1,3,4-Oxadiazole-containing hybrids as potential anticancer agents: Recent developments,mechanism of action and structure-activity relationships

Chemotherapy is an important therapeutic approach for the treatment of cancer. Currently, many anticancer drugs are available in the market that plays an important role in cancer treatment, but concerns such as, drug resistance and side effects create an urgent need for the development of new anti-tumor drugs with high potency and less side effects. Heterocycles are of great interest due to their fascinating anticancer activity. Among them, 1,3,4-oxadiazoles showed attracting anti-tumor activity and its derivatives are under clinical trials for the treatment of cancer. Hybridization of 1,3,4-oxadiazole moiety with other heterocyclic pharmacophoresis a promising approach to overcome various disadvantages of current anticancer drugs such as drug resistance, toxicity, and other side effects. Thus, 1,3,4-oxadiazole-heterocycle hybrids occupy a significant position in the discovery of anti-tumor drugs. Among the reported oxadiazole-based hybrids reviewed here, compounds 45i, 59j, and 62x showed the highest anticancer activity with IC₅₀ values in the nanomolar range. This review summarizes the recent developments in the anticancer potential, structure–activity relationships, and mechanisms of actions of 1,3,4-oxadiazole-heterocycle hybrids.     

Synthesis,Photophysics and PDT Evaluation of Mono‐, Di‐, Tri‐ and Hexa‐PEG Chlorins for Pointsource Photodynamic Therapy

Pointsource photodynamic therapy (PSPDT) is a newly developed fiber optic method aimed at the delivery of photosensitizer, light and oxygen to a diseased site. Because of a need for developing photosensitizers with desirable properties for PSPDT, we have carried out a synthetic, photophysical and phototoxicity study on a series of PEGylated sensitizers. Chlorin and pheophorbide sensitizers were readily amenable to our synthetic PEGylation strategy to reach triPEG and hexaPEG galloyl pheophorbides and mono‐, di‐, triPEG chlorins. On screening these PEG sensitizers, we found that increasing the number of PEG groups, except for hexaPEGylation, increases phototoxicity. We found that three PEG groups but not less or more were optimal. Of the series tested, a triPEG gallyol pheophorbide and a triPEG chlorin were the most efficient at generating singlet oxygen, and produced the highest phototoxicity and lowest dark toxicity to Jurkat cells. A detailed kinetic analysis of the PEGylated sensitizers in solution and cell culture and media is also presented. The data provide us with steps in the development of PSPDT to add to the PDT tools we have in general.     

Reversed Crystal Growth of RHO Zeolitic Imidazolate Framework (ZIF)

RHO zeolitic imidazolate framework (ZIF), Zn_1.33(O.OH)_0.33(nim)_1.167(pur), crystals with a rhombic dodecahedral morphology were synthesized by a solvothermal process. The growth of the crystals was studied over time using scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X‐ray diffraction (PXRD) and Brunauer–Emmett–Teller (BET) analyses, and a reversed crystal growth mechanism was revealed. Initially, precursor materials joined together to form disordered aggregates, which then underwent surface recrystallization forming a core–shell structure, in which a disordered core is encased in a layer of denser, less porous crystal. When the growth continued, the shell became less and less porous, until it was a layer of true single crystal. The crystallization then extended from the surface to the core over a six‐week period until, eventually, true single crystals were formed.     

Nucleation of the Al6(Fe,Mn)-to-α-Al–(Fe,Mn)–Si transformation in 3XXX aluminium alloys. I. Roll-bonded diffusion couples

Roll-bonded diffusion couples are used to investigate a transformation of intermetallic particles from Al₆(Fe,?Mn) to α-Al–(Fe,?Mn)–Si that occurs upon homogenization of 3XXX aluminium alloys. By diffusing silicon into an Al–Fe–Mn alloy, the couples permit a progressive increase in the driving force for this 6-to-α transformation, thus allowing study of the nucleation of the transformation. Initially, the aluminium matrix is highly defected from rolling. This microstructure gives frequent (yet stochastic) nucleation of a eutectoid 6-to-α transformation expected from study of direct-chill-cast 3XXX alloys. However, once the matrix has recrystallized, nucleation is restricted to particles that lie on the matrix grain boundaries. The remaining particles, unable to transform eutectoidally, dissolve and supply growth of these α-phase particles, producing marked coarsening.     

Analysis of uniaxial compression of vertically aligned carbon nanotubes

We carry out axisymmetric, finite deformation finite element analyses of the uniaxial compression of cylindrical bundles of vertically aligned carbon nanotubes (VACNTs) firmly attached to a Si substrate. A compressible elastic–viscoplastic constitutive relation with a piecewise, linear hardening–softening–hardening flow strength is used to model the material. Calculations are performed for VACNTs both with uniform properties and with axially graded properties. We show that, with uniform properties, sequential buckling initiates at the substrate and propagates away from it, in agreement with previous experimental findings. We investigate the dependence of the magnitude and wavelength of the buckles on characteristics of the function defining the flow strength. When a property gradient giving a more compliant response at the end opposite to the substrate is specified, we find that sequential buckling initiates at that end and propagates toward the substrate. Results of the analyses are compared with the experimental observations and capture many of the experimentally obtained stress–strain and morphological features. The proposed model serves as a promising foundation for capturing the underlying energy absorption mechanisms in these systems. Comparison of the model predictions with the experimental results also suggests directions for model improvement.     

Photosensitization reactions in vitro and in vivo

This review of Photochemistry and Photobiology summarizes articles published in 2010, and highlights progress in the area of photosensitization. The synthesis of conjugated photosensitizers is an area of interest where increasing water solubility has been a goal. Targeting infrared sensitizer absorption has been another goal, and relates to the practical need of deep tissue absorption of light. Photodynamic techniques for inactivating microbes and destroying tumors have been particularly successful. Biologically, singlet oxygen [(1)O(2)((1)Δ(g))] is an integral species in many of these reactions, although photosensitized oxidations tuned to electron and hydrogen transfer (Type I) give rise to other reactive species, such as superoxide and hydrogen peroxide. How photoprotection against yellowing, oxygenation and degradation occurs was also an area of topical interest.     

Fluorine end-capped optical fibers for photosensitizer release and singlet oxygen production

The usefulness of a fiber optic technique for generating singlet oxygen and releasing the pheophorbide photosensitizer has been increased by the fluorination of the porous Vycor glass tip. Singlet oxygen emerges through the fiber tip with 669-nm light and oxygen, releasing the sensitizer molecules upon a [2 + 2] addition of singlet oxygen with the ethene spacer and scission of a dioxetane intermediate. Switching from a nonfluorinated to a fluorinated glass tip led to a clear reduction of the adsorbtive affinity of the departing sensitizer with improved release into homogeneous toluene solution and bovine tissue, but no difference was found in water since the sensitizer was insoluble. High surface coverage of the nonafluorohexylsilane enhanced the cleavage efficiency by 15% at the ethene site. The fluorosilane groups also caused crowding and seemed to reduce access of (1)O(2) to the ethene site, which attenuated the total quenching rate constant k(T), although there was less wasted (1)O(2) (from surface physical quenching) at the fluorosilane-coated than the native SiOH silica. The observations support a quenching mechanism that the replacement of the SiOH groups for the fluorosilane C-H and C-F groups enhanced the (1)O(2) lifetime at the fiber tip interface due to less efficient electronic-to-vibronic energy transfer.     

The Isis problem as an experimental probe and teaching resource

The Isis problem, which has a link with the Isis cult of ancient Egypt, asks: “Find which rectangles with sides of integral length (in some unit) have area and perimeter (numerically) equal, and prove the result.” Since the solution requires minimal technical mathematics, the problem is accessible to a wide range of students. Further, it is notable for the variety of proofs (empirically grounded, algebraic, geometrical) using different forms of argument, and their associated representations, and it provides an instrument for probing students’ ideas about proof, and the interplay between routine and adaptive expertise. A group of 39 Flemish pre-service mathematics teachers was confronted with the Isis problem. More specifically, we first asked them to solve the problem and to look for more than one solution. Second, we invited them to study five given contrasting proofs and to rank these proofs from best to worst. The results highlight a preference of many students for algebraic proofs as well as their rejection of experimentation. The potential of the problem as a teaching tool is outlined.     

“Pointsource” Delivery of a Photosensitizer Drug and Singlet Oxygen: Eradication of Glioma Cells In Vitro

We describe a pointsource sensitizer‐tipped microoptic device for the eradication of glioma U87 cells. The device has a mesoporous fluorinated silica tip which emits singlet oxygen molecules and small quantities of pheophorbide sensitizer for additional production of singlet oxygen in the immediate vicinity. The results show that the device surges in sensitizer release and photokilling with higher rates about midway through the reaction. This was attributed to a self‐amplified autocatalytic reaction where released sensitizer in the extracellular matrix provides positive feedback to assist in the release of additional sensitizer. The photokilling of the glioma cells was analyzed by global toxicity and live/dead assays, where a killing radius around the tip with ~0.3 mm precision was achieved. The implication of these results for a new PDT tool of hard‐to‐resect tumors, e.g. in the brain, is discussed.