Polyamine Aza-Cyclic Compounds Demonstrate Anti-Proliferative Activity In Vitro But Fail to Control Tumour Growth In Vivo

Wong, Pui Ee; Tetley, Laurence; Dufès, Christine; Chooi, Kar Wai; Bolton, Katherine; Schätzlein, Andreas; Uchegbu, Ijeoma F.

doi:10.1002/jps.22165

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…Samples were imaged under a Philips CM120 BioTwin transmission electron microscope (FEI Company, Eindhoven, The Netherlands). Prior to imaging, the samples were negatively stained using uranyl acetate (1% w/v) as previously described. , …”

Section: Methodsmentioning

confidence: 99%

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Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

Mazza¹,

Notman

Anwar

et al. 2013

ACS Nano

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The delivery of therapeutic peptides and proteins to the central nervous system is the biggest challenge when developing effective neuropharmaceuticals. The central issue is that the blood-brain barrier is impermeable to most molecules. Here we demonstrate the concept of employing an amphiphilic derivative of a peptide to deliver the peptide into the brain. The key to success is that the amphiphilic peptide should by design self-assemble into nanofibers wherein the active peptide epitope is tightly wrapped around the nanofiber core. The nanofiber form appears to protect the amphiphilic peptide from degradation while in the plasma, and the amphiphilic nature of the peptide promotes its transport across the blood-brain barrier. Therapeutic brain levels of the amphiphilic peptide are achieved with this strategy, compared with the absence of detectable peptide in the brain and the consequent lack of a therapeutic response when the underivatized peptide is administered.

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Section: Methodsmentioning

confidence: 99%

“…Prior to imaging, the samples were negatively stained using uranyl acetate (1% w/v) as previously described. 51,52 Coarse-Grained Molecular Dynamics. To investigate the selfassembly and molecular organization of pDal nanofibers, coarsegrained (CG) molecular dynamics (MD) simulations were carried out using the GROMACS 4.5.1 simulation package.…”

Section: Methodsmentioning

confidence: 99%

Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

Mazza¹,

Notman

Anwar

et al. 2013

ACS Nano

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“…Our efforts focused on trying to replicate the original toxicity experiments (by CO-ADD) with tamoxifen using a protocol modified for use with 96-well plates. Given the variability of protocols and results in the literature, it was important to compare with a standard protocol we have reliably used in our own laboratories. − When both CC 50 values and D max were mapped against the other two experimental variables (i.e., recovery status after treatment (yes/no) and the detection output (MTT/resazurin)), the majority of compounds were found to be toxic, as classified by CO-ADD, with a small spread of the data for most variations of protocol used (Figure A). Truly “non-toxic” compounds might be expected to show D max < 50% for all experiment variations, e.g., 861 .…”

Section: Resultsmentioning

confidence: 99%

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus

Klug,

Tse,

Silva

et al. 2023

ACS Infect. Dis.

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Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium ( ). Of the 18 compounds tested (at 32 μg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure–activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

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Nanomedicines and Nanodiagnostics Come of Age

Uchegbu

Siew

2013

Journal of Pharmaceutical Sciences

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Polyamine Aza-Cyclic Compounds Demonstrate Anti-Proliferative Activity In Vitro But Fail to Control Tumour Growth In Vivo

Cited by 4 publications

References 29 publications

Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus

Nanomedicines and Nanodiagnostics Come of Age

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