Identification of Proteolysis Targeting Chimeras (PROTACs) for Lysine Demethylase 5 and Their Neurite Outgrowth-Promoting Activity.

Lysine demethylase 5 (KDM5) proteins are involved in various neurological disorders, including Alzheimer's disease, and KDM5 inhibition is expected to be a therapeutic strategy for these diseases. However, the pharmacological effects of conventional KDM5 inhibitors are insufficient, as they only target the catalytic functionality of KDM5. To identify compounds that exhibit more potent pharmacological activity, we focused on proteolysis targeting chimeras (PROTACs), which degrade target proteins and thus inhibit their entire functionality. We designed and synthesized novel KDM5 PROTAC candidates based on previously identified KDM5 inhibitors. The results of cellular assays revealed that two compounds, 20b and 23b, exhibited significant neurite outgrowth-promoting activity through the degradation of KDM5A in neuroblastoma neuro 2a cells. These results suggest that KDM5 PROTACs are promising drug candidates for the treatment of neurological disorders.

The effect of dexmedetomidine, remifentanil and metoral in reducing patient bleeding during rhinoplasty surgery.

INTRODUCTION: Rhinoplasty is one of the most common surgeries in the ENT department. Rhinoplasty hemorrhage is one of the complications that different strategies have been used to reduce it. Reduction of bleeding reduces the risk of complications such as hemolytic and non-hemolytic reactions, acute lung damage, viral and bacterial infections, hypothermia and coagulation disorders. Therefore, the aim of this study was to compare the effect of dexmedetomidine, remifentanil and metoral in reducing patient bleeding during rhinoplasty surgery. MATERIALS AND METHODS: This randomized, double-blind trial was performed on rhinoplasty patients. Rhinoplasty candidates who had the inclusion and exclusion criteria were divided into three groups of remifentanil, metoral and dexmedetomidine according to the random number table. Then 0.5 mg/kg/h of dexmedetomidine in the first group was administered, followed by 100-150 kg/h remifentanil in the second group and 50 mg metoral in the third group. Mean blood pressure, heart rate, mean bleeding and surgeon satisfaction were recorded in designed form. Data were analyzed by Spss-22 software. RESULTS: The mean blood pressure of patients in remifentanil group was lower than the other two groups (P = 0.03). In all three times during surgery, recovery and overall time, the amount of bleeding in the remifentanil group was found to be less than the other two groups. Furthermore, the rate of bleeding in the dexmedetomidine group was found to be less than the metoral group (P = 0.03, P = 0.02). The surgeon's satisfaction score in the remifentanil group was higher than the other two groups. Satisfaction score was higher in dexmedetomidine group than metoral group (P = 0.03). The recovery time in the metoral group was shorter than the other two groups (P = 0.02). CONCLUSION: Remifentanil caused a good and appropriate reduction of blood pressure in rhinoplasty surgery, causing less bleeding and higher satisfaction.

SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer's Disease.

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer's disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1ß, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms.

Because the overexpression of histone deacetylase enzymes (HDACs) has been linked to numerous diseases, including various cancers and neurodegenerative disorders, HDAC inhibitors have emerged as promising therapeutic agents. However, most HDAC inhibitors lack both subclass and isoform selectivity, which leads to potential toxicity. Unlike classical hydroxamate HDAC inhibitors, slow-binding HDAC inhibitors form tight and prolonged bonds with HDAC enzymes. This distinct mechanism of action improves both selectivity and toxicity profiles, which makes slow-binding HDAC inhibitors a promising class of therapeutic agents for various diseases. Therefore, the development of slow-binding HDAC inhibitors that can effectively target a wide range of HDAC isoforms is crucial. This Perspective provides valuable insights into the potential and progress of slow-binding HDAC inhibitors as promising drug candidates for the treatment of various diseases.

Glottal Function Index: Validity and Reliability of the Persian Language Version in Patients With Voice Disorders.

OBJECTIVE: To translate and cross-culturally adapt the Glottal Function Index into the Persian language (GFIp) and validate it in patients with voice disorders. STUDY DESIGN: A cross-sectional and prospective validation design was adopted. METHOD: The GFI was translated and culturally adapted into Persian language according to the methodology of standard forward-backward translations to obtain semantic, idiomatic, and conceptual equivalence. One hundred patients with voice disorders (53 men; mean age: 41.4 ± 13.6 years) and 40 healthy volunteers (21 women; mean age: 36.7 ± 10.0 years) completed the GFIp. Patients with voice disorders also completed the Persian Voice Handicap Index (VHIp) to assess the construct validity. RESULTS: There were no floor and ceiling effects. Evidence for construct validity was found with a significant very good correlation between the GFIp and the VHIp total scores (r = 0.70; P < 0.001). Differences of GFIp scores between the patients and healthy participants were statistically significant (P < 0.001) confirming discriminant validity. The internal consistency reliability was acceptable for GFIp (Cronbach's α = 0.74). Absolute reliability measures of Standard Error of Measurement and the Smallest Detectable Change for GFIp were 2.5 (confidence interval 95% = ±4.9) and 6.93, respectively. Factor analysis revealed the GFIp as a single factor instrument. CONCLUSION: The GFIp is a valid and reliable self-administered instrument for use in Persian-speaking patients with voice disorders.

Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates.

Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1, 9, and 32, conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs.

Synthetic RNA Modulators in Drug Discovery.

RNAs are involved in an enormous range of cellular processes, including gene regulation, protein synthesis, and cell differentiation, and dysfunctional RNAs are associated with disorders such as cancers, neurodegenerative diseases, and viral infections. Thus, the identification of compounds with the ability to bind RNAs and modulate their functions is an exciting approach for developing next-generation therapies. Numerous RNA-binding agents have been reported over the past decade, but the design of synthetic molecules with selectivity for specific RNA sequences is still in its infancy. In this perspective, we highlight recent advances in targeting RNAs with synthetic molecules, and we discuss the potential value of this approach for the development of innovative therapeutic agents.

Synthesis of tetrazolo[1,5-a]pyrimidine-6-carbonitriles using HMTA-BAIL@MIL-101(Cr) as a superior heterogeneous catalyst.

A one-pot three component reaction of benzaldehydes, 1H-tetrazole-5-amine, and 3-cyanoacetyl indole in the presence of a new hexamethylenetetramine-based ionic liquid/MIL-101(Cr) metal-organic framework as a recyclable catalyst was explored. This novel catalyst, which was fully characterized by XRD, FE-SEM, EDX, FT-IR, TGA, BET, and TEM exhibited outstanding catalytic activity for the preparation of a range of pharmaceutically important tetrazolo[1,5-a]pyrimidine-6-carbonitriles with good to excellent yields in short reaction time.

Comparison of the Effect of Dexmedetomidine and Remifentanil on Controlled Hypotension During Rhinoplasty: A Clinical Trial Study.

INTRODUCTION: One of the most important problems during cosmetic nose surgery is excessive bleeding. Controlled hypotension is an appropriate technique for reducing intraoperative bleeding as well as satisfactory and non-bloody surgical field. Different drugs, such as dexmedetomidine and remifentanil, are used to control hypotension. The aim of this study was to compare the effect of dexmedetomidine and remifentanil on the creation of control hypotension during rhinoplasty. MATERIAL AND METHOD: This study is a randomized, double-blind clinical trial which was performed on 60 patients randomly divided into two groups D (Dexmedetomidine) and R (Remifentanil). In group D (0.5 mg / kg / h) Dexmedetomidine infusion and in group R (50-100 µg / kg / h) Remifentanil infusion. The study groups were compared in terms of hemodynamics and intraoperative bleeding. The data obtained from completed questionnaires were analyzed using SPSS software, T-test and ANOVA statistical tests and were presented in tables and statistical charts. RESULTS: The results of this study showed that the mean MAP (Mean Arterial Pressure) was significantly lower in remifentanil group patients than in dexmedetomidine group, while the intraoperative bradycardia rate was different at various time. CONCLUSION: During rhinoplasty surgery, both dexmedetomidine and remifentanil were effective in controlling hypotension and reducing intraoperative bleeding, but the effect of remifentanil was more pronounced than dexmedetomidine.

Divergent Pd-catalyzed cross-coupling of allenyloxazolidinones to give chiral 1,3-dienes and vinyloxazolidinones.

The divergent reactivity of 5-allenyloxazolidinones has been explored. This novel building block undergoes Pd(0)-catalyzed cross-coupling with boronic acids to form a wide range of chiral 1,3-dienes and pharmaceutically useful vinyloxazolidinones, the chemoselectivity being tightly controlled by a simple switch in additive.

Dual Gold-Catalyzed Cycloaromatization of Unconjugated (E)-Enediynes.

A synthesis of unconjugated (E)-enediynes from allenyl amino alcohols is reported and their gold-catalyzed cascade cycloaromatization to a broad range of enantioenriched substituted isoindolinones has been developed. Experimental and computational studies support the reaction proceeding via a dual-gold σ,π-activation mode, involving a key gold-vinylidene- and allenyl-gold-containing intermediate.

Oxazolidinones and 2,5-Dihydrofurans via Zinc-Catalyzed Regioselective Allenylation Reactions of l-α-Amino Aldehydes.

The simultaneous control of diastereoselectivity and regioselectivity in Zn-catalyzed allenylation reactions of N-protected l-α-amino aldehydes is reported. A reversal in diastereoselectivity could be realized by variation of the α-amino aldehyde protecting groups. A range of 1-allenyl-2-amino alcohols were obtained with excellent regioselectivity and converted to oxazolidinones and dihydrofurans. Many of which could be isolated as single diastereoisomers and without significant erosion of ee, making this a practical catalytic synthesis of highly functionalized heterocycles.

Preparation and Catalytic Study on a Novel Amino-functionalized Silica-coated Cobalt Oxide Nanocomposite for the Synthesis of Some Indazoles.

In this research an efficient synthesis of a novel nanocomposite including SiO2@(3-aminopropyl)triethoxysilane-coated cobalt oxide (Co3O4) nanocomposite has been reported by three step method. The structure and magnetic characterization of Co3O4@SiO2@NH2 have been done by using various spectroscopic analyses which include FT-IR, X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy and vibrating sample magnetometry. Amino-functionalized SiO2 coated Co3O4 nanocomposite exhibited superparamagnetic behavior and strong magnetization at room temperature. The average crystallite sizes of the Co3O4 are 23.7 nm. The obtained magnetic nanocomposite showed excellent catalytic activity as a new heterogeneous magnetic catalyst for the synthesis of some indazole derivatives under mild reaction conditions along with high level of reusability.

Cr(III)-containing Fe3O4/mercaptopropanoic acid-poly(2-hydroxyethyl acrylate) nanocomposite: a highly active magnetic catalyst in solvent-free aerobic oxidation of alcohols.

In this study, polymer-grafted magnetic nanoparticles containing chromium(iii) ions incorporated onto Fe3O4/mercaptopropanoic acid-poly(2-hydroxyethyl acrylate) (Fe3O4/MPA-PHEA-Cr) was prepared via a simple and in situ method. The obtained magnetic nanocomposite exhibited a high catalytic activity and excellent selectivity in the aerobic oxidation of alcohols under solvent-free conditions. The magnetic catalyst could also be separated by an external magnet and reused seven times without any significant loss of activity/selectivity.