Radiolabeling and preclinical animal model evaluation of DTPA coupled 99mTc-labelled flutamide complex ([99mTc]DTPA-FLUT) as a potential radiotracer for cancer imaging.

BACKGROUND: Advances in molecular imaging strategies have had an effect on precise diagnosis and treatment. Research has been intensified to develop more effective and versatile radiopharmaceuticals to uplift diagnostic efficiency and, consequently, the treatment. PURPOSE: To label the flutamide (FLUT) coupled with diethylenetriamine pentaacetate (DTPA) with technetium-99 m (99mTc) and to evaluate its binding efficiency with rhabdomyosarcoma (RMS) cancer cells. MATERIAL AND METHODS: Radiolabeling of FLUT with 185 MBq freshly eluted 99mTcO4-1 was carried out via DTPA bifunctional chelating agent using stannous chloride reducing agent at pH 5. The labeled compound was assessed for its purity using chromatography analysis, stability in saline and blood serum, AND charge using paper electrophoresis. Normal biodistribution was studied using a mouse model, while binding affinity with RMS cancer cells was studied using an internalization assay. The in vivo accumulation of RMS cancer cells in a rabbit model was monitored using a SPECT gamma camera. RESULTS: Radiolabeling reaction displayed a pharmaceutical yield of 97% and a stability assay showed >95% intact radiopharmaceutical up to 6 h in saline and blood serum. In vitro internalization studies showed the potential of [99mTc]DTPA-FLUT to enter into cancer cells. This biodistribution study showed rapid blood clearance and minimum uptake by body organs, and scintigraphy displayed the [99mTc]DTPA-FLUT uptake by lesion, induced by RMS cancer cell lines in rabbit. CONCLUSION: Stable, newly developed [99mTc]DTPA-FLUT seeks its way to internalize into RMS cancer cells, indicating it could be a potential candidate for the diagnosis of RMS cancer.

Efficient chromium removal from leather industrial wastewater in batch experimental study: Green synthesis and characterization of zinc oxide nanoparticles using Ficus benghalensis extracts.

The urgent need to address the severe environmental risk posed by chromium-contaminated industrial wastewater necessitates the development of eco-friendly cleanup methodologies. Utilizing the Ficus benghalensis plant extracts, the present study aims to develop green zinc oxide nanoparticles for the removal of Cr metal ions from wastewater. The leaves of Ficus benghalensis, often known as the banyan tree, were used to extract a solution for synthesizing ZnO NPs. These nanoparticles were developed with the goal of efficiently eliminating chromium (Cr) from industrial effluents. Batch studies were carried out to assess the efficiency of these synthesized ZnO NPs in treating leather industrial effluent, with aiming for optimal chromium removal. This involved measuring the nanoparticles' capacity to adsorb Cr ions from wastewater samples by comparing chromium levels before and after treatment. Removal efficiency for Cr was estimated through the batches such as optimization of pH, contact time, initial Cr concentration and sorbent dose of ZnO NPs were of the batches. These synthesized ZnO NPs were found to be successful in lowering chromium levels in wastewater to meet permissible limit. The nanoparticles exhibited their highest absorption capacity, reaching 94 % (46 mg/g) at pH 4, with a contact time of 7 hours with the optimum sorbent dose of 0.6 g/L. Hence, the excellent adsorption capabilities of these nanoparticles, together with their environmentally benign manufacturing technique, provide a long-term and efficient solution for chromium-contaminated wastewater treatment. Its novel nature has the potential to significantly improve the safety and cleanliness of water ecosystems, protecting the both i.e. human health and the environment.

BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies.

In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3ß, AKT, and Tubulin polymerization enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and BF-6 displayed the best anti-cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2 liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and Tubulin polymerization enzymes, which are major cancer targets. Bromobenzofuran-oxadiazoles BF-2, BF-5, and BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and Tubulin polymerization enzymes in the molecular docking studies as well as in MMGBSA and MM-PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and BF-6 with the enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and Tubulin polymerization enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental biological data of bromobenzofuran-oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-oxadiazole hybrid BF-5 possesses prominent anti-liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2 liver cancer therapy.

Synthetic Potential of Regio- and Stereoselective Ring Expansion Reactions of Six-Membered Carbo- and Heterocyclic Ring Systems: A Review.

Ring expansion reactions fascinate synthetic chemists owing to their importance in synthesizing biologically active compounds and their efficacy in medicinal chemistry. The present review summarizes a number of synthetic methodologies, including stereoselective and regioselective pathways adopted by scientists, for framing medium- to large-size carbo- and heterocycles involving lactams, lactone, azepine and azulene derivatives via ring expansion of six-membered carbo- and heterocycles that have been reported from 2007-2022. Numerous rearrangement and cycloaddition reactions involving Tiffeneau-Demjanov rearrangement, Aza-Claisen rearrangement, Schmidt rearrangement, Beckmann rearrangement, etc., have been described in this regard.

Unfolding the Antibacterial Activity and Acetylcholinesterase Inhibition Potential of Benzofuran-Triazole Hybrids: Synthesis, Antibacterial, Acetylcholinesterase Inhibition, and Molecular Docking Studies.

In this study, a series of novel benzofuran-based 1,2,4-triazole derivatives (10a-e) were synthesized and evaluated for their inhibitory potential against acetylcholinesterase (AChE) and bacterial strains (E. coli and B. subtilis). Preliminary results revealed that almost all assayed compounds displayed promising efficacy against AChE, while compound 10d was found to be a highly potent inhibitor of AChE. Similarly, these 5-bromobenzofuran-triazoles 10a-e were screened against B. subtilis QB-928 and E. coli AB-274 to evaluate their antibacterial potential in comparison to the standard antibacterial drug penicillin. Compound 10b was found to be the most active among all screened scaffolds, with an MIC value of 1.25 ± 0.60 µg/mL against B. subtilis, having comparable therapeutic efficacy to the standard drug penicillin (1 ± 1.50 µg/mL). Compound 10a displayed excellent antibacterial therapeutic efficacy against the E. coli strain with comparable MIC of 1.80 ± 0.25 µg/mL to that of the commercial drug penicillin (2.4 ± 1.00 µg/mL). Both the benzofuran-triazole molecules 10a and 10b showed a larger zone of inhibition. Moreover, IFD simulation highlighted compound 10d as a novel lead anticholinesterase scaffold conforming to block entrance, limiting the swinging gate, and disrupting the catalytic triad of AChE, and further supported its significant AChE inhibition with an IC50 value of 0.55 ± 1.00 µM. Therefore, compound 10d might be a promising candidate for further development in Alzheimer's disease treatment, and compounds 10a and 10b may be lead antibacterial agents.

Simmons-Smith Cyclopropanation: A Multifaceted Synthetic Protocol toward the Synthesis of Natural Products and Drugs: A Review.

Simmons-Smith cyclopropanation is a widely used reaction in organic synthesis for stereospecific conversion of alkenes into cyclopropane. The utility of this reaction can be realized by the fact that the cyclopropane motif is a privileged synthetic intermediate and a core structural unit of many biologically active natural compounds such as terpenoids, alkaloids, nucleosides, amino acids, fatty acids, polyketides and drugs. The modified form of Simmons-Smith cyclopropanation involves the employment of Et2Zn and CH2I2 (Furukawa reagent) toward the total synthesis of a variety of structurally complex natural products that possess broad range of biological activities including anticancer, antimicrobial and antiviral activities. This review aims to provide an intriguing glimpse of the Furukawa-modified Simmons-Smith cyclopropanation, within the year range of 2005 to 2022.

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review.

Sharpless asymmetric dihydroxylation is an important reaction in the enantioselective synthesis of chiral vicinal diols that involves the treatment of alkene with osmium tetroxide along with optically active quinine ligand. Sharpless introduced this methodology after considering the importance of enantioselectivity in the total synthesis of medicinally important compounds. Vicinal diols, produced as a result of this reaction, act as intermediates in the synthesis of different naturally occurring compounds. Hence, Sharpless asymmetric dihydroxylation plays an important role in synthetic organic chemistry due to its undeniable contribution to the synthesis of biologically active organic compounds. This review emphasizes the significance of Sharpless asymmetric dihydroxylation in the total synthesis of various natural products, published since 2020.

Unveiling the Chemistry and Synthetic Potential of Catalytic Cycloaddition Reaction of Allenes: A Review.

Allenes with two carbon-carbon double bonds belong to a unique class of unsaturated hydrocarbons. The central carbon atom of allene is sp hybridized and forms two σ-bonds and two π-bonds with two terminal sp2 hybridized carbon atoms. The chemistry of allenes has been well documented over the last decades. They are more reactive than alkenes due to higher strain and exhibit significant axial chirality, thus playing a vital role in asymmetric synthesis. Over a variety of organic transformations, allenes specifically undergo classical metal catalyzed cycloaddition reactions to obtain chemo-, regio- and stereoselective cycloadducts. This review briefly describes different types of annulations including [2+2], [2+2+1], [3+2], [2+2+2], [4+2], [5+2], [6+2] cycloadditions using titanium, cobalt, rhodium, nickel, palladium, platinum, gold and phosphine catalyzed reactions along with a mechanistic study of some highlighted protocols. The synthetic applications of these reactions towards the synthesis of natural products such as aristeromycin, ent-[3]-ladderanol, waihoensene(-)-vindoline and (+)-4-epi-vindoline have also been described.

The Corey-Seebach Reagent in the 21st Century: A Review.

The Corey-Seebach reagent plays an important role in organic synthesis because of its broad synthetic applications. The Corey-Seebach reagent is formed by the reaction of an aldehyde or a ketone with 1,3-propane-dithiol under acidic conditions, followed by deprotonation with n-butyllithium. A large variety of natural products (alkaloids, terpenoids, and polyketides) can be accessed successfully by utilizing this reagent. This review article focuses on the recent contributions (post-2006) of the Corey-Seebach reagent towards the total synthesis of natural products such as alkaloids (lycoplanine A, diterpenoid alkaloids, etc.), terpenoids (bisnorditerpene, totarol, etc.), polyketide (ambruticin J, biakamides, etc.), and heterocycles such as rodocaine and substituted pyridines, as well and their applications towards important organic synthesis.

Recent Trends in the Petasis Reaction: A Review of Novel Catalytic Synthetic Approaches with Applications of the Petasis Reaction.

The Petasis reaction, also called the Petasis Borono-Mannich reaction, is a multicomponent reaction that couples a carbonyl derivative, an amine and boronic acids to yield substituted amines. The reaction proceeds efficiently in the presence or absence of a specific catalyst and solvent. By employing this reaction, a diverse range of chiral derivatives can easily be obtained, including α-amino acids. A broad substrate scope, high yields, distinct functional group tolerance and the availability of diverse catalytic systems constitute key features of this reaction. In this review article, attention has been drawn toward the recently reported methodologies for executing the Petasis reaction to produce structurally simple to complex aryl/allyl amino scaffolds.

Recent trends in the chemistry of Sandmeyer reaction: a review.

Metal-catalyzed reactions play a vital part to construct a variety of pharmaceutically important scaffolds from past few decades. To carry out these reactions under mild conditions with low-cost easily available precursors, various new methodologies have been reported day by day. Sandmeyer reaction is one of these, first discovered by Sandmeyer in 1884. It is a well-known reaction mainly used for the conversion of an aryl amine to an aryl halide in the presence of Cu(I) halide via formation of diazonium salt intermediate. This reaction can be processed with or without copper catalysts for the formation of C-X (X = Cl, Br, I, etc.), C-CF3/CF2, C-CN, C-S, etc., linkages. As a result, corresponding aryl halides, trifluoromethylated compounds, aryl nitriles and aryl thioethers can be obtained which are effectively used for the construction of biologically active compounds. This review article discloses various literature reports about Sandmeyer-related transformations developed during 2000-2021 which give different ideas to synthetic chemists about further development of new and efficient protocols for Sandmeyer reaction. An updated compilation of new approaches for Sandmeyer reaction is described in this review to construct a variety of carbon-halogen, carbon-phosphorous, carbon-sulfur, carbon-boron etc. linkages.

Fukuyama reduction, Fukuyama coupling and Fukuyama-Mitsunobu alkylation: recent developments and synthetic applications.

Fukuyama reaction for the synthesis of multifunctional aldehydes, secondary amines and ketones has gained considerable importance in synthetic organic chemistry because of mild reaction conditions. The use of thioesters in both Fukuyama aldehydes and ketones synthesis is highly attractive for organic chemists as they are easily accessible from corresponding carboxylic acids. Fukuyama-Mitsunobu reaction utilizes 2-nitrobenzenesulfonyl (Ns) for the protection/activation/deprotection of primary amines to afford secondary amines in good yields and high enantioselectivities. This review presents recent synthetic developments and applications of Fukuyama reaction for the synthesis of aldehydes, secondary amines and ketones.

Cross-coupling reactions towards the synthesis of natural products.

Cross-coupling reactions are powerful synthetic tools for the formation of remarkable building blocks of many naturally occurring molecules, polymers and biologically active compounds. These reactions have brought potent transformations in chemical and pharmaceutical disciplines. In this review, we have focused on the use of cross-coupling reactions such as Suzuki, Negishi, Heck, Sonogashira and Stille in the total synthesis of some natural products of recent years (2016-2020). A short introduction of mentioned cross-coupling reactions along with highlighted aspects of natural products has been stated in separate sections. Additionally, few examples of natural products via incorporation of more than one type of cross-coupling reaction have also been added to demonstrate the importance of these reactions in organic synthesis.

Ultrasonic-Assisted Synthesis of Benzofuran Appended Oxadiazole Molecules as Tyrosinase Inhibitors: Mechanistic Approach through Enzyme Inhibition, Molecular Docking, Chemoinformatics, ADMET and Drug-Likeness Studies.

Furan-oxadiazole structural hybrids belong to the most promising and biologically active classes of oxygen and nitrogen containing five member heterocycles which have expanded therapeutic scope and potential in the fields of pharmacology, medicinal chemistry and pharmaceutics. A novel series 5a-j of benzofuran-oxadiazole molecules incorporating S-alkylated amide linkage have been synthesized using ultrasonic irradiation and screened for bacterial tyrosinase inhibition activity. Most of the synthesized furan-oxadiazole structural motifs exhibited significant tyrosinase inhibition activity in the micromolar range, with one of the derivatives being more potent than the standard drug ascorbic acid. Among the tested compounds, the scaffold 5a displayed more tyrosinase inhibition efficacy IC50 (11 ± 0.25 µM) than the ascorbic acid IC50 (11.5 ± 0.1 µM). Compounds 5b, 5c and 5d efficiently inhibited bacterial tyrosinase with IC50 values in the range of 12.4 ± 0.0-15.5 ± 0.0 µM. The 2-fluorophenylacetamide containing furan-oxadiazole compound 5a may be considered as a potential lead for tyrosinase inhibition with lesser side effects as a skin whitening and malignant melanoma anticancer agent.

Exploring the Synergistic Anticancer Potential of Benzofuran-Oxadiazoles and Triazoles: Improved Ultrasound- and Microwave-Assisted Synthesis, Molecular Docking, Hemolytic, Thrombolytic and Anticancer Evaluation of Furan-Based Molecules.

Ultrasound- and microwave-assisted green synthetic strategies were applied to furnish benzofuran-oxadiazole 5a-g and benzofuran-triazole 7a-h derivatives in good to excellent yields (60-96%), in comparison with conventional methods (36-80% yield). These synthesized derivatives were screened for hemolysis, thrombolysis and anticancer therapeutic potential against an A549 lung cancer cell line using an MTT assay. Derivatives 7b (0.1%) and 5e (0.5%) showed the least toxicity against RBCs. Hybrid 7f showed excellent thrombolysis activity (61.4%) when compared against reference ABTS. The highest anticancer activity was displayed by the 5d structural hybridwith cell viability 27.49 ± 1.90 and IC50 6.3 ± 0.7 µM values, which were considerably lower than the reference drug crizotinib (IC50 8.54 ± 0.84 µM). Conformational analysis revealed the spatial arrangement of compound 5d, which demonstrated its significant potency in comparison with crizotinib; therefore, scaffold 5d would be a promising anticancer agent on the basis of cytotoxicity studies, as well as in silico modeling studies.

Transition Metal Catalyzed Hiyama Cross-Coupling: Recent Methodology Developments and Synthetic Applications.

Hiyama cross-coupling is a versatile reaction in synthetic organic chemistry for the construction of carbon-carbon bonds. It involves the coupling of organosilicons with organic halides using transition metal catalysts in good yields and high enantioselectivities. In recent years, hectic progress has been made by researchers toward the synthesis of diversified natural products and pharmaceutical drugs using the Hiyama coupling reaction. This review emphasizes the recent synthetic developments and applications of Hiyama cross-coupling.

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review.

The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years.

Ultrasound-Assisted Synthesis and In Silico Modeling of Methanesulfonyl-Piperazine-Based Dithiocarbamates as Potential Anticancer, Thrombolytic, and Hemolytic Structural Motifs.

Piperazine-based dithiocarbamates serve as important scaffolds for numerous pharmacologically active drugs. The current study investigates the design and synthesis of a series of dithiocarbamates with a piperazine unit as well as their biological activities. Under ultrasound conditions, the corresponding piperazine-1-carbodithioates 5a-5j were synthesized from monosubstituted piperazine 2 and N-phenylacetamides 4a-4j in the presence of sodium acetate and carbon disulfide in methanol. The structures of the newly synthesized piperazines were confirmed, and their anti-lung carcinoma effects were evaluated. A cytotoxic assay was performed to assess the hemolytic and thrombolytic potential of the synthesized piperazines 5a-5j. The types of substituents on the aryl ring were found to affect the anticancer activity of piperazines 5a-5j. Piperazines containing 2-chlorophenyl (5b; cell viability = 25.11 ± 2.49) and 2,4-dimethylphenyl (5i; cell viability = 25.31 ± 3.62) moieties demonstrated the most potent antiproliferative activity. On the other hand, piperazines containing 3,4-dichlorophenyl (5d; 0.1%) and 3,4-dimethylphenyl (5j; 0.1%) rings demonstrated the least cytotoxicity. The piperazine with the 2,5-dimethoxyphenyl moiety (5h; 60.2%) showed the best thrombolytic effect. To determine the mode of binding, in silico modeling of the most potent piperazine (i.e., 5b) was performed, and the results were in accordance with those of antiproliferation. It exhibits a similar binding affinity to PQ10 and an efficient conformational alignment with the lipophilic site of PDE10A conserved for PQ10A.

Assessment of Binary Agarose-Carbopol Buccal Gels for Mucoadhesive Drug Delivery: Ex Vivo and In Vivo Characterization.

Agarose (AG) is a naturally occurring biocompatible marine seaweed extract that is converted to hydrocolloid gel in hot water with notable gel strength. Currently, its mucoadhesion properties have not been fully explored. Therefore, the main aim of this study was to evaluate the mucoadhesive potential of AG binary dispersions in combination with Carbopol 934P (CP) as mucoadhesive gel preparations. The gels fabricated via homogenization were evaluated for ex vivo mucoadhesion, swelling index (SI), dissolution and stability studies. The mucoadhesive properties of AG were concentration dependent and it was improved by the addition of CP. Maximum mucoadhesive strength (MS) (27.03 g), mucoadhesive flow time (FT) (192.2 min), mucoadhesive time in volunteers (MT) (203.2 min) and SI (23.6% at 4 h) were observed with formulation F9. The mucoadhesive time investigated in volunteers (MT) was influenced by AG concentration and was greater than corresponding FT values. Formulations containing 0.3%, w/v AG (F3 and F9) were able to sustain the release (~99%) for both drugs till 3 h. The optimized formulation (F9) did not evoke any inflammation, irritation or pain in the buccal cavity of healthy volunteers and was also stable up to 6 months. Therefore, AG could be considered a natural and potential polymer with profound mucoadhesive properties to deliver drugs through the mucosal route.

In-vitro cytotoxic evaluation, hemolytic and thrombolytic potential of newly designed acefylline based hydrazones as potent anticancer agents against human lung cancer cell line (A549).

Hydrazones of theophylline-7-acetic acid 5a-g have been synthesized using ultrasonic irradiation as well as conventional heating system and analyzed for their anticancer characteristics against human lung cancer cell line (A549). Compound 5g with cell viability 33.19±0.49% (100 µg/µL) compared to the starting reference drug acefylline having cell viability 86.32±11.75% (100 µg/µL) was found to be the most active anticancer agent among all. The synthesized derivatives were also exposed to hemolytic and thrombolytic studies to determine their cytotoxic profile and results revealed their low toxicity and moderate clot lysis activity.