Doxorubicin loaded magnesium oxide nanoflakes as ph dependent carriers for simultaneous treatment of cancer and hypomagnesemia

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Doxorubicin (DOX) is an anticancer drug commonly used in treating cancer; however, it has severe cytotoxicity effects. To overcome both the adverse effects of the drug and mineral deficiency (i.e., hypomagnesemia) experienced by cancer patients, we have developed magnesium oxide (MgO) nanoflakes as drug carriers and loaded them with DOX for use as a targeted drug delivery (TDD) system for potential application in cancer therapy. The synthesis employed herein affords pure, highly porous MgO nanoparticles that are void of the potentially harmful metal contaminants often discussed in the literature. Purposed for dual therapy, the nanoparticles exhibit an impressive 90% drug loading capacity with pH dependent drug releasing rates of 10% at pH 7.2, 50.5% at pH 5.0, and 90.2% at pH 3. Results indicate that therapy is achievable via slow diffusion where MgO nanoflakes degrade (i.e., dissolve) under acidic conditions releasing the drug and magnesium ions to the cancerous region. The TDD system therefore minimizes cytotoxicity to healthy cells while supplying magnesium ions to overcome hypomagnesemia

A Raman spectroscopic and computational study of new aromatic pyrimidine-based halogen bond acceptors

© 2019 by the authors. Two new aromatic pyrimidine-based derivatives designed specifically for halogen bond directed self-assembly are investigated through a combination of high-resolution Raman spectroscopy, X-ray crystallography, and computational quantum chemistry. The vibrational frequencies of these new molecular building blocks, pyrimidine capped with furan (PrmF) and thiophene (PrmT), are compared to those previously assigned for pyrimidine (Prm). The modifications affect only a select few of the normal modes of Prm, most noticeably its signature ring breathing mode, ν1. Structural analyses afforded by X-ray crystallography, and computed interaction energies from density functional theory computations indicate that, although weak hydrogen bonding (C-H...O or C-H...N interactions) is present in these pyrimidine-based solid-state co-crystals, halogen bonding and π-stacking interactions play more dominant roles in driving their molecular-assembly

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

© 2020 Balasubramaniam et al. Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma

SWIR Emissive RosIndolizine Dyes With Nanoencapsulation In Water Soluble Dendrimers

Shortwave infrared (SWIR) emission has great potential for deep-tissue in vivo biological imaging with high resolution. In this article, the synthesis and characterization of two new xanthene-based RosIndolizine dyes coded PhRosIndz and tolRosIndz is presented. The dyes are characterized via femtosecond transient absorption spectroscopy as well as steady-state absorption and emission spectroscopies. The emission of these dyes is shown in the SWIR region with peak emission at 1097 nm. TolRosIndz was encapsulated with an amphiphilic linear dendritic block co-polymer (LDBC) coded 10-PhPCL-G3 with high uptake yield. Further, cellular toxicity was examined in vitro using HEK (human embryonic kidney) cells where a \u3e90% cell viability was observed at practical concentrations of the encapsulated dye which indicates low toxicity and reasonable biocompatibility

Heteroacene-Based Amphiphile as a Molecular Scaffold for Bioimaging Probes

The challenges faced with current fluorescence imaging agents have motivated us to study two nanostructures based on a hydrophobic dye, 6H-pyrrolo[3,2-b:4,5-b’]bis [1,4]benzothiazine (TRPZ). TRPZ is a heteroacene with a rigid, pi-conjugated structure, multiple reactive sites, and unique spectroscopic properties. Here we coupled TRPZ to a tert-butyl carbamate (BOC) protected 2,2-bis(hydroxymethyl)propanoic acid (bisMPA) dendron via azide-alkyne Huisgen cycloaddition. Deprotection of the protected amine groups on the dendron afforded a cationic terminated amphiphile, TRPZ-bisMPA. TRPZ-bisMPA was nanoprecipitated into water to obtain nanoparticles (NPs) with a hydrodynamic radius that was \u3c150 nm. For comparison, TRPZ-PG was encapsulated in pluronic-F127 (Mw = 12 kD), a polymer surfactant to afford NPs almost twice as large as those formed by TRPZ-bisMPA. Size and stability studies confirm the suitability of the TRPZ-bisMPA NPs for biomedical applications. The photophysical properties of the TRPZ-bisMPA NPs show a quantum yield of 49%, a Stokes shift of 201 nm (0.72 eV) and a lifetime of 6.3 ns in water. Further evidence was provided by cell viability and cellular uptake studies confirming the low cytotoxicity of TRPZ-bisMPA NPs and their potential in bioimaging

Bis-spironaphthooxazine based photochromic polymer materials

The photochromism and guest binding of spiro-naphtho-oxazine dimer (SNOD) based materials were investigated. The specifically angled, conjugated dimer, SNOD, was covalently connected to α-methoxy-ω-amino-poly(ethylene glycol) (PEG) and studied under UV irradiation. Results showed the specific effects of the polymer chain on their photochromic properties and relaxation kinetics. These new materials exhibited repeatable photo-switchability and little kinetics dependency on solvent polarity. The nanoscale micelles were prepared by self-assembly of amphiphilic SNOD-PEG conjugates in aqueous medium. A palladium catalyst as a guest agent was encapsulated in the micelle core, which reduced the thermal closing rate of the merocyanine isomer of the spirooxazine dimer. SNOD was also conjugated onto solid polymer beads and investigated for the binding affinity with dyes and catalysts. The stable binding affinity towards the palladium catalyst indicated potential applications for selective recognition, extraction, and controlled release. © The Royal Society of Chemistry 2013

Synthesis, characterization, and solvent-independent photochromism of spironaphthooxazine dimers

Specifically angled, conjugated spiroindolinonaphthooxazine dimers (SNOD) have been synthesized. The photochromic reactions of two types of SNOD were studied under continuous UV irradiation in solvents of different polarity. Comparison of these results with the single unit provides the examination of the specific effect of substituents on their photochromic properties and relaxation kinetics. The photomerocyanine isomers showed positive solvatochromism, supporting the premise for a less polar quinoidal structure. The thermal closing rate at 25 °C ranged from 0.2 to 1.6 s -1 depending on the compound and solvent. Photochromism of these new compounds showed little dependency on solvent polarity and stable cyclability. © 2011 Elsevier B.V. All rights reserved

A tailored spirooxazine dimer as a photoswitchable binding tool

A uniquely angled spirooxazine dimer was synthesized as a smart photoswitch for sensing and delivery applications; the dimer showed reversible binding and release ability towards a palladium catalyst. © The Royal Society of Chemistry 2009

In silico design of novel histone deacetylase 4 inhibitors: Design guidelines for improved binding affinity

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas