Discovery of dual GyrB/ParE inhibitors active against Gram-negative bacteria.

Even though many GyrB and ParE inhibitors have been reported in the literature, few possess activity against Gram-negative bacteria. This is primarily due to limited permeability across Gram-negative bacterial membrane as well as bacterial efflux mechanisms. Permeability of compounds across Gram-negative bacterial membranes depends on many factors including physicochemical properties of the inhibitors.

Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors.

Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.

Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.

Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics.

The use of porcupine inhibitors to target Wnt-driven cancers.

Over the past decade, academic groups and pharmaceutical companies have uncovered several components and targets for intervention in the Wnt pathway. One approach is to block Wnt signalling through the use of orally bioavailable small molecules that prevent Wnt ligand secretion. In recent years, the membrane bound O-acyl transferase (MBOAT) porcupine (PORCN) has emerged as a molecular target of interest in the search for clinical options to treat Wnt-driven cancers.

Discovery and Optimization of a Porcupine Inhibitor.

Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and function.

Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design.

Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt.

Phyllodes tumours of the breast: the role of CD34, vascular endothelial growth factor and β-catenin in histological grading and clinical outcome.

Aims: The grading and prognostication of breast phyllodes tumours remain challenging, and the value of biological markers continues to be elusive. The aim of this study was to evaluate CD34, vascular endothelial growth factor (VEGF) and β-catenin in a series of 185 breast phyllodes tumours comprising 120 benign, 48 borderline and 17 malignant lesions.

Methods And Results: Immunohistochemistry on tissue microarrays of phyllodes tumours was performed.

Fragment-based ligand design of novel potent inhibitors of tankyrases.

Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding.

[μ-1,2-Bis(diphenyl-phosphino)methane-κP:P']bis-{[(Z)-O-ethyl N-(4-nitro-phen-yl)thio-carbamato-κS]gold(I)}.

Each gold atom in the binuclear title compound, [Au(2)(C(9)H(9)N(2)O(3)S)(2)(C(25)H(22)P(2))], is coordinated within an S,P-donor set that defines a slightly distorted linear geometry [S-Au-P angles = 172.77 (6) and 173.84 (6)°], with the distortion due in part to a close intra-molecular Au⋯O contact [2.

[μ-1,1'-Bis(diphenyl-phosphino)ferrocene]bis-{[(Z)-O-ethyl N-phenyl-thio-carbamato-κS]gold(I)} dichloro-methane solvate.

The binuclear title compound, [Au(2)Fe(C(9)H(10)NOS)(2)(C(17)H(14)P)(2)]·CH(2)Cl(2), which has the Fe atom located on a crystallographic centre of inversion, crystallizes as a 1:1 dichloro-methane solvate, which is disordered about a centre of inversion. There is a small deviation from linearity defined by the SP donor set [S1-Au-P1 angle is 175.35 (5) °] which is due to an intra-molecular Au⋯O contact [3.

[(Z)-O-Ethyl N-(4-nitro-phen-yl)thio-carbamato-κS](triphenyl-phosphine-κP)gold(I) dichloro-methane solvate.

An S,P-donor set in the title solvate, [Au(C(9)H(9)N(2)O(3)S)(C(18)H(15)P)]·CH(2)Cl(2), defines a linear geometry for the Au(I) atom [S-Au-P = 177.75 (7)°], with the minor distortion ascribed to the influence of an intra-molecular Au⋯O contact [3.019 (6) Å].

μ-1,1'-Bis(diphenyl-phosphino)ferrocene-κP:P'-bis-{[(Z)-O-isopropyl N-(4-nitro-phen-yl)thio-carbamato-κS]gold(I)} chloro-form disolvate.

The dinuclear title mol-ecule, [Au(2)Fe(C(10)H(11)N(2)O(3)S)(2)(C(17)H(14)P)(2)]·2CHCl(3), has crystallographic twofold symmetry with the Fe atom (bonded to two η(5)-cyclo-penta-dienyl rings) situated on the rotation axis. The Au atom exists within a linear geometry defined by an S,P-donor set with a deviation from linearity [S-Au-P = 176.86 (6)°] due to the close approach of the thio-carbamate O atom [Au⋯O = 3.

[(Z)-O-Ethyl N-(4-nitro-phen-yl)thio-carbamato-κS](triethyl-phosphine-κP)gold(I).

In the title compound, [Au(C(9)H(9)N(2)O(3)S)(C(6)H(15)P)], two virtually identical mol-ecules comprise the asymmetric unit. These are connected by Au⋯Au [3.6796 (4) Å] and Au⋯S [3.

[(Z)-Isopropoxy(4-nitrophenylimino)methanethiolato-κS](tricyclo-hexyl-phosphine-κP)gold(I).

In the title compound, [Au(C(10)H(11)N(2)O(3)S)(C(18)H(33)P)], the gold(I) atom is linearly coordinated within a SP donor set. The distortion from linearity [S-Au-P = 177.54 (3)°] can be traced to an intra-molecular Au⋯O contact of 3.

Cytotoxicity profiles for a series of triorganophosphinegold(I) dithiocarbamates and triorganophosphinegold(I) xanthates.

A series of triorganophosphinegold(1) dithiocarbamate (R(3)PAuS(2)CNR'(2)) and xanthate (R(3)PAuS(2)COR') complexes have been prepared and characterised spectroscopically. Based on crystallographic evidence, the molecules feature linear gold(1) geometries defined by sulphur and phosphorus donors. The complexes, along with a series of known anti-cancer agents, have been screened against a panel of seven human cancer cell lines.

Luminescent phosphine gold(I) thiolates: correlation between crystal structure and photoluminescent properties in [R3PAu{SC(OMe)=NC6H4NO2-4}] (R = Et, Cy, Ph) and [(Ph2P-R-PPh2){AuSC(OMe)=NC6H4NO2-4}2] (R = CH2, (CH2)2, (CH2)3, (CH2)4, Fc).

X-ray crystallography shows the gold atoms in [R3PAu{SC(OMe)=NC6H4NO2-4}] (R = Et, Cy, Ph; 1-3, respectively) and [(Ph2P-R-PPh2){AuSC(OMe)=NC6H4NO2-4}(2)] (R = CH2, (CH2)2, (CH2)3, (CH2)4, Fc; 4-8, respectively) are linearly coordinated by phosphorus and thiolate-sulfur; weak intramolecular Au...