Diazo-Transfer Reaction of Nonactivated Ketones with 2-Azido-1,3-bis(2,6-diisopropylphenyl)imidazolium Hexafluorophosphate (IPrAP).

The diazo-transfer reaction of nonactivated ketone under mild reaction conditions was developed. Various nonactivated ketones such as aryl methyl ketones, sec-alkyl methyl ketones, and cyclic ketones were transformed into their corresponding α-diazoketones in one step by treating 2-azido-1,3-bis(2,6-diisopropylphenyl)imidazolium hexafluorophosphate (IPrAP) in the presence of iPr2NH in ethylene glycol. In the reaction of IPrAP with prim-alkyl methyl ketone and prim-alkyl aryl ketones, migratory amidation proceeded under the reaction conditions to afford the corresponding amides.

Review of the Specific Features, and New Demands for Antibacterial Peptides.

The emergent disaster of antimicrobial resistance developed by virulent bacteria has highlighted the need to investigate substitutes for the presently existing antibiotics. Antibacterial peptides (ABPs) have arisen as promising substitutes because of their unique killing effect on bacteria: bacterial resistance toward ABPs is negligible. ABPs have many beneficial subsidiary effects, such as protection of labile bioactive compounds, and they can be covalently connected to different materials to enhance their antibacterial effect. Many researchers have investigated many applications of these peptides recently, such as in a variety of pharmaceutical dosage forms and wastewater treatment.

Synthesis, Derivatization and Photochemical Control of an ortho-Functionalized Tetrafluorinated Azobenzene-Modified siRNA.

We report the synthesis of an ortho-functionalized tetrafluorinated azobenzene phosphoramidite for its site-specific incorporation into RNA. The tetrafluorinated azobenzene is embedded within the antisense strand of an siRNA duplex to form an ortho-functionalized tetrafluorinated azobenzene-containing siRNA (F-siRNAzo). The F-siRNAzo is inactivated via trans to cis conversion with green light (530 nm), and reactivated with blue light (470 nm) via cis to trans conversion in cell culture. The long half-life and stability of the tetrafluorinated azobenzene unit allows for reversible control of the F-siRNAzo in cell culture for up 72 hours.

Building siRNAs with Cubes: Synthesis and Evaluation of Cubane-Modified siRNAs.

Cubane molecules hold great potential for medicinal chemistry applications due to their inherent stability and low toxicity. In this study, we report the synthesis of a cubane derivative phosphoramidite for the incorporation of cubane into small interfering RNAs (siRNAs). Synthetic siRNAs rely on chemical modifications to improve their pharmacokinetic profiles. However, they are still able to mediate sequence-specific gene silencing via the endogenous RNA interference pathway. We designed a library of siRNAs bearing cubane at different positions within the sense and antisense strands. All siRNAs showed excellent gene-silencing activity, with IC50 values ranging from 45.4 to 305 pM. Incorporating the cubane modification in both the sense and antisense strand led to viable duplexes with good biological activity. To the best of our knowledge, this is the first report of siRNAs bearing a cubane derivative within the backbone.

Management of tinnitus in patients with vestibular schwannoma who underwent surgical resection.

PURPOSE: To evaluate tinnitus and its management in patients with vestibular schwannoma (VS) who underwent surgery, we investigate the effect of surgical approach or residual hearing on tinnitus severity and the effects of intervention for tinnitus including educational counseling, sound therapy using hearing aids (HAs), and medication (selective serotonin reuptake inhibitors, and SSRIs). METHODS: Seventy-one subjects of VS patients who underwent surgery were included. Their tinnitus severity was evaluated using the Japanese version of the Tinnitus Handicap Inventory (THI). The relationships between postoperative THI scores and surgery types or residual hearing levels were examined. We also examined longitudinal changes in THI scores and the efficacy of the intervention. RESULTS: Surgery approach, hearing preservation or hearing loss surgery, and residual hearing levels were not significantly related to the postoperative tinnitus severity. In 71 cases, 45 cases did not require any management for tinnitus. On the contrary, 26 patients had at least one episode of tinnitus distress (THI score was greater than or equal to 18). Educational counseling alone was found to be effective in 17 cases out of the 26 cases, and the remaining 9 cases required more intervention than educational counseling alone. We selected sound therapy with HA for 7 cases and administration of SSRI for 2 cases, which was found to be highly effective in 8 cases. CONCLUSION: Based on the present study, we consider that appropriate management may be possible for tinnitus in the majority of VS patients who underwent surgery.

Design, Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives.

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.

Azidoimidazolinium Salts: Safe and Efficient Diazo-transfer Reagents and Unique Azido-donors.

2-Azido-1,3-dimethylimidazolinium chloride (ADMC) and its corresponding hexafluorophosphate (ADMP) were found to be efficient diazo-transfer reagents to various organic compounds. ADMC was prepared by the reaction of 2-chloro-1,3-dimethylimidazolinium chloride (DMC) and sodium azide. ADMP was isolated as a crystal having good thermal stability and low explosibility. ADMC and ADMP reacted with 1,3-dicarbonyl compounds under mild basic conditions to give 2-diazo-1,3-dicarbonyl compounds in high yields, which were easily isolated in virtue of the high water solubility of the by-products. ADMP showed high diazo-transfer ability to primary amines even in the absence of metal salt such as Cu(II). Using this diazotization approach, various alkyl/aryl azides were directly obtained from their corresponding primary amines in high yields. Furthermore, naphthols reacted with ADMC to give the corresponding diazonaphthoquinones in good to high yields. In addition, 2-azido-1,3-dimethylimidazolinium salts were employed as azide-transfer and migratory amidation reagents.

Axially Chiral Bifunctional 8,8'-Biquinolyl: Synthesis of 7,7'-Dihydroxymethyl-8,8'-biquinolyl via Pd-Catalyzed Double C-H Oxidation of 7,7'-Dimethyl-8,8'-biquinolyl.

Bifunctional C2-symmetric 7,7'-dihydroxymethyl-8,8'-biquinolyl (2) was synthesized in short steps via (i) Cu/Pd-catalyzed homo coupling of 7-methyl-8-bromoquinoline and (ii) Pd(II)-catalyzed double C-H oxidation. Axial chirality of 2 and its synthetic precursor 7,7'-dimethyl-8,8'-biquinolyl (3) is stable. Optically active 2 was obtained through separation of racemic 2 by chiral column HPLC or Pd(II)-catalyzed double C-H oxidation of optically active 3. The absolute stereochemistry of enantiomers of 2 and 3 was determined using the exciton chirality method.

Rh-Catalyzed Cyclization of 3-Aryloxycarbonyldiazonaphthoquinones for the Synthesis of ß-Phenylnaphthalene Lactones and Formal Synthesis of Pradimicinone.

In this study, we developed a novel method for the synthesis of ß-phenylnaphthalene lactones. The diazo-transfer reactions of 2-azido-1,3-dimethylimidazolinium chlorides to 3-aryloxycarbonyl-1-naphthols proceeded smoothly to give corresponding 3-aryloxycarbonyldiazonaphthoquinones in high yields. These intermediates were further transformed to ß-phenylnaphthalene lactones through a Rh-catalyzed intramolecular formal C-H insertion reaction. This method of lactone formation was efficiently applied to the formal total synthesis of pradimicinone.

A reagent for safe and efficient diazo-transfer to primary amines: 2-azido-1,3-dimethylimidazolinium hexafluorophosphate.

Organic azides were prepared from primary amines in high yields by a metal free diazo-transfer reaction using 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), which is safe and stable crystalline. The choice of base was important in the diazo-transfer reaction. In general, 4-(N,N-dimethyl)aminopyridine (DMAP) was efficient, but a stronger base such as alkylamine or DBU was more appropriate for the reaction of nucleophilic primary amines. X-ray single crystal structural analysis and geometry optimization using density functional theory (B3LYP/6-31G**) were conducted to study the ADMP structure, and the diazo-transfer reaction mechanism was explained with the help of the results of these analyses.

Identification of compounds with potential antibacterial activity against Mycobacterium through structure-based drug screening.

To identify novel antibiotics against Mycobacterium tuberculosis, we performed a hierarchical structure-based drug screening (SBDS) targeting the enoyl-acyl carrier protein reductase (InhA) with a compound library of 154,118 chemicals. We then evaluated whether the candidate hit compounds exhibited inhibitory effects on the growth of two model mycobacterial strains: Mycobacterium smegmatis and Mycobacterium vanbaalenii. Two compounds (KE3 and KE4) showed potent inhibitory effects against both model mycobacterial strains. In addition, we rescreened KE4 analogs, which were identified from a compound library of 461,383 chemicals through fingerprint analysis and genetic algorithm-based docking simulations. All of the KE4 analogs (KES1-KES5) exhibited inhibitory effects on the growth of M. smegmatis and/or M. vanbaalenii. Based on the predicted binding modes, we probed the structure-activity relationships of KE4 and its analogs and found a correlative relationship between the IC50 values and the interaction residues/LogP values. The most potent inhibitor, compound KES4, strongly and stably inhibited the long-term growth of the model bacteria and showed higher inhibitory effects (IC50 = 4.8 µM) than isoniazid (IC50 = 5.4 µM), which is a first-line drug for tuberculosis therapy. Moreover, compound KES4 did not exhibit any toxic effects that impede cell growth in several mammalian cell lines and enterobacteria. The structural and experimental information of these novel chemical compounds will likely be useful for the development of new anti-TB drugs. Furthermore, the methodology that was used for the identification of the effective chemical compound is also likely to be effective in the SBDS of other candidate medicinal drugs.

Synthesis of an Ortho-Functionalized Tetrafluorinated Azobenzene Phosphoramidite for Incorporation into a Tetrafluorinated Azobenzene-Containing siRNA for Photocontrolled Gene Silencing.

This article presents the detailed synthesis and characterization protocols for an ortho-functionalized tetrafluorinated azobenzene containing siRNA, which has photoswitchable properties. To design this tetrafluorinated azobenzene scaffold, several synthetic steps are performed to generate a symmetrical tetrafluorinated azobenzene diol. This diol is treated with dimethoxytrityl chloride (DMT-Cl) to protect one of the alcohols. Next, the DMT-protected tetrafluorinated monoalcohol is phosphitylated to afford the DMT-phosphoramidite building block used for solid-phase synthesis. This paper also contains the detailed biophysical characterization, biological testing, and photo-switching protocols of an ortho-functionalized fluorinated azobenzene containing siRNA (F-siRNA), which has photoswitchable properties that can be controlled with visible light. First, the F-siRNA was characterized by annealing the sense and antisense strands together and then measuring the circular dichroism (CD) profile and melting temperature (Tm ) of the duplexes. Second, biological testing of the F-siRNA is performed in cell culture to determine their gene silencing efficacy. Finally, their gene-silencing activities are measured after exposure to green light to inactivate the F-siRNA, followed by blue light, which reactivates the F-siRNA. The F-siRNA can be kept inactive for up to 72 hr and reactivated at any time within this 72-hr window. © 2023 Wiley Periodicals LLC.

Synthesis of Dinucleotide Non-Symmetrical Triester Phosphate Phosphoramidites and Their Incorporation Within Oligonucleotides.

In this protocol article, the synthesis of dinucleotide non-symmetrical triester phosphate phosphoramidites will be highlighted. Specifically, we use a selective transesterification starting with tris(2,2,2-trifluoroethyl) phosphate to afford a dinucleotide derivative phosphate ester. Substitution of the final trifluoroethyl group with various alcohols affords a dinucleotide triester phosphate with a hydrophobic group, which can then be deprotected and converted to a phosphoramidite for incorporation within oligonucleotides. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of a DMT- and TBS-protected unsymmetrical dinucleotide Basic Protocol 2: Synthesis of a DMT-protected unsymmetrical dinucleotide phosphotriester monoalcohols Basic Protocol 3: Synthesis of DMT-protected phenylethyl phosphotriester dinucleotide phosphoramidites Basic Protocol 4: Synthesis, purification, and characterization of RNAs containing triester phosphate modifications.

Intracochlear signal in FIESTA-C and hearings of patients with cerebellopontine angle schwannoma.

BACKGROUND: Hearing loss in patients with cerebellopontine angle (CPA) schwannoma, is thought to be caused by the damage to the cochlea and the cochlear nerve. AIM: This study aimed to examine the relationships between the intracochlear signal in magnetic resonance imaging (MRI) and hearing in patients with CPA schwannoma. MATERIAL AND METHOD: In 79 patients with CPA schwannoma, we retrospectively examined the signal in the cochlea on the affected side was compared with that on the unaffected side to determine signal degradation in fast imaging reagents steady-state acquisition with cycle phases (FIESTA-C) MRI. For hearing evaluation, pure tone audiometry (PTA), speech audiometry, distortion product otoacoustic emissions (DPOAE), and auditory brainstem response (ABR) were used. For each parameter, we examined the differences between the groups with and without signal degradation. RESULTS: In the hearing test results, the I-wave latency of ABR was significantly longer in the group with signal degradation in FIESTA-C (1.84 ± 0.35 msec vs. 2.04 ± 0.37 msec, p = 0.048). There was no statistically significant difference in other tests. CONCLUSION: The MRI signal changes in the cochlear were related to the I-wave latency of ABR and reflected cochlear function. SIGNIFICANCE: We suggested the cochlear signal changes in CPA schwannoma patients related the hearing.

Effective cochlear implantation for idiopathic hypertrophic pachymeningitis with bilateral profound hearing loss: A case report.

RATIONALE: Hypertrophic pachymeningitis (HP) is a local or diffuse fibrous thickness of the dura mater of the brain or spinal cord, caused by infection or connective tissue disease. Headache is the most common clinical symptom, followed by various cranial nerve disorders such as visual impairment, diplopia, and hearing loss. HP can be classified into secondary and idiopathic. Here, we report a case of bilateral progressive profound sensorineural hearing loss diagnosed in a patient with idiopathic HP, where a cochlear implant was effectively used. PATIENT CONCERNS: The patient was a 77-year-old woman. Hearing loss gradually progressed bilaterally, and magnetic resonance imaging showed a space-occupying lesion with a continuous contrast enhancement in the bilateral internal auditory canals, and diffused dural thickening from the middle to the posterior cranial fossa. DIAGNOSES: A trans-labyrinthine biopsy was conducted, and a definite diagnosis of idiopathic HP was made. Thickening of the dura mater in the bilateral internal auditory canals was thought to cause profound hearing loss. INTERVENTIONS AND OUTCOMES: A cochlear implant was implemented 4 months after biopsy, and a favorable hearing response was obtained postoperatively. LESSONS: This is the first report of a cochlear implant in a patient with idiopathic HP. Cochlear implantation was considered a good treatment for profound hearing loss due to idiopathic HP, which provides a reference for patients to receive timely and correct treatment.

Design optimization of functionally graded lattice infill total hip arthroplasty stem for stress shielding reduction.

Reducing stress shielding of stem-inserted femurs in total hip arthroplasty caused by the high stiffness of the stem is an emerging medical engineering issue. In this study, a numerical design optimization methodology lattice infill stem was developed to realize a stem, balancing the low stiffness and strength requirements. Two pairs of models and loading conditions were introduced for the stress shielding and strength criteria. The objective function was set as the weighted sum of the criteria. Its effective density distribution was optimized by handling the representative size of the lattice as a design variable, assuming that the so-called body-centered cubic lattice was the base shape of the lattice. In the optimization, the approximated model of the lattice was handled as a solid material with the effective physical properties of the lattice derived by the homogenization method. After optimization, the detailed lattice stem geometry was modeled based on the obtained optimal lattice distribution, and the actual performance was numerically evaluated. The developed stem increased the stress applied to the remaining femur by 32.4% compared with the conventional stem.

SiRNAs with Neutral Phosphate Triester Hydrocarbon Tails Exhibit Carrier-Free Gene-Silencing Activity.

Short interfering RNAs (siRNAs) show promise as gene-silencing therapeutics, but their cellular uptake remains a challenge. We have recently shown the synthesis of siRNAs bearing a single neutral phenylethyl phosphotriester linkage within the sense strand. Here, we report the synthesis of siRNAs bearing three different hydrophobic phosphate triester linkages at key positions within the sense strand and assess their gene silencing in the absence of a transfection carrier. The best siRNAs bearing hydrophobic phosphate triester tails were not aromatic and exhibited effective gene silencing (IC50 ≈ 56-141 nM), whereas the aromatic derivative with three hydrophobic tails did not exhibit carrier-free gene silencing.

1-Diazo-naphthalen-2(1H)-one.

The mol-ecule of the title compound, C(10)H(6)N(2)O, is nearly planar [maximum deviation = 0.030 (1) Å]. The CN(2) moiety is almost linear, with a C-N-N angle of 175.50 (14)°. A single inter-molecular C-H⋯O hydrogen bond is observed in the crystal structure. A π-π inter-action is also observed with the shortest distance being 3.6832 (12) Šbetween the the centroids of the six-membered rings.

A Case Report of a Middle Ear Mass Originated From Cartilage-like Tissue Treated With Transcanal Endoscopic Ear Surgery.

Middle ear tumors are relatively rare, and among them, the diagnoses of middle ear lesions originating from cartilage-like tissue are even rarer. Use of transcanal endoscopic ear surgery (TEES) has increased in recent years because of its advantages, such as clear visual field and minimally invasive procedure. Here, we report a middle ear mass originating from cartilage-like tissue treated with TEES. A 62-year-old woman presented with progressive right-sided hearing loss. A white mass was revealed through the tympanic membrane, and pure-tone audiometry detected a mean 50.0 dB conductive hearing loss. Computed tomography showed a mass in the tympanic cavity. TEES was performed for diagnosis and treatment. A white translucent tumor was observed intraoperatively, and it was completely resected. Histopathological examination confirmed the diagnosis of a mass originating from degenerated cartilage-like tissue. To the best of our knowledge, this is the first study of a middle ear mass originating from cartilage-like tissue treated with TEES. TEES with its clear visual field and precise techniques was beneficial in treating the middle ear lesions circumscribed in the tympanic cavity.

Nanophotonic code embedded in embossed hologram for hierarchical information retrieval.

A hierarchical hologram works in both optical far-fields and near-fields, the former being associated with conventional holographic images, and the latter being associated with the optical intensity distribution based on a nanometric structure that is accessible only via optical near-fields. We propose embedding a nanophotonic code, which is retrievable via optical near-field interactions involving nanometric structures, within an embossed hologram. Due to the one-dimensional grid structure of the hologram, evident polarization dependence appears in retrieving the code. Here we describe the basic concepts, numerical simulations, and experimental results in fabrication of a prototype hierarchical hologram and describe its optical characterization.