Synthesis of Functionalized Organosilicon Compounds/Distal Ketones via Ring-Opening Giese Addition of Cycloalkanols under Organophotocatalytic Conditions.

Visible-light-induced organophotocatalyzed ring-opening followed by remote Giese addition of tertiary cycloalkanols with ß-silylmethylene malonates has been developed under mild reaction conditions for the synthesis of organosilicon compounds, bearing a ketone group distally substituted with a silyl group with an additional dialkyl malonate functional handle in moderate to good yields (34-72%). The protocol also worked well with diverse Michael acceptors, such as alkylidene/benzylidene malonates, trifluoro methylidene malonate, benzylidene malononitrile, α-cyano-enone, and α-cyano vinyl sulfone, and delivered desired valuable distally functionalized ketones. To showcase the potential of the method, various synthetic transformations of the obtained product were also demonstrated.

Deoxyglucose-conjugated persistent luminescent nanoparticles for theragnostic application in fibrosarcoma tumor model.

Deoxyglucose conjugated nanoparticles with persistent luminescence have shown theragnostic potential. In this study, deoxyglucose-conjugated nano-particles with persistent luminescence properties were synthesized, and their theragnostic potential was evaluated in fibrosarcoma cancer cells and a tumor model. The uptake of nano-formulation was found to be higher in mouse fibrosarcoma (WEHI-164) cells cultured in a medium without glucose. Nanoparticles showed a higher killing ability for cancer cells compared to normal cells. A significant accumulation of nanoparticles to the tumor site in mice was evident by the increased tumor/normal leg ratio, resulting in a significant decrease in tumor volume and weight. Histopathological studies showed a significant decrease in the number of dividing mitotic cells but a greater number of apoptotic/necrotic cells in nanoparticle-treated tumor tissues, which was correlated with a lower magnitude of Ki-67 expression (a proliferation marker). Consequently, our results showed the potential of our nano-formulation for cancer theragnosis.

Multimodal Applications of Zinc Gallate-Based Persistent Luminescent Nanoparticles in Cancer Treatment: Tumor Margining, Diagnosis, and Boron Neutron Capture Therapy.

On the basis of the boron neutron capture therapy (BNCT) modality, we have designed and synthesized a zinc gallate (ZnGa2O4)-based nanoformulation for developing an innovative theranostic approach for cancer treatment. Initially, the (ZnGa1.995Cr0.005O4 or ZnGa2O4:(0.5%)Cr persistent luminescence nanoparticles (PLNPs) embedded on silica matrix were synthesized. Their surface functionalization was performed using organic synthesis strategies to attach the amine functional moieties which were further coupled with poly(vicinal diol). These diols were helpful for conjugation with 10B(OH)3, which subsequently served to couple with an in-house-synthesized variant of pH-(low)-insertion peptide (pHLIP) finally giving a tumor-targeting nanoformulation. Most importantly, the polymeric diols helped in conjugation of a substantial number of 10B to provide the therapeutic dose required for effective BNCT. This nanoformulation internalized substantially (∼80%) to WEHI-164 cancer cells within 6 h. Tumor homing studies indicated that the accumulation of this formulation at the acidic tumor site was within 2 h. The in vitro evaluation of the formulation against WEHI-164 cancer cells followed by neutron irradiation revealed its potent cytotoxicity with IC50 ∼ 25 µM. In the case of studies on animal models, the melanoma-induced C57BL/6 and fibrosarcoma-induced BALB/c mice were treated with formulations through intratumoral and intravenous injections, respectively, followed by neutron irradiation, leading to a significant killing of the cancer cells, which was evidenced by a reduction in tumor volume (75-80%) as compared with a control tumor. Furthermore, the histopathological studies confirmed a damaging effect only on tumor cells, while there was no sign of damage to the vital organs in treated mice as well as in controls.

Mesoporous Silica-Coated Upconversion Nanoparticles Assisted Photodynamic Therapy Using 5-Aminolevulinic Acid: Mechanistic and In Vivo Studies.

Exclusively red-emitting upconversion nanoparticles (UCNPs) with the composition NaErF4:0.5%Tm as a core and NaYF4 as a shell were synthesized for performing photodynamic therapy (PDT). A possible mechanism was proposed for core-shell UCNPs formation. For loading a maximum amount of 5-aminolevulinic acid (5-ALA), mesoporous silica coating was performed on UCNPs. Studies under dark conditions confirmed the biocompatibility of 5-ALA-loaded UCNPs formulation (UCNPs-5-ALA) with MCF-7 cells. Meanwhile, studies under light-exposed conditions exhibited effective cytotoxicity against MCF-7 cells. Studies employing D2O-based cell cultured media and addition of DABCO in cell culture established that the cell death was due to oxidation of cellular components by reactive oxygen species (ROS) triggering the apoptosis. The formation of ROS was confirmed by DCF(H)DA-based ROS analysis via fluorescence microscopy to demonstrate the ROS production, which mediates the programmed cell death. Additionally, we have validated the apoptosis in MCF-7 cells with flow cytometry analyses. This was further confirmed by an electrophoretic mobility shift assay on nuclear extract and measurement of mitochondrial membrane potential. In the case of animal model studies, the formulation UCNPs-5-ALA without irradiation (980 nm) did not possess any in vivo cytotoxicity on tumor-induced SCID mice and there was a minimum migration of UCNPs-5-ALA to the vital organs but maximum retention at the tumor site only. Meanwhile, only the mice treated with UCNPs-5-ALA and irradiated on the tumor region with 980 nm laser (500 mW) for 20 min possessed a tumor with a size reduced to about 75% as compared with the corresponding control groups. To the best of our knowledge, this type of study was conducted for the first time employing exclusively red-emitting phosphors for effective PDT.

Solvent-free synthesis of enantioenriched ß-silyl nitroalkanes under organocatalytic conditions.

An enantioselective 1,4-conjugate addition of nitromethane to ß-silyl α,ß-unsaturated carbonyl compounds catalyzed by bifunctional squaramide catalysts has been developed. This methodology offers both enantiomers of ß-silyl nitroalkanes in good to excellent yields (up to 92%) and enantioselectivities (up to 97.5% ee) under solvent-free conditions at room temperature. Control experiments reveal that the presence of a ß-silyl group in the enones is crucial for high reactivity under the optimized reaction conditions.

Ag(I)-Fesulphos-Catalyzed Enantioselective Synthesis of 3-Silylproline Derivatives.

An efficient catalytic asymmetric 1,3-dipolar cycloaddition of N-benzylidineiminoglycinate-derived azomethine ylides to ß-silylmethylene malonates catalyzed by a Ag(I)-Fesulphos complex has been developed, affording fully substituted 3-silylproline derivatives with an all carbon quaternary center. The silylproline derivatives were obtained in moderate-to-good yields (up to 81%) in high diastereoselectivities and enantioselectivities (dr up to 95:5; er up to 96:4). Tamao-Fleming oxidation of selected 3-silylproline derivatives provided not only an efficient route but also the shortest route to 3-hydroxyproline derivatives, which are not accessible by direct 1,3-dipolar cycloadditions of azomethine ylide with frequently used arylidene/alkylidene malonates.