Design,synthesis and structure–activity relationships of mangostin analogs as cytotoxic agents

In order to better understand the structure–activity relationship of mangostin, a series of xanthone derivatives based on α-mangostin were designed and synthesized. All the compounds were evaluated for their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) using MTT assays. Most of them showed cytotoxicity and most of all, compounds 1a and 2h showed the highest cytotoxic potency by HL-60 cancer cell lines with IC₅₀ values of 5.96 μM and 6.90 μM respectively; compound 3e showed the highest cytotoxic potency against SMMC-7221 cancer cell line with IC₅₀ values of 3.98 μM; compounds 2e and 2m showed lower cytotoxicity but higher selectivity than α-mangostin against HL-60 and SMMC-7221 cancer cell lines respectively. Structure–activity relationship analysis indicates that the maintenance of the isopentene group at C-8 is essential for the cytotoxic activity.

A series xanthone derivatives were synthesized and cytotoxicity results indicated that the isopentene group at C-8 is essential.     

Research developments in the syntheses,anti-inflammatory activities and structure–activity relationships of pyrimidines

Pyrimidines are aromatic heterocyclic compounds that contain two nitrogen atoms at positions 1 and 3 of the six-membered ring. Numerous natural and synthetic pyrimidines are known to exist. They display a range of pharmacological effects including antioxidants, antibacterial, antiviral, antifungal, antituberculosis, and anti-inflammatory. This review sums up recent developments in the synthesis, anti-inflammatory effects, and structure–activity relationships (SARs) of pyrimidine derivatives. Numerous methods for the synthesis of pyrimidines are described. Anti-inflammatory effects of pyrimidines are attributed to their inhibitory response versus the expression and activities of certain vital inflammatory mediators namely prostaglandin E₂, inducible nitric oxide synthase, tumor necrosis factor-α, nuclear factor κB, leukotrienes, and some interleukins. Literature studies reveal that a large number of pyrimidines exhibit potent anti-inflammatory effects. SARs of numerous pyrimidines have been discussed in detail. Several possible research guidelines and suggestions for the development of new pyrimidines as anti-inflammatory agents are also given. Detailed SAR analysis and prospects together provide clues for the synthesis of novel pyrimidine analogs possessing enhanced anti-inflammatory activities with minimum toxicity.

This review sums up recent developments in the syntheses, anti-inflammatory activities, and structure–activity relationship (SAR) studies of pyrimidine derivatives.     

Pyrazole-based lamellarin O analogues: synthesis,biological evaluation and structure–activity relationships

A library of pyrazole-based lamellarin O analogues was synthesized from easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates which were subsequently modified by bromination, N-alkylation and Pd-catalysed Suzuki cross-coupling reactions. Synthesized ethyl and methyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were evaluated for their physicochemical property profiles and in vitro cytotoxicity against three human colorectal cancer cell lines HCT116, HT29, and SW480. The most active compounds inhibited cell proliferation in a low micromolar range. Selected ethyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were further investigated for their mode of action. Results of combined viability staining via Calcein AM/Hoechst/PI and fluorescence-activated cell sorting data indicated that cell death was triggered in a non-necrotic manner mediated by mainly G2/M-phase arrest.

Isosteric pyrrole–pyrazole exchange in the natural alkaloid lamellarin O resulted in 18 fully characterized derivatives. Obtained compounds were investigated as potent agents against human colon cancer cell lines HCT116, HT29 and SW480.     

Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors

Since its first report in December 2019, the novel coronavirus virus, SARS-CoV-2, has caused an unprecedented global health crisis and economic loss imposing a tremendous burden on the worldwide finance, healthcare system, and even daily life. Even with the introduction of different preventive vaccines, there is still a dire need for effective antiviral therapeutics. Nature has been considered as the historical trove of drug discovery and development, particularly in cases of worldwide crises. Herein, a comprehensive in silico investigation of a highly focused chemical library of 34 pederin-structurally related marine compounds, belonging to four polyketides families, was initiated against the SARS-CoV-2 main protease, Mpro, being the key replicating element of the virus and main target in many drugs development programs. Two of the most potent SARS-CoV-2 Mpro co-crystallized inhibitors, O6K and N3, were added to the tested database as reference standards. Through molecular docking simulation, promising compounds including Pederin (1), Dihydro-onnamide A (11), Onnamide C (14), Pseudo-onnamide A (17), and Theopederin G (29) have been identified from different families based on their superior ligand–protein energies and relevant binding profiles with the key Mpro pocket residues. Thermodynamic behaviors of the identified compounds were investigated through 200 ns all-atom molecular dynamics simulation illustrating their significant stability and pocket accommodation. Furthermore, structural activity preferentiality was identified for the pederin-based marine compounds highlighting the importance of the terminal guanidine and cyclic hemiacetal linker, and the length of the sidechain. Our findings highlight the challenges of targeting SARS-CoV-2 Mpro as well as recommending further in vitro and in vivo studies regarding the examined marine products either alone or in combination paving the way for promising lead molecules.

Marine natural polyketides showed promising SARS-CoV-2 main protease inhibitory activities.     

Investigations into the structure–activity relationship in gemini QACs based on biphenyl and oxydiphenyl linker

Eighteen novel gemini quaternary ammonium compounds were synthesized to examine the effect of linker nature, aliphatic chain length and their relative position on antibacterial and antifungal activity. The synthesized compounds showed strong bacteriostatic activity against a panel of both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and two fungi. Some of these compounds exhibited a wider and more potent antimicrobial spectrum than commonly-used antiseptics, such as benzalkonium chloride (BAC), cetylpyridinium chloride (CPC), chlorhexidine digluconate (CHG) and octenidine dihydrochloride (OCT).

The synthesis and biological evaluations of new gemini QACs possessing high antibacterial and antifungal activity were performed.     

Synthesis,structure–fluorescence relationships and density functional theory studies of novel naphthalimide–piperazine–pyridine-based polystyrene sensors for Hg(ii) detection

Two novel naphthalimide–piperazine–pyridine-based polystyrene solid-phase fluorescent sensors PS-NA and PS-ND with different lengths of the linker were synthesized and shown to be able to detect Hg(ii) ions. Their structures were characterized by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) analysis. Fluorescence properties, including response time, pH effects, fluorescence titration, metal ion selectivity and regeneration, were investigated and compared. Sensor PS-NA displayed a higher fluorescence response to Hg(ii) than PS-ND, with a lower detection limit of 1.01 μM. The detection mechanism involving the Hg(ii) chelation-induced photo-induced electron transfer (PET) was proposed with the aid of density functional theory (DFT) calculations. Sensors PS-NA and PS-ND with seven other similar sensors from our previous studies were collected together for thorough structure–fluorescence relationship (SFR) studies. Sensor PS-NA being recyclable and environmentally friendly was successfully employed in the fluorescence detection of Hg(ii) in real water samples, indicating its good potential in practical application.

Naphthalimide-appended polystyrene fluorescent sensors.     

Screening of metal–organic frameworks for water adsorption heat transformation using structure–property relationships

It is of great importance to correlate the water adsorption performance of MOFs to their physicochemical features in order to design and prepare MOFs for applications in adsorption heat transformation. In this work, both data analysis from existing studies and Grand Canonical Monte Carlo molecular simulation investigations were carried out. The results indicated that the highest water adsorption capacity was determined by the pore volume of MOF adsorbents, while there was a linear correlation interrelationship between isosteric heats of adsorption and the water adsorption performance at a low relative pressure. More detailed analysis showed that the charge distribution framework and pore size of MOFs contributed together to the hydrophilicity. Electrostatic interaction between water molecules and the framework atoms played a key role at low relative water pressure. A quantitative structure–property relationship model that can correlate the hydrophilicity of MOFs to their pore size and atomic partial charge was established. Along with some qualitative considerations, the screening methodology is proposed and is used to screen proper MOFs in the CoRE database. Seven MOFs were detected, and four of them were synthesized to validate the screening principle. The results indicated that these four MOFs possessed outstanding water adsorption performance and could be considered as promising candidates in applications for adsorption heating and cooling.

Quantitative structure–property relationship models that correlate the water adsorption performance of MOFs to their physicochemical features have been established.     

Journey of anthraquinones as anticancer agents – a systematic review of recent literature

Anthraquinones are privileged chemical scaffolds that have been used for centuries in various therapeutic applications. The anthraquinone moiety forms the core of various anticancer agents. However, the emergence of drug-resistant cancers warrants the development of new anticancer agents. The research endeavours towards new anthraquinone-based compounds are increasing rapidly in recent years. They are used as a core chemical template to achieve structural modifications, resulting in the development of new anthraquinone-based compounds as promising anticancer agents. Mechanistically, most of the anthraquinone-based compounds inhibit cancer progression by targeting essential cellular proteins. Herein, we review new anthraquinone analogues that have been developed in recent years as anticancer agents. This includes a systematic review of the recent literature (2005–2021) on anthraquinone-based compounds in cell-based models and key target proteins such as kinases, topoisomerases, telomerases, matrix metalloproteinases and G-quadruplexes involved in the viability of cancer cells. In addition to this, the developments in PEG-based delivery of anthraquinones and the toxicity aspects of anthraquinone derivatives are also discussed. The review dispenses a compact background knowledge to understanding anthraquinones for future research on the expansion of anticancer therapeutics.

Anthraquinones are privileged chemical motifs with diverse therapeutic applications, especially in the treatment of cancer. The extensive literature highlights the significance of anthraquinones as potent anticancer agents.     

Glycosylation of luteolin in hydrophilic organic solvents and structure–antioxidant relationships of luteolin glycosides

An effective approach was developed to biotransform luteolin glycosides in hydrophilic organic solvents. Bacillus cereus A46 cells showed high activity and stability in 5–20% (v/v) DMSO with 90–98% conversion rates of luteolin glycosides. Five glycosides of luteolin 7-O-β-glucoside, luteolin 4′-O-β-glucoside, luteolin 3′-O-β-glucoside, luteolin 7,3′-di-O-β-glucoside and luteolin 7,4′-di-O-β-glucoside were obtained. The addition of DMSO greatly promoted the solubility of luteolin and further regulated the formation of the main products from five luteolin glycosides to luteolin 7-O-β-glucoside (931.2 μM). Fourteen flavonoids and anthraquinones were used as tentative substrates. Glycosylation positions were located at the C-7, C-3′ or C4′ hydroxyl groups of flavonoids and C-5 hydroxyl group of anthraquinones. The 3′,4′-dihydroxy arrangement played the key role for the antioxidant activity of luteolin.

Efficient glycosylation of luteolin in organic solvents and the structure–antioxidant relationships of luteolin glycosides were reported for the first time.     

Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure–activity relationship,activity profile,mode of action,and molecular docking

In an attempt to develop effective and potentially active antibacterial and/or antifungal agents, we designed, synthesized, and characterized thiolated CoQ analogs (CoQ1–8) with an extensive antimicrobial study. The antimicrobial profile of these analogs was determined using four Gram-negative bacteria, three Gram-positive bacteria, and three fungi. Because of the fact that the thiolated CoQ analogs were quite effective on all tested Gram-positive bacterial strains, including Staphylococcus aureus (ATCC® 29213) and Enterococcus faecalis (ATCC® 29212), the first two thiolated CoQ analogs emerged as potentially the most desirable ones in this series. Importantly, after the evaluation of the antibacterial and antifungal activity, we presented an initial structure–activity relationship for these CoQ analogs. In addition, the most promising thiolated CoQ analogs (CoQ1 and CoQ2) having the lowest MIC values on all tested Gram-positive bacterial strains, were further evaluated for their inhibition capacities of biofilm formation after evaluating their in vitro potential antimicrobial activity against each of 20 clinically obtained resistant strains of Gram-positive bacteria. CoQ1 and CoQ2 exhibited potential molecular interactions with S. aureus DNA gyrase in addition to excellent pharmacokinetics and lead-likeness profiles. Our findings offer important implications for a potential antimicrobial drug candidate, in particular for the treatment of infections caused by clinically resistant MRSA isolates.

In an attempt to develop effective and potentially active antibacterial and/or antifungal agents, we designed, synthesized, and characterized thiolated CoQ analogs (CoQ1–8) with an extensive antimicrobial study.     

Effects of calcination temperatures on the structure–activity relationship of Ni–La/Al2O3 catalysts for syngas methanation

A series of Ni–La/Al₂O₃ catalysts for the syngas methanation reaction were prepared by a mechanochemical method and characterized by thermogravimetric analysis (TG-DTA), X-ray fluorescence (XRF), X-ray diffraction (XRD), N₂ adsorption–desorption, H₂ temperature-programmed reduction (H₂-TPR), and X-ray photoelectron spectroscopy (XPS). The calcination temperatures (350–700 °C) had significant impacts on the crystallite sizes and interactions between NiO and Al₂O₃. The catalyst calcined at 400 °C (cat-400) showed a 12.1% Ni dispersion degree and the maximum bound state of NiO (54%) through the Gaussian fitting of H₂-TPR. Cat-400 also achieved the highest CO conversion, CH₄ selectivity and yield. Cat-400 exhibited good stability and catalytic activity in a lifetime testing of 200 h. The deactivation of cat-400 was mainly caused by carbon deposition according to the data from XRD, TG-DTG and XPS.

Calcination temperature affects the existing types of NiO, and the influence of the three NiO types on the catalytic activity of samples is bound type ≫ free type > combined type.     

Synthesis and evaluation of new chalcones and oximes as anticancer agents

Complex illnesses, such as cancer, are often caused by many disorders, gene mutations, or pathways. Biological pathways play a significant part in the development of these diseases. Multi-target directed ligands (MTDLs) have been used by medicinal chemists recently in an effort to find single molecules that can affect many targets concurrently. In this work, several chalcones containing the ligustrazine moiety were synthesized and tested for their in vitro anticancer activity and several cancer markers, including EGFR, BRAF^V600E, c-Met, and tubulin polymerization, in order to uncover multitarget bioactive compounds. In assays using multiple cancer cell lines, the majority of the compounds examined showed strong anticancer activity against them. To synthesize oximes, all of the chalcones were used as precursors. The IC₅₀ values of two compounds (11g and 11e) were found to be 0.87, 0.28, 2.43, 1.04 μM and 11d, 1.47, 0.79, 3.8, 1.63 μM respectively, against A-375, MCF-7, HT-29 and H-460 cell lines. These IC₅₀ values revealed an excellent antiproliferative activity compared to those of the positive control foretinib, (IC₅₀ = 1.9, 1.15, 3.97, and 2.86 μM). Careful examination of their structure and configuration revealed that both compounds had an oxime functional group with z configuration, in place of carbonyl functional group, along with a 2-phenyl thiophenyl moiety with or without a bromo group at position-5. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with a detailed structure activity relationship discussion, this work might stimulate new ideas in further modification of multitarget anti-cancer agents and therapeutic approaches.

Discovery of multitarget anticancer agents by modifications of natural compound.     

Characterizing the structure–activity relationships of natural products,tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications. Here, we employed pharmacophore-based drug screening combined with biochemical assay and molecular dynamics (MD) simulations to identify and characterize inhibitors targeting SYK. The built pharmacophore model, phar-TanI, successfully identified tanshinone (TanI (IC₅₀ = 1.72 μM)) and its analogs (TanIIA (IC₅₀ = 3.2 μM), ST32da (IC₅₀ = 46 μM), and ST32db (IC₅₀ = 51 μM)) which apparently attenuated the activities of SYK in vitro. Additionally, the MD simulations followed by Ligplot analyses revealed that TanI and TanIIA interfered SYK activity through binding deeply into the active site. Besides, TanI and TanIIA mainly interact with residues L377, A400, V433, M448, M450, A451, E452, L453, G454, P455, and L501, which are functional hotspots for structure-based inhibitor optimization against SYK. The structure–activity relationships (SAR) study of the identified SYK inhibitors demonstrated that the pharmacophore model, phar-TanI is reliable and precise in screening inhibitors against SYK. This study disclosed the structure–function relationships of tanshinones from Traditional Chinese Medicine (Danshen), revealing their binding site and mode of action in inhibiting SYK and provides applicability in developing new therapeutic agents.

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.     

Effect of Ce doping on the structure–activity relationship of MoVOx composite metal oxides

A series of Ce-doped MoVO_x composite metal oxide catalysts were prepared by the rotary evaporation method. The effects of Ce doping ratio on the crystal phase composition, morphology and surface properties of the catalysts were investigated. The results show that the crystal phase composition of samples with different Ce doping content is also obviously different. When the doping amount is small, V_0.95Mo_0.97O₅ is the main crystal phase, while MoO₃ is dominant when the doping amount is large. The Ce-doped catalyst showed obvious rod-shaped morphology and its average single point pore diameter and the number of acidic sites increased. Compared to the un-doped MoVO_x, the pore size of the sample synthesized at a Mo/Ce atomic ratio of 10/1 exhibited an increase of 41.11 nm. In addition, the effect of Ce doping on the catalytic performance of MoVO_x was investigated with the selective oxidation of benzyl alcohol as a probe reaction. After doping, the MoVO_x catalyst showed improved benzyl alcohol conversion and selectivity to benzaldehyde. At a Mo/Ce atomic ratio of 10/1, the conversion rate of benzyl alcohol reaches 83.26%, which is 64.56% higher than that without doping, and the highest product yield can reach 76.47%.

Ce-doped MoVO_x with disperse rod-shaped exhibits excellent catalytic performance in selective oxidation of benzyl alcohol.     

Lecithin–chitosan–TPGS nanoparticles as nanocarriers of (−)-epicatechin enhanced its anticancer activity in breast cancer cells

Natural compounds such as (−)-epicatechin show a variety of biological properties including anticancer activity. Nonetheless, (−)-epicatechin''s therapeutic application is limited due to its low water solubility and sensitivity to oxygen and light. Additionally, previous studies have reported that the encapsulation of flavonoids in nanoparticles might generate stable deliverable forms, which improves the availability and solubility of the bioactive compounds. The aims of this study were to generate (−)-epicatechin-loaded lecithin–chitosan nanoparticles (EC-LCT-NPs) by molecular self-assembly and to assess their cytotoxic potential against breast cancer cells. Various parameters were measured to characterize the EC-LCT-NPs including size, polydispersity index (PdI), zeta potential, morphology and entrapment efficiency. The results showed that the mean particle size of the EC-CLT-NPs was 159 ± 2.23 nm (PdI, 0.189), and the loading and entrapment efficiencies of (−)-epicatechin were 3.42 ± 0.85% and 56.1 ± 3.9%, respectively. The cytotoxic effect of the EC-CLT-NPs was greater than that of free (−)-epicatechin on breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-436 and SK-Br3). Indeed, EC-LCT-NPs showed an IC₅₀ that was four-fold lower (85 μM) than free (−)-epicatechin (350 μM) and showed selectivity to cancerous cells. This study demonstrated that encapsulating (−)-epicatechin into lecithin–chitosan nanoparticles opens new options for breast cancer treatment.

Natural compounds such as (−)-epicatechin show a variety of biological properties including anticancer activity.     

Thermodynamic insight into the growth of calcia inclusions at the nanoscale: the case of Fe–O–Ca melt

A thermodynamic model was developed to investigate the relationship between the thermodynamics of nano-CaO as a deoxidation reaction product and their size in an Fe–O–Ca melt. The results of thermodynamic model coupling with DFT (density functional theory) calculation prediction showed that the solubility product of calcium and oxygen for nanoscale CaO decreased with the increase of calcia product size in an Fe–O–Ca melt. The existing experimental data about the Ca-deoxidation equilibrium in liquid iron are covered by the region between the bulk-calcia equilibrium curve and the nano-CaO of 2 nm size curve. This result indicates that the partial product in most of the Ca-deoxidation experiments could be nanoscale CaO particles. Most of the Ca-deoxidation experimental equilibrium states are not reaching the equilibrium state between bulk calcia and liquid iron but a multi-equilibria between bulk- and nano-CaO and liquid iron.

Thermodynamics of the formation of nano-CaO in liquid iron is important to explore the relationship between deoxidation reaction and size of inclusions, and is very useful in the size controlling of inclusions.     

Carbohydrate structure–activity relations of Au-catalysed base-free oxidations: gold displaying a platinum lustre

This paper describes the base-free gold-catalysed oxidation of four different carbohydrates in a packed bed plug flow reactor. The influence of the carbohydrate structure on the catalytic activity and selectivity was investigated by comparing two neutral sugars (glucose (Glc) and galactose (Gal), both with primary alcohols at C6), with their sugar-acid analogues (glucuronic acid (GlcA) and galacturonic acid (GalA), both with carboxylic acids at C6). The orientation of OH-groups at the C4-position (equatorial in Glc/GlcA and axial in Glc/GlcA), and the C6-functionality (primary alcohols in Gal/Glc and carboxylic acids in GalA/GlcA) has a profound influence on the catalytic activity. When the OH-groups are in an axial position their reactivity was higher compared to the OH-groups in the equatorial position for both the sugars and the sugar acids. In addition the reactivity of carbohydrates over Au-catalysts under base-free conditions is different compared to alkaline conditions, and is more in line with a Pt-catalysed dehydrogenation mechanism.

Gold mimicking Platinum in base-free catalytic carbohydrate oxidations.     

Molecular targets and anticancer activity of quinoline–chalcone hybrids: literature review

α,β-Unsaturated chalcone moieties and quinoline scaffolds play an important role in medicinal chemistry, especially in the identification and development of potential anticancer agents. The multi-target approach or hybridization is considered as a promising strategy in drug design and discovery. Hybridization may improve the affinity and potency while simultaneously decreasing the resistance and/or side effects. The conjugation of quinolines with chalcones has been a promising approach to the identification of potential anticancer agents. Most of these hybrids showed anticancer activities through the inhibition of tubulin polymerization, different kinases, topoisomerases, or by affecting DNA cleavage activity. Accordingly, this class of compounds can be classified based on their molecular modes of action. In this article, the quinolone–chalcone hybrids with potential anticancer activity have been reviewed. This class of compounds might be helpful for the design, discovery and development of new and potential multi-target anticancer agents or drugs.

α,β-Unsaturated chalcone moieties and quinoline scaffolds play an important role in medicinal chemistry, especially in the identification and development of potential anticancer agents.     

Revealing biomedically relevant cell and lectin type-dependent structure–activity profiles for glycoclusters by using tissue sections as an assay platform

The increasing realization of the involvement of lectin-glycan recognition in (patho)physiological processes inspires envisioning therapeutic intervention by high-avidity/specificity blocking reagents. Synthetic glycoclusters are proving to have potential for becoming such inhibitors but the commonly used assays have their drawbacks to predict in vivo efficacy. They do not represent the natural complexity of (i) cell types and (ii) spatial and structural complexity of glycoconjugate representation. Moreover, testing lectins in mixtures, as present in situ, remains a major challenge, giving direction to this work. Using a toolbox with four lectins and six bi- to tetravalent glycoclusters bearing the cognate sugar in a model study, we here document the efficient and versatile application of tissue sections (from murine jejunum as the model) as a platform for routine and systematic glycocluster testing without commonly encountered limitations. The nature of glycocluster structure, especially core and valency, and of protein features, i.e. architecture, fine-specificity and valency, are shown to have an influence, as cell types can differ in response profiles. Proceeding from light microscopy to monitoring by fluorescence microscopy enables grading of glycocluster activity on individual lectins tested in mixtures. This work provides a robust tool for testing glycoclusters prior to considering in vivo experiments.

Introducing tissue sections for testing glycocluster activity as inhibitors of lectin binding close to in vivo conditions.