Next-generation of BBQ analogues that selectively target breast cancer.

We previously reported on the interaction of 10-chloro-7-benzo[]benzo[4,5]imidazo[2,1-]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI values of 0.

Novel piperazine-1,2,3-triazole leads for the potential treatment of pancreatic cancer.

From lead 1, (-(4-((4-(3-(4-(3-methoxyphenyl)-1-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2-p53 protein-protein interaction inhibitor based on an modelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1's phenylacetamide moiety, gave with only modest pancreatic cancer activity.

Wiskostatin and other carbazole scaffolds as off target inhibitors of dynamin I GTPase activity and endocytosis.

Wiskostatin (1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol) (1) is a carbazole-based compound reported as a specific and relatively potent inhibitor of the N-WASP actin remodelling complex (S-isomer EC = 4.35 μM; R-isomer EC = 3.44 μM).

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens.

Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains.

Antigiardial Activity of Novel Guanidine Compounds.

From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter-screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC <5 μM, seven with IC <1.

3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety.

Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target.

Synthesis of Phthaladyn-29 and Naphthalimide-10, GTP Site Directed Dynamin GTPase Inhibitors.

Herein we describe the detailed synthesis of the dynamin inhibitors Phthaladyn-29 and Napthaladyn-10, and their chemical scaffold matched partner inactive compounds. Combined with the assay data provided, this allows the interrogation of dynamin in vitro and potentially in vivo.

Dynole 34-2 and Acrylo-Dyn 2-30, Novel Dynamin GTPase Chemical Biology Probes.

This protocol describes the chemical synthesis of the dynamin inhibitors Dynole 34-2 and Acrylo-Dyn 2-30, and their chemical scaffold matched partner inactive compounds. The chosen active and inactive paired compounds represent potent dynamin inhibitors and very closely related dynamin-inactive compounds, with the synthesis of three of the four compounds readily possible via a common intermediate. Combined with the assay data provided, this allows the interrogation of dynamin in vitro and potentially in vivo.

Pyrimidyn-Based Dynamin Inhibitors as Novel Cytotoxic Agents.

Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono-substituted to trisubstituted.

Amino alcohol acrylonitriles as broad spectrum and tumour selective cytotoxic agents.

We have identified specific dichlorophenylacrylonitriles as lead compounds in the development of novel anticancer compounds, notably, ()--(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide () and ANI-7 (). Herein we specifically probe the SAR associated with the terminal aromatic ring and associated cytoxicity in a broad range of human cancer cell lines. Synthesis of three focused libraries revealed a poor tolerance for electron withdrawing and donating moieties (Library A).

Cytotoxic 1,2,3-Triazoles as Potential Leads Targeting the S100A2-p53 Complex: Synthesis and Cytotoxicity.

In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor.

Targeting the S100A2-p53 Interaction with a Series of 3,5-Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity.

In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 μM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line.

Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology.

In this study, we optimized and compared different transmission electron microscopy (TEM) methods to visualize changes to Gram-negative bacterial morphology induced by treatment with a robenidine analogue (NCL195) and colistin combination. Aldehyde-fixed bacterial cells (untreated, treated with colistin or NCL195 + colistin) were prepared using conventional TEM methods and compared with ultrathin Tokuyasu cryo-sections. The results of this study indicate superiority of ultrathin cryo-sections in visualizing the membrane ultrastructure of and , with a clear delineation of the outer and inner membrane as well as the peptidoglycan layer.

In vitro synergistic activity of NCL195 in combination with colistin against Gram-negative bacterial pathogens.

In this study, the potential of using the novel antibiotic NCL195 combined with subinhibitory concentrations of colistin against infections caused by Gram-negative bacteria (GNB) was investigated. We showed synergistic activity of the combination NCL195 + colistin against clinical multidrug-resistant GNB pathogens with minimum inhibitory concentrations (MICs) for NCL195 ranging from 0.5-4 μg/mL for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, whereas NCL195 alone had no activity.

Small molecule inhibitors in pancreatic cancer.

Pancreatic cancer (PC), with a 5 year survival of <7%, is one of the most fatal of all human cancers. The highly aggressive and metastatic character of this disease poses a challenge that current therapies are failing, despite significant efforts, to meet. This review examines the current status of the 35 small molecule inhibitors targeting pancreatic cancer in clinical trials and the >50 currently under investigation.

Activity of Robenidine Analog NCL195 in Combination With Outer Membrane Permeabilizers Against Gram-Negative Bacterial Pathogens and Impact on Systemic Gram-Positive Bacterial Infection in Mice.

Multidrug-resistant (MDR) pathogens, particularly the ESKAPE group (, , , , , , and spp.), have become a public health threat worldwide. Development of new antimicrobial classes and the use of drugs in combination are potential strategies to treat MDR ESKAPE pathogen infections and promote optimal antimicrobial stewardship.

A Direct Fluorescent Activity Assay for Glycosyltransferases Enables Convenient High-Throughput Screening: Application to O-GlcNAc Transferase.

Glycosyltransferases carry out important cellular functions in species ranging from bacteria to humans. Despite their essential roles in biology, simple and robust activity assays that can be easily applied to high-throughput screening for inhibitors of these enzymes have been challenging to develop. Herein, we report a bead-based strategy to measure the group-transfer activity of glycosyltransferases sensitively using simple fluorescence measurements, without the need for coupled enzymes or secondary reactions.

Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome.

Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI =30 nM and 400-fold selective c.f. MCF10A (normal breast tissue).

Discovery of 4,6-bis(2-(()-benzylidene)hydrazinyl)pyrimidin-2-Amine with Antibiotic Activity.

Robenidine ()-'-(()-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl)ethylidene)hydrazine-1-carboximidhydrazide displays methicillin-resistant (MRSA) and vancomycin-resistant Enterococci (VRE) MICs of 2 μg mL. Herein we describe the structure-activity relationship development of a novel series of guanidine to 2-aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2-NH pyrimidine moiety renders these analogues inactive.

A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides.

The Ugi four component reaction of an aldehyde, amine, isocyanide and an ethanoic acid was effected smoothly in protic ionic liquids ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) to afford analogues of α-phenylacetamido amides in good to excellent isolated yields. The corresponding reactions in [BMIM][PF] and the protic ionic liquid ethanolammonium nitrate (ETAN) failed. Microwave irradiation in EAN facilitated rapid access to three focused libraries, based on the parent isocyanide: cyclohexyl isocyanide, benzyl isocyanide and ethyl isocyanoacetate.

Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues.

Desymmetrisation of robenidine (1: N',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL .

A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone.

Bolinaquinone is a natural product that is a structurally complex, cytotoxic sesquiterpene quinone. A scaffold simplification and focused library approach using a microwave-assisted Suzuki coupling gave 32 bolinaquinone analogues with good-to-excellent cytotoxicity profiles. Mono-arylbenzoquinones, Library , were preferentially toxic towards BE2-C (neuroblastoma) cells with growth inhibition (GI) values of 4-12 µM; only the 3,4-dimethoxyphenyl and 3-biphenyl variants were broad-spectrum active-HT29 (colon carcinoma), U87 and SJ-G2 (glioblastoma), MCF-7 (breast carcinoma), A2780 (ovarian carcinoma), H460 (lung carcinoma), A431 (skin carcinoma), Du145 (prostate carcinoma), BE2-C (neuroblastoma), MIA (pancreatic carcinoma) and SMA (spontaneous murine astrocytoma).

A facile hybrid 'flow and batch' access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones.

We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a-l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a-l) in 38-87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a-l was devoid of toxicity.

Robenidine Analogues as Gram-Positive Antibacterial Agents.

Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 μM, respectively.