.

The natriuretic peptide/helokinestatin precursor from Mexican beaded lizard (Heloderma horridum) venom: Amino acid sequence deduced from cloned cDNA and identification of two novel encoded helokinestatins

Natriuretic peptides are common components of reptile venoms and molecular cloning of their biosynthetic precursors has revealed that in snakes, they co-encode bradykinin-potentiating peptides and in venomous lizards, some co-encode bradykinin inhibitory peptides such as the helokinestatins. The common natriuretic peptide/helokinestatin precursor of the Gila Monster, Heloderma suspectum, encodes five helokinestatins of differing primary structures. Here we report the molecular cloning of a natriuretic peptide/helokinestatin precursor cDNA from a venom-derived cDNA library of the Mexican beaded lizard (Heloderma horridum). Deduction of the primary structure of the encoded precursor protein from this cloned cDNA template revealed that it consisted of 196 amino acid residues encoding a single natriuretic peptide and five helokinestatins. While the natriuretic peptide was of identical primary structure to its Gila Monster (H. suspectum) homolog, the encoded helokinestatins were not, with this region of the common precursor displaying some significant differences to its H. suspectum homolog. The helokinestatin-encoding region contained a single copy of helokinestatin-1, 2 copies of helokinestatin-3 and single copies of 2 novel peptides, (Phe)(5)-helokinestatin-2 (VPPAFVPLVPR) and helokinestatin-6 (GPPFNPPPFVDYEPR). All predicted peptides were found in reverse phase HPLC fractions of the same venom. Synthetic replicates of both novel helokinestatins were found to antagonize the relaxing effect of bradykinin on rat tail artery smooth muscle. Thus lizard venom continues to provide a source of novel biologically active peptides. (C) 2011 Published by Elsevier Inc.