21 research outputs found
Biocompatibility of a self-assembled crosslinkable hyaluronic acid nanogel
Hyaluronic acid nanogel (HyA-AT) is a redox sensitive crosslinkable nanogel, obtained through the conjugation of a thiolated hydrophobic molecule to the hyaluronic acid chain. Engineered nanogel was studied for its biocompatibility, including immunocompatibility and hemocompatability. The nanogel did not compromise the metabolic activity or cellular membrane integrity of 3T3, microvascular endothelial cells, and RAW 264.7 cell lines, as determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase release assays. Also, we didn't observe any apoptotic effect on these cell lines through the Annexin V-FITC test. Furthermore, the nanogel cell internalization was analyzed using murine bone marrow derived macrophages, and the in vivo and ex vivo biodistribution of the Cy5.5 labeled nanogel was monitored using a non-invasive near-infrared fluorescence imaging system. The HyA-AT nanogel exhibits fairly a long half-live in the blood stream, thus showing potential for drug delivery applications.The authors thank the FCT Strategic
Project of UID/BIO/04469/2013 unit, the project RECI/
BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and
the Project “BioHealth – Biotechnology and Bioengineering
approaches to improve health quality”, Ref. NORTE-07-0124-
FEDER-000027, co-funded by the Programa Operacional Regional
do Norte (ON.2 – O Novo Norte), QREN, FEDER. The authors would
like to acknowledge also the support of FCT for the PhD grant
reference SFRH/BD/61516/2009. They would also like to thank
Bioimaging department on Molecular Medicine Institute (IMM)
in Lisbon, namely Dr José Rino and Dr António Temudo. Also
thank the animal facilities in IMM (Lisbon), specially Dr. Dolores
Bonaparte and Dr. Joana Marques.
Finally, the authors thank Dr Africa Gonzalez and Mercedes
Pelletero the performance of the studies on the activation of
complement
Progress in the development of non-​BET bromodomain chemical probes
The bromodomain and extra terminal (BET) family of bromodomains have been the focus of extensive research, leading to the development of many potent, selective chem. probes and recent clinical assets. The profound biol. associated with BET bromodomain inhibition has provided a convincing rationale for targeting bromodomains for the treatment of disease. However, the BET family represents just eight of the at least 56 human bromodomains identified to date. Until recently, there has been significantly less interest in non-​BET bromodomains, leaving a vast area of research and the majority of this new target class yet to be thoroughly investigated. It has been widely reported that several non-​BET bromodomain containing. proteins are associated with various diseases including cancer and HIV. Therefore, the development of chem. probes for non-​BET bromodomains will facilitate elucidation of their precise biol. roles and potentially lead to the development of new medicines. This review summarises the progress made towards the development of non-​BET bromodomain chem. probes to date. In addn., we highlight the potential for future work in this new and exciting area
Design, synthesis and biological evaluation of biphenyl urea derivatives as novel VEGFR-2 inhibitors
Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (<i>S</i>)‑3-Amino-2-methylpropan-1-ol
This
work describes the optimization and scale-up of a Buchwald–Hartwig
amination reaction for the preparation of a pharmaceutical intermediate.
This C–N bond formation is challenged by the use of a chiral
primary amine, which both adds cost and favors formation of biaryl
byproducts. In order to develop a scalable process, a number of factors
had to be investigated including catalyst selection and stoichiometry
of the chiral amine. These all needed to be optimized while maintaining
low palladium levels in the isolated product. The reaction was found
to be most effective using PdÂ(dba)<sub>2</sub> with BINAP and Cs<sub>2</sub>CO<sub>3</sub> in THF. When executed on 2.5 kg scale, these
conditions provided 2.06 kg of the desired product in 80% yield with
only 73 ppm residual palladium. To date, this process has been successfully
executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>
Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain
Chemical
probes are required for preclinical target validation
to interrogate novel biological targets and pathways. Selective inhibitors
of the CREB binding protein (CREBBP)/EP300 bromodomains are required
to facilitate the elucidation of biology associated with these important
epigenetic targets. Medicinal chemistry optimization that paid particular
attention to physiochemical properties delivered chemical probes with
desirable potency, selectivity, and permeability attributes. An important
feature of the optimization process was the successful application
of rational structure-based drug design to address bromodomain selectivity
issues (particularly against the structurally related BRD4 protein)