Structural Analogues Research Articles

Indomethacin Derivatives as Potential Anticancer Agents ‐ Daybreak of New Epoch

AbstractNon‐steroidal anti‐inflammatory drugs (NSAIDs) are extensively prescribed pharmaceutical agents worldwide. Due to their analgesic, antipyretic, and anti‐inflammatory properties, they are used in clinical practice for the treatment of numerous inflammatory diseases. The mechanism of action primarily involves the inhibition of prostaglandin synthesis mediated by cyclooxygenases (COX), key enzymes of the inflammatory cascade. Indomethacin, a non‐selective derivative of indole‐3‐acetic acid exhibits diverse mechanisms to exert its anti‐tumor effects, including angiogenesis suppression, induction of apoptosis, and reduction of tumorigenesis through immune modulation. Numerous studies suggest that derivatives of indomethacin may inhibit cell proliferation and reduce levels of anti‐apoptotic proteins through COX‐independent mechanisms. Given the diverse potential mechanisms through which indomethacin impacts cancer progression, this review provides an overview of structural analogs that possess antitumor activity and outlines future directions in developing new candidates that may have substantial efficacy in cancer therapy.

Recent Advances in the Synthesis of Bicyclo[3.1.1]heptanes

AbstractIn the past three years, bicyclo[3.1.1]heptanes and their structural analogues have emerged as useful bioisosteres of meta-substituted (hetero)arenes. To meet the increasing demand for bicyclo[3.1.1]heptanes, chemists have developed a plethora of novel methods for their synthesis. In this short review, we assess the research progress on their synthesis and functionalization, considering both the scope and mechanistic aspects. In addition, we discuss the posed challenges and the outlook for the identification of new reaction manifolds to access novel functionalized bicyclo[3.1.1]heptanes.1 Introduction2 Synthesis of Bicyclo[3.1.1]heptanes (BCHeps)3 Synthesis of 3-Azabicyclo[3.1.1]heptanes (3-Aza-BCHeps)4 Conclusion and Outlook

Investigation on the Anticancer Activity of [6]-Gingerol of Zingiber officinale and its Structural Analogs against Skin Cancer.

Skin cancer is the most common type of cancer caused by the uncontrolled growth of abnormal cells in the epidermis and the outermost skin layer. This study aimed to study the anti-skin cancer potential of [6]-Gingerol and 21 related structural analogs using in vitro</i> and in silico</i> studies. The ethanolic crude extract of the selected plant was subjected to phytochemical and GC-MS analysis to confirm the presence of the [6]-gingerol. The anticancer activity of the extract was evaluated by MTT (3-[4, 5-dimethylthiazol-2-y]-2, 5-diphenyl tetrazolium bromide) assay using the A431 human skin adenocarcinoma cell line. The GC-MS analysis confirmed the presence of [6]-Gingerol compound, and its promising cytotoxicity IC50 was found at 81.46 ug/ml in the MTT assay. Furthermore, the in silico studies used [6]-Gingerol and 21 structural analogs collected from the PubChem database to investigate the anticancer potential and drug-likeliness properties. Skin cancer protein, DDX3X, was selected as a target that regulates all stages of RNA metabolism. It was docked with 22 compounds, including [6]-Gingerol and 21 structural analogs. The potent lead molecule was selected based on the lowest binding energy value. Thus, the [6]-Gingerol and its structure analogs could be used as lead molecules against skin cancer and future drug development process.

Total synthesis of Comfreyn A and structural analogues via two photochemical key steps.

In this work the influence of o-fluorine substituents on the photo-dehydro-Diels-Alder (PDDA) reaction was investigated and the findings of this study were applied to the total synthesis of natural products. The reactant molecules consisted of two alkyl arylpropiolates, connected by a suberic acid tether and bearing fluorine substituents in each of the o-positions. While quantum chemical calculations suggested that a fluorine substituent prevents an attack of the adjacent carbon atom in the second C-C bond forming step of the PDDA reaction, this attack took place nevertheless. The subsequent fluoride elimination, assisted by protic solvents or trialkylsilanes, resulted in an "Umpolung" of the 4-position of the cycloallene intermediate enabling the introduction of nucleophiles at this position. The nucleophilic replacement of the second fluorine substituent could also be triggered photochemically. After removal of the tether, the two arene moieties stand nearly perpendicular to each other and a selective excitation of the naphthalene moiety was possible. This led to an intramolecular photoinduced electron transfer (PET) followed by a nucleophilic replacement of the fluoride according to a SR+N1Ar* mechanism. The formed phenolic hydroxyl group underwent spontaneous lactonization with the adjacent ester group. Based on these results, the first total synthesis of the lignan Comfreyn A and some structural analogues were developed.

Synthesis and Biological Evaluations of Granulatamide B and its Structural Analogues.

While granulatamides A and B have been previously isolated, their biological activities have been only partially examined. The aim of this study was to synthesize granulatamide B (4b), a tryptamine-derivative naturally occurring in Eunicella coral species, using the well-known procedure of Sun and Fürstner and its 12 structural analogues by modifying the side chain, which differs in length, degree of saturation as well as number and conjugation of double bonds. The prepared library of compounds underwent comprehensive assessment for their biological activities, encompassing antioxidative, antiproliferative, and antibacterial properties, in addition to in vivo toxicity evaluation using a Zebrafish model. Compound 4i, which consists of a retinoic acid moiety, exhibited the strongest scavenging activity against ABTS radicals (IC50 = 36 ± 2 μM). In addition, 4b and some of the analogues (4a, 4c and 4i), mostly containing an unsaturated chain and conjugated double bonds, showed moderate but non-selective activity with certain IC50 values in the range of 20-40 μM. In contrast, the analogue 4l, a derivative of alpha-linolenic acid, was the least toxic towards normal cell lines. Moreover, 4b was also highly active against Gram-positive Bacillus subtilis with an MIC of 125 μM. Nevertheless, both 4b and 4i, known for the best-observed effects, caused remarkable developmental abnormalities in the zebrafish model Danio rerio. Since modification of the side chain did not significantly alter the change in biological activities compared to the parent compound, granulatamide B (4b), the substitution of the indole ring needs to be considered. Our group is currently carrying out new syntheses focusing on the functionalization of the indole core.

Novel Piperazine Derivatives as Potent Antihistamine, Anti-Inflammatory, and Anticancer Agents, their Synthesis and Characterization.

In this study, a series of novel piperazine derivatives were synthesised with high-to-good yields, and their structural analogies were confirmed using FTIR, 1H-NMR, and LC-MS techniques. The synthesised compounds were evaluated for antioxidant and antimicrobial activities. Among the four synthesised piperazine derivatives, compound PD-2 exhibited relatively good antioxidant activity, with an IC50 value of 2.396 μg/mL, while the other three derivatives showed moderate to low antioxidant activity. Furthermore, compound PD-2 displayed antimicrobial activity against Pseudomonas aeruginosa, a gram-negative bacterium, and Candida albicans, a fungus. However, all four compounds showed strong resistance against grampositive bacteria, Staphylococcus aureus. Additionally, compound PD-1 exhibited significant antihistamine activity, eliciting an 18.22% reduction in histamine levels. Both PD-1 and PD-2 demonstrated noteworthy anti-inflammatory activity in a dosedependent manner (5-10 μM), leading to the inhibition of nitrite production up to 39.42% and 33.7% at higher concentrations (10 μM) and inhibition of tumour necrosis factor-alpha (TNF-α) generation up to 56.97% and 44.73% at 10 μM, respectively. Additionally, both novel molecules PD-1 and PD-2 effectively restrained the growth of HepG2 cells in a manner that is dependent on the dosage up to 55.44% and 90.45% at the highest concentrations (100 μg/mL), respectively. These findings substantiate the rationale for further investigation into the novel series of persuasive piperazine analogues as potential agents with anti-inflammatory, antihistamine and anticancer properties.

Acetalax (Oxyphenisatin Acetate, NSC 59687) and Bisacodyl Cause Oncosis in Triple-Negative Breast Cancer Cell Lines by Poisoning the Ion Exchange Membrane Protein TRPM4.

Acetalax and bisacodyl kill cancer cells by causing oncosis following poisoning of the plasma membrane sodium transporter TRPM4 and represent a new therapeutic approach for TNBC.

Mechanistic insights and in vivo efficacy of thiosemicarbazones against methicillin-resistant Staphylococcus aureus

Staphylococcus aureus poses a significant threat in both community and hospital settings due to its infective and pathogenic nature combined with its ability to resist the action of chemotherapeutic agents. Methicillin-resistant S. aureus (MRSA) poses a critical challenge. Metal-chelating thiosemicarbazones (TSCs) have shown promise in combating MRSA and while previous studies hinted at the antimicrobial potential of TSCs, their mechanisms of action against MRSA are still under investigation. We screened a chemical library for anti-staphylococcal compounds and identified a potent molecule named R91 that contained the NNSN structural motif found within TSCs. We identified that R91 and several structural analogs exhibited antimicrobial activity against numerous S. aureus isolates as well as other Gram-positive bacteria. RNAseq analysis revealed that R91 induces copper and oxidative stress responses. Checkerboard assays demonstrated synergy of R91 with copper, nickel, and zinc. Mutation of the SrrAB two-component regulatory system sensitizes S. aureus to R91 killing, further linking the oxidative stress response to R91 resistance. Moreover, R91 was found to induce hydrogen peroxide production, which contributed to its antimicrobial activity. Remarkably, no mutants with elevated R91 resistance were identified, despite extensive attempts. We further demonstrate that R91 can be used to effectively treat an intracellular reservoir of S. aureus in cell culture and can reduce bacterial burdens in a murine skin infection model. Combined, these data position R91 as a potent TSC effective against MRSA and other Gram-positive bacteria, with implications for future therapeutic development.

Computer simulation‐guided template selection for a molecularly imprinted polymer for selective trifluralin adsorption

AbstractTo meet selective adsorption toward trifluralin, a novel molecularly imprinted polymer (MIP) was fabricated by the dummy template molecular imprinting technology. First, computational simulation was performed to select a suitable dummy template, 3,5‐dinitro‐4‐methylbenzoic acid (T1), based on the maximum basis set superposition error (BSSE)‐corrected binding interaction energy (ΔE) of the monomer N‐vinylpyrrolidone (NVP)‐T1 complex and its structural overlap with trifluralin. Then, the MIP was prepared via the bulk polymerization. The adsorption experiments showed the MIP exhibited a trifluralin adsorption capacity of 5.1 mg g−1, an imprinting factor (IF) of 2.2, and short adsorption equilibrium time of 5 min. The adsorption of trifluralin conformed to the Freundlich adsorption (R2 = 0.985) and pseudo‐second‐order model (R2 = 0.999). In addition, the MIP exhibited selectivity to trifluralin over other adsorbents, including structural analogs (pendimethalin and oryzalin), pesticide (carbendazim), and nitrocompounds (nitrofurantoin, furazolidone, and furaltadone), with the selectivity factor (β) in the range of 1.2–3.0, respectively. In trifluralin/oryzalin mixture, the IF toward oryzalin was still as high as 1.9. The removal rate of the MIP to trifluralin in environmental water samples ranged from 90.08% to 99.04%. This study provides theoretical and experimental insights for the preparation of MIP using dummy templates.

Chemical Modifications on the αvβ6 Intergrin Targeting A20FMDV2 Peptide: A review.

Integrin proteins have received a significant increase in attention in recent scientific endeavors. The current trend uses the pre-established knowledge that the arginyl-glycyl-aspartic acid (RGD) structural motif present in the A20FMDV2 peptide is highly selective for the integrin class αvβ6 which is overexpressed in many cancer types. This review will provide an extensive overview of the existing literature research to date to the best of our knowledge, highlighting significant improvements and drawbacks of structure-activity relationships (SAR) work undertaken, aiding future research to identify established SAR for a rational design of future A20FMDV2 mimetic inhibitors. Herein, the review aims to collate the existing structural chemical modifications present on A20FMDV2 in the literature to highlight key structural analogues that display more potent biological activity.

Recent Advances in the Research on Luotonins A, B, and E.

This digest review summarises the most recent progress in the study on luotonins A, B and E. The literature covered in this overview spans from January 2012 to April 2024 and presents synthetic methodologies for the assembly of the quinolinopyrrolo-quinazoline scaffold, the structural motifs present in luotonins A, B, and E, and the evaluation of the biological activities of their derivatives and structural analogues.

A multifaceted role of bisphosphonates from palliative care to anti-cancer therapy in solid tumors.

Bisphosphonates (P-C-Ps) also called diphosphonates are the structural analogs of naturally occurring pyrophosphates. Bisphosphonates are traditionally used and shown to provide long-term success in the treatment and prevention of osteoporosis and other bone loss pathologies. Furthermore, bisphosphonates are gaining popularity in the present era of cancer therapeutics and prevention. The usage of bisphosphonates as adjuvant or neoadjuvant therapy, either as a single agent or combined with other chemotherapy, has been studied in different solid tumors. This review aims to present the various roles of bisphosphonates in solid tumors. Articles in MEDLINE/PubMed and the National Institutes of Health Clinical Trials Registry (http://www. Clinicaltrials.gov) between 1 January 2011 and 1 February 2022 were extracted using MeSH terms "bisphosphonates/diphosphosphonates and mechanism," "bisphosphonates and breast cancer," "bisphosphonates and prostate cancer," "bisphosphonates and lung cancer," "bisphosphonates and cancer risk," and "bisphosphonates and adverse events." Manual searches of some major oncology journals were also conducted. This review article focuses on the antitumor activity of bisphosphonates, safety profile, and the role of bisphosphonates as preventive, neoadjuvant, and adjuvant chemotherapy. A significant improvement in overall survival and cancer-specific survival and recurrence-free survival with the usage of bisphosphonates is noted in breast cancer patients, particularly in post-menopausal women. Though great progress has been achieved in over 20 years, further research is needed to identify the subgroup of patients that are most likely to benefit from adjuvant bisphosphonate therapy and to determine regimens with greater efficacy and better safety profile.

Novel water-compatible surface molecularly imprinted polymer microspheres based on boronate affinity and hydrophilic coating for efficient enrichment and separation of capecitabine from urine samples

A novel water-compatible surface molecularly imprinted polymer microspheres (SMIMs) based on boronate affinity and hydrophilic coating were developed for the specific recognition and extraction of capecitabine (CAP). The boronic acid-functionalized polymer microspheres (BPMs) were first prepared as the carrier through dispersion polymerization using methyl methacrylate, ethylene glycol dimethacrylate, and 4-vinylphenylboronic acid as the polymerization monomers. Subsequently, the CAP template was immobilized onto the surface of the BPMs by virtue of boronate affinity. Finally, a thin and adherent imprinting layer was coated onto the surface of the BPMs via in-water self-polymerization of dopamine (DA) and polyethyleneimine (PEI). The resulting SMIMs exhibited strong hydrophilicity, high adsorption capacity (151.52 μmol/g) and a great imprinting factor (5.99) for CAP in aqueous media. The adsorption behavior of CAP onto the SMIMs was in good agreement with the Langmuir model and the pseudo-second-order equation. Selective adsorption indicated that the SMIMs exhibited a higher specific recognition for CAP compared to other structural analogs. In addition, the SMIMs showed excellent reproducibility and reusability, and could be utilized as anadsorbent in solid-phase extraction (SPE) for the selective pre-concentration, purification, and detection of trace amounts of CAP in spiked urine samples in combination with HPLC. The elution recovery of CAP for the various spiked levels ranged from 91.7 % to 104.9 %, with a relative standard deviation (RSD) of less than 5.8 % (n = 3).

A candidate reference measurement procedure for quantification of glycocholic acid in human serum based on isotope dilution liquid chromatography-tandem mass spectrometry

Accurate measurement of serum glycocholic acid (GCA) is crucial for evaluating the activity of chronic hepatitis. Moreover, GCA is a novel identified biomarker for hepatocellular carcinoma. Although some laboratories have used the liquid chromatography-tandem mass spectrometry (LC–MS/MS) method to measure GCA in recent years, the problem of potential interference of GCA analogues has not been solved well yet. Neither reference measurement procedures nor reference materials for GCA have been listed in the Joint Committee for Traceability in Laboratory Medicine (JCTLM) database. For standardization of GCA, it is urgent to establish a candidate measurement procedure for GCA. In this study, a candidate reference measurement procedure for the quantification of GCA in human serum based on isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC–MS/MS) by a two-step sample pretreatment of protein precipitation and MAX solid-phase extraction was developed and validated. GCA can be completely separated from its structural analogues with gradient elution in 9 min compared with short time gradients published in previous literature by Huang’s group. Method validation indicated perfect quantitation precision with intra-day and inter-day values that were ≤1.30% and ≤1.80%, respectively. The method showed excellent linearity with high regression coefficients (R2 > 0.999) over a range of 0.92 ng/g–38.38 μg/g and perfect recoveries at three spiked levels (99.87–100.43%). No interference, matrix effect, and carryover were observed. Moreover, the cRMP was successfully applied to measure GCA in serum samples and compared with two immunoassays in a clinical laboratory. As a candidate reference method, this method can promote a GCA standardization program.Graphical

Metabolome analysis revealed the critical role of betaine for arsenobetaine biosynthesis in the marine medaka (Oryzias melastigma)

Arsenobetaine (AsB), a non-toxic arsenic (As) compound found in marine fish, structurally resembles betaine (GB), a common methyl donor in organisms. This study investigates the potential role of GB in AsB synthesis in marine medaka (Oryzias melastigma) using metabolomic analysis. Dietary exposure to arsenate (As(V)) and varying GB concentrations (0.05% and 0.1% in diets) increased total As and AsB bioaccumulation, particularly in marine medaka muscle. Metabolomic analysis revealed that GB played a crucial role in promoting up-regulation in methylthioadenosine (MTA) by modulating the methionine cycle and down-regulation in glutathione (GSH) by modulating the glutathione cycle. Methionine metabolism and GSH, potentially binding again to exogenous GB, could synchronously produce more non-toxic AsB. Combining verification experiments of differential metabolites of Escherichia coli in vitro, GB, GSH, S-adenosylmethionine (SAM), and arsenocholine (AsC) entered methionine and glutathione metabolism pathways to generate more AsB. These findings underscore the GB's crucial regulatory role in modulating the synthesis of AsB. This study provides vital insights into the interplay between the structural analogs GB and AsB, offering specific strategies to enhance the detoxification mechanisms of marine fish in As-contaminated environments.

Improving Proposal Writing by Looking to Information Operations

This article examines the subject of persuasion in technical and professional communications (TPC) with a specific focus on proposals in U.S. Government contracting. It demonstrates a fundamental disconnect between the intent of proposals, which is to persuade, and the rhetorical traditions and professional boundaries of technical writers. The analysis draws on the existing rhetorical- and genre-based TPC literature and borrows from theory in other disciplines—management, organizational theory, sociology, and psychology among others. To advance the scholarship on proposals, this analysis is framed within the overall context of a structural analogy to U.S. military Information Operations (IO). Through use of analogy, it is suggested that the IO community's approach to the concepts of “influence,” “narrative,” “target audience,” and “unity of effort” may offer useful insight for State and Federal contractors to consider in their efforts to write persuasive proposals. This analysis is then used to develop a research agenda for the study of proposals. Areas for future research include the science of persuasion and the use of narrative as it relates to proposals, improved rigor in the use of target audience research, and organizational constructs to improve collaborative writing in proposals.

Structure‐Activity Relationships of the Structural Analogs Au8Cu1 and Au8Ag1 in the Electrocatalytic CO2 Reduction Reaction

AbstractOwing to the significant attention directed toward alloy metal nanoclusters, it is crucial to explore the relationship between their structures and their performance during the electrocatalytic CO2 reduction reaction (eCO2RR) and discover potential synergistic effects for the design of novel functional nanoclusters. However, a lack of suitable analogs makes this investigation challenging. In this study, we synthesized a well‐defined pair of structural analogs, [Au8Cu1(SAdm)4(Dppm)3Cl]2+ and [Au8Ag1(SAdm)4(Dppm)3Cl]2+ (Au8Cu1 and Au8Ag1, respectively), and characterized them. Single‐crystal X‐ray diffraction analysis revealed that Au8M1 (M=Cu/Ag) consists of a tetrahedral Au3M1 core capped by three (Dppm)Au staples, one Au2(SR)3 staple, one lone SR ligand, and a terminal Cl ligand. Ag and Cu were doped at the same site in the Au8M1 nanoclusters, which has rarely been reported. Au8Cu1 exhibited a significantly higher CO Faradaic efficiency (FECO; ~82.2 %) during eCO2RR than that of Au8Ag1 (FECO; ~33.1 %). Density functional theory calculations demonstrated that *COOH is the key intermediate in the reduction of CO2 to CO. The formation of *COOH on Au8Cu1 is more thermodynamically stable than on Au8Ag1, and Au8Cu1 shows a smaller *CO formation energy than that on Au8Ag1, which promotes the reduction of CO2. We believe that the structural analogs Au8Cu1 and Au8Ag1 offer a suitable template for the in‐depth investigation of structure‐property correlations at the atomic level.

Structure-Activity Relationships of the Structural Analogs Au8Cu1 and Au8Ag1 in the Electrocatalytic CO2 Reduction Reaction.

Owing to the significant attention directed toward alloy metal nanoclusters, it is crucial to explore the relationship between their structures and their performance during the electrocatalytic CO2 reduction reaction (eCO2RR) and discover potential synergistic effects for the design of novel functional nanoclusters. However, a lack of suitable analogs makes this investigation challenging. In this study, we synthesized a well-defined pair of structural analogs, [Au8Cu1(SAdm)4(Dppm)3Cl]2+ and [Au8Ag1(SAdm)4(Dppm)3Cl]2+ (Au8Cu1 and Au8Ag1, respectively), and characterized them. Single-crystal X-ray diffraction analysis revealed that Au8M1 (M=Cu/Ag) consists of a tetrahedral Au3M1 core capped by three (Dppm)Au staples, one Au2(SR)3 staple, one lone SR ligand, and a terminal Cl ligand. Ag and Cu were doped at the same site in the Au8M1 nanoclusters, which has rarely been reported. Au8Cu1 exhibited a significantly higher CO Faradaic efficiency (FECO; ~82.2 %) during eCO2RR than that of Au8Ag1 (FECO; ~33.1 %). Density functional theory calculations demonstrated that *COOH is the key intermediate in the reduction of CO2 to CO. The formation of *COOH on Au8Cu1 is more thermodynamically stable than on Au8Ag1, and Au8Cu1 shows a smaller *CO formation energy than that on Au8Ag1, which promotes the reduction of CO2. We believe that the structural analogs Au8Cu1 and Au8Ag1 offer a suitable template for the in-depth investigation of structure-property correlations at the atomic level.

Detection and Differentiation of Amines and N‐Heterocycles via Recognition Enabled Chromatographic 19F NMR

AbstractIn this study, we successfully employed a 19F‐labeled cyclopalladium probe to achieve simultaneous differentiation and detection of various amines and N‐heterocyclic compounds. This method features a broad detection window, facilitating the discrimination and multi‐component analysis of structural analogs and isomers through the generation of characteristic 19F NMR signals with distinct chemical shifts. The utility of this approach is demonstrated in monitoring chemical reactions and identifying components in food, beverages, and cosmetics.

Identification of substituted variants of plastoquinone-9 as potent and specific photosynthetic inhibitors in cyanobacteria and plants

The unprenylated benzoquinones 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone), 2-chloro-1,4-benzoquinone (CBQ), 2,6-dimethyl-1,4-benzoquinone (DMBQ), 2,6-dichloro-1,4-benzoquinone (DCBQ), and 2,6-dimethoxy-1,4-benzoquinone (DMOBQ) were tested as putative antimetabolites of plastoquinone-9, a vital electron and proton carrier of oxygenic phototrophs. Duroquinone and CBQ were the most effective at inhibiting the growth of the cyanobacterium Synechocystis sp. PCC 6803 either in photomixotrophic or photoautotrophic conditions. Duroquinone, a close structural analog of the photosynthetic inhibitor methyl-plastoquinone-9, was found to possess genuine bactericidal activity towards Synechocystis at a concentration as low as 10 μM, while at the same concentration CBQ acted only as a mild bacteriostat. In contrast, only duroquinone displayed marked cytotoxicity in axenically-grown Arabidopsis, resulting in damages to photosystem II and hindered net CO2 assimilation. Metabolite profiling targeted to photosynthetic cofactors and pigments indicated that in Arabidopsis duroquinone does not directly inhibit plastoquinone-9 biosynthesis. Taken together, these data indicate that duroquinone offers prospects as an algicide and herbicide.