Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents.

In the present work, the synthesis of new ethacrynic acid (EA) derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical synthetic procedures was reported. The synthesised compounds were screened for their anti-proliferative activity against two different cancer cell lines, namely, HL60 (promyelocytic leukaemia) and HCT116 (human colon carcinoma). The results of the in vitro tests reveal that compounds 1-3, 10, 16(a-c), and 17 exhibit potent anti-proliferative activity against the HL60 cell line, with values of the percentage of cell viability ranging from 20 to 35% at 1 µM of the drug and IC50 values between 2.37 µM and 0.86 µM. Compounds 2 and 10 showed a very interesting anti-proliferative activity of 28 and 48% at 1 µM, respectively, against HCT116. Two PyTAP-based fluorescent EA analogues were also synthesised and tested, showing good anti-proliferative activity. A test on the drug-likeness properties in silico of all the synthetised compounds was performed in order to understand the mechanism of action of the most active compounds. A molecular docking study was conducted on two human proteins, namely, glutathione S-transferase P1-1 (pdb:2GSS) and caspase-3 (pdb:4AU8) as target enzymes. The docking results show that compounds 2 and 3 exhibit significant binding modes with these enzymes. This finding provides a potential strategy towards developing anticancer agents, and most of the synthesised and newly designed compounds show good drug-like properties.

"Click" Chemistry for the Functionalization of Graphene Oxide with Phosphorus Dendrons: Synthesis, Characterization and Preliminary Biological Properties.

Two families of phosphorhydrazone dendrons having either an azide or an alkyne linked to the core and diverse types of pyridine derivatives as terminal functions have been synthesized and characterized. These dendrons were grafted via click reaction to graphene oxide (GO) functionalized with either alkyne or azide functions, respectively. The resulting modified-GO and GO-dendrons materials have been characterized by Fourier Transform Infrared (FTIR), Raman spectroscopy (RS), and Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analyses. In addition, the free dendrons and the dendrons grafted to GO were tested toward cancerous (HCT116) and non-cancerous (RPE1) cell lines.

Unlocking the Potential of Deep Eutectic Solvents for C-H Activation and Cross-Coupling Reactions: A Review.

Green chemistry principles have underpinned the development of deep eutectic solvents (DESs). In this brief overview, we discuss the potential of DESs as a greener alternative to volatile organic solvents for cross-coupling and C-H activation reactions in organic chemistry. DESs offer numerous benefits, such as easy preparation, low toxicity, high biodegradability, and the potential to replace volatile organic compounds. The ability of DESs to recover the catalyst-solvent system enhances their sustainability. This review highlights recent advances and challenges in utilizing DESs as a reaction media, as well as the impact of physicochemical properties on the reaction process. Several types of reactions are studied to highlight their effectiveness at promoting C-C bond formation. Aside from demonstrating the success of DESs in this context, this review also discusses the limitations and future prospects of DESs in organic chemistry.

Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities.

The present study aims to report the design, synthesis, and biological activity of new ethacrynic acid (EA) analogs (6-10) obtained by the double modulation of the carboxylic acid moiety and the aromatic ring with the aim to increase the chemical reactivity of Michael acceptor of EA. All obtained compounds were characterized by 1H and 13C NMR, IR, and high-resolution mass spectrometry. The antiproliferative activity was evaluated in vitro using MMT test, in a first step, against HL60 cell line and in a second step, on a panel of human cancer cell lines such as HCT116, A549, MCF7, PC3, U87-MG, and SKOV3, and normal cell line MRC5 in comparison with positive control doxorubicin. Among all the tested compounds, the product 8 containing a propargyl and a hydroxyl groups, allowing an intramolecular hydrogen bond with the keto group of EA, exhibited a pronounced and selective activity in a nanomolar range against HL60, A549, PC3, and MCF7 with IC50 values of 15, 41.2, 68.7, and 61.5 nM, respectively. Compound 8 also showed a good selectivity index (SI) against HL60 and moderate SI against the other three human cancer cells (A549, PC3, and MCF7). The study of the structure-activity relationship showed that both modifications of the carboxylic group and the introduction of an intramolecular hydrogen bond are highly required to improve the antiproliferative activities. The molecular modeling studies of compound 8 revealed that it favorably binds to the glutathione S-transferase active site, which may explain its interesting anticancer activity. These new compounds have potential to be developed as novel therapeutic agents against various cancer types.

Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides.

In the present study, new 2-phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazines bearing sulfonamides were synthesized, characterized and evaluated for their anticancer activities. The structures of these derivatives were elucidated by 1H NMR, 13C NMR, infrared and high-resolution mass spectrometry for further validation of the target compound structures. The anticancer activities of the new molecules were evaluated against five human cancer cell lines, including A-549, Hs-683, MCF-7, SK-MEL-28 and B16-F10 cell lines using 5-fluorouracil and etoposide as the reference drugs. Among the tested compounds, 4e and 4f exhibited excellent activities in the same range of the positive controls, 5-fluorouracil and etoposide, against MCF-7 and SK-MEL-28 cancer cell lines, with IC50 values ranging from 1 to 10 µM. The molecular docking studies of 4e and 4f showed a strong binding with some kinases, which are linked to MCF-7 and SK-MEL-28 cancer cell lines.

Near-Infrared Emitting Poly(amidoamine) Dendrimers with an Anthraquinone Core toward Versatile Non-Invasive Biological Imaging.

Today, there is a very strong demand for versatile near-infrared (NIR) imaging agents suitable for non-invasive optical imaging in living organisms (in vivo imaging). Here, we created a family of NIR-emitting macromolecules that take advantage of the unique structure of dendrimers. In contrast to existing fluorescent dendrimers bearing fluorophores at their periphery or in their cavities, a NIR fluorescent structure is incorporated into the core of the dendrimer. Using the poly(amidoamine) dendrimer structure, we want to promote the biocompatibility of the NIR-emissive system and to have functional groups available at the periphery to obtain specific biological functionalities such as the ability to deliver drugs or for targeting a biological location. We report here the divergent synthesis and characterization by NMR and mass spectrometries of poly(amidoamine) dendrimers derived from the fluorescent NIR-emitting anthraquinone core (AQ-PAMAF). AQ-PAMAFs ranging from the generation -0.5 up to 3 were synthesized with a good level of control resulting in homogeneous and complete dendrimers. Absorption, excitation, and emission spectra, as well as quantum yields, of AQ-PAMAFs have been determined in aqueous solutions and compared with the corresponding properties of the AQ-core. It has been demonstrated that the absorption bands of AQ-PAMAFs range from UV to 750 nm while emission is observed in the range of 650-950 nm. Fluorescence macroscopy experiments confirmed that the NIR signal of AQ-PAMAFs can be detected with a satisfactory signal-to-noise ratio in aqueous solution, in blood, and through 1 mm thick tissue-mimicking phantom. The results show that our approach is highly promising for the design of an unprecedented generation of versatile NIR-emitting agents.

Regioselective C-H Functionalization of the Six-Membered Ring of the 6,5-Fused Heterocyclic Systems: An Overview.

The regioselective C-H functionalization of the five-membered ring of the 6,5-fused heterocyclic systems is nowadays well documented due to its high reactivity compared to the six-membered ring. So, developing new procedures of C-H functionalization of the six-membered ring "by thinking out of the box" is extremely challenging, which explains the limited number of reports published to date. This review paper aims to highlight advances achieved in this emerging chemistry research and discusses recently reported methods.

Synthesis and evaluation of a novel class of ethacrynic acid derivatives containing triazoles as potent anticancer agents.

For unmet clinical needs, a novel class of ethacrynic acid (EA) derivatives containing triazole moieties (3a-i and 8) were designed, synthesized and evaluated as new anticancer agents. The in vitro anti-proliferative activities were assessed first on HL60 cell line and in a second stage, the two selected compounds 3a and 3c were tested on a panel of human cancer cell lines (A549, MCF7, PC3, U87-MG, SKOV3 and HCT116) and on a normal cell line (MCR5). Compound3c exhibited very good antitumor activities with IC50 values of 20.2, 56.5 and 76.8 nM against A549, PC3 and U87-MG cell lines respectively, which is 2.8- and 1.3-fold more active than doxorubicin on A549 and U87-MG cancer cells, respectively. In addition, compound 3c displays a very good safety index (SI) of 82 fold for A549. Compound 3a showed also good IC50 values of 50 nM on both A549 and PC3 cells and lower selectivity compared to 3c for A549 and PC3 vs. MCR5 with SI of 33 and 18 fold, respectively. The measurement of mitochondrial membrane potential on HCT116 cells after treatments by either 3a or 3c showed that both compounds induced mitochondrial dysfunctions causing thus caspase-induced apoptosis.

A regioselective C7 bromination and C7 palladium-catalyzed Suzuki-Miyaura cross-coupling arylation of 4-substituted NH-free indazoles.

A direct and efficient regioselective C7-bromination of 4-substituted 1H-indazole has been achieved. Subsequently, a successful palladium-mediated Suzuki-Miyaura reaction of C7-bromo-4-substituted-1H-indazoles with boronic acids has been performed under optimized reaction conditions. A series of new C7 arylated 4-substituted 1H-indazoles was obtained in moderate to good yields.

Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents.

A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC50 values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker's best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.

Interfacial complexation driven three-dimensional assembly of cationic phosphorus dendrimers and graphene oxide sheets.

High content nitrogen, sulfur and phosphorus heteroatoms assembled in tree-like dendrimers (DG n ) are confined within the galleries of two-dimensional graphene oxide (GO). The presence of the ternary diethyl-N-ethyl-ammonium groups on the dendrimer peripheries ensures the exfoliation of graphene sheets thereby affording interfacially bridged, three-dimensional heteroatom-enriched graphene-based hybrid nanostructures (DG n -GO). Dendrimer generation (from 1 to 4) that reflects the bulkiness of these conceived nano-trees impacts increasingly the degree of dispersion-exfoliation and sheet desordering. The long-term stability of these aqueous suspensions associated with their handling flexibility allows uniform accommodation of the resulting hybrid materials as flame-retardants in bioplastics.

Elucidating the role of surface chemistry on cationic phosphorus dendrimer-siRNA complexation.

In the field of dendrimers targeting small interfering RNA (siRNA) delivery, dendrimer structural properties, such as the flexibility/rigidity ratio, play a crucial role in the efficiency of complexation. However, advances in organic chemistry have enabled the development of dendrimers that differ only by a single atom on their surface terminals. This is the case for cationic phosphorus dendrimers functionalized with either pyrrolidinium (DP) or morpholinium (DM) terminal groups. This small change was shown to strongly affect the dendrimer-siRNA complexation, leading to more efficient anti-inflammatory effects in the case of DP. Reasons for this different behavior can hardly be inferred only by biological in vitro and in vivo experiments due to the high number of variables and complexity of the investigated biological system. However, an understanding of how small chemical surface changes may completely modify the overall dendrimer-siRNA complexation is a significant breakthrough towards the design of efficient dendrimers for nucleic acid delivery. Herein, we present experimental and computational approaches based on isothermal titration calorimetry and molecular dynamics simulations to elucidate the molecular reasons behind different efficiencies and activities of DP and DM. Results of the present research highlight how chemical surface modifications may drive the overall dendrimer-siRNA affinity by influencing enthalpic and entropic contributions of binding free energy. Moreover, this study elucidates molecular reasons related to complexation stoichiometry that may be crucial in determining the dendrimer complexation efficiency.

First-in-Class Combination Therapy of a Copper(II) Metallo-Phosphorus Dendrimer with Cytotoxic Agents.

The metallo-phosphorus dendrimer 1G3-Cu (generation 3 dendrimer bearing 48 conjugated copper(II) on its surface) has antiproliferative activity related to its capacity to activate Bax translocation. In the present study, we evaluate the activity of an association of 1G3-Cu with 5 cytotoxic agents used in chemotherapy having different modes of action. Data show no additive effect with camptothecin and cisplatin, additivity with paclitaxel and MG132, and synergy with doxorubicin. Results suggest that the multivalent Cu-conjugated dendrimer 1G3-Cu (activator of Bax translocation) plays an important role in boosting the clinical impact of Bax accumulation stimulated by the proteasome inhibitor MG132, antimitotic taxanes, and the topo II inhibitor doxorubicin.

Original Multivalent Gold(III) and Dual Gold(III)-Copper(II) Conjugated Phosphorus Dendrimers as Potent Antitumoral and Antimicrobial Agents.

Original metallophosphorus dendrimers (generation 3, 48 terminal groups) have been prepared via the complexation of phosphorus dendrimers bearing imino-pyridino end groups with Au(III) or with both Au(III) and Cu(II). The complexation of the dendrimer with Au(III), leading to 1G3-[Au48][AuCl4]48, strongly increased the antiproliferative activities against both KB and HL-60 tumoral cell lines, showing IC50s in the low nanomolar range. It can be noticed also that this gold conjugated phosphorus dendrimer displayed low activity on the quiescent cell line EPC versus its potent antiproliferative activity against actively dividing cells. In order to evaluate the potential synergistic effect between Au(III) and Cu(II) and the influence of the number of Au(III) moieties on the surface of dendrimer against the proliferative activities, nine other original dendrimers with several surface modifications have been prepared. Whatever the number of Au(III) moieties introduced on the surface of dendrimers, all the dendrimers prepared displayed similar potency (nanomolar range) to 1G3-[Au48][AuCl4]48 against KB and HL60. In marked contrast synergistic effects on the antimicrobial activity of some of these phosphorus dendrimers are observed when both Au(III) and Cu(II) are present on the dendritic structure.

Anti-Inflammatory Effect of Anti-TNF-α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model.

Inflammation is an essential component of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), or acute lung injury. Our purpose was to design efficient carriers for lung delivery of small interfering RNA (siRNA) targeting tumor necrosis factor (TNF-α) in an acute lung injury model. To achieve this goal, two different types of phosphorus-based dendrimers with either pyrrolidinium or morpholinium as terminal protonated amino groups were selected for their better biocompatibility compared to other dendrimers. Dendriplexes containing pyrrolidinium surface groups demonstrated a stronger siRNA complexation, a higher cellular uptake, and enhanced in vitro silencing efficiency of TNF-α in the lipopolysaccharide (LPS)-activated mouse macrophage cell line RAW264.7, compared to morpholinium-containing dendriplexes. The better performance of the pyrrolidium dendriplexes was attributed to their higher pKa value leading to a stronger siRNA complexation and improved protection against enzymatic degradation resulting in a higher cellular uptake. The superior silencing effect of the pyrrolidinium dendriplexes, compared to noncomplexed siRNA, was confirmed in vivo in an LPS-induced murine model of short-term acute lung injury upon lung delivery via nasal administration. These data suggest that phosphorus dendriplexes have a strong potential in lung delivery of siRNA for treating inflammatory lung diseases.

Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

A multivalent phosphorus dendrimer 1G3 and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway.

A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action.

The well-known diuretic Ethacrynic acid (EA, Edecrin), showing low anti-proliferative activities, was chemically modified at different positions. The new EA derivatives have been tested in vitro in anti-proliferative assays on both tumor KB (epidermal carcinoma) and leukemia HL60 (promyelocytic) cells suitable targets for anticancer activity. Reduction of the α-ß double bond of EA completely abolished anti-cancer activities, whereas introduction of either 2-(4-substituted phenyl)ethanamine (series A) or 4-(4-substituted phenyl)piperazine (series B) moieties generated compounds showing moderate to strong anti-proliferative activities against human cancer cell lines. Several substitutions on the phenyl of these two moieties are tolerated. The mechanism of action of the EA derivatives prepared in this study is more complex than the inhibition of glutathione S-transferase π ascribed as unique effect to EA and might help to overcome tumor resistances.

Synthesis of onion-peel nanodendritic structures with sequential functional phosphorus diversity.

The preparation of novel families of phosphorus-based macromolecular architectures called "onion peel" phosphorus nanodendritic systems is reported. This construct is based on the versatility of methods of synthesis using several building blocks and on the capability of these systems to undergo regioselective reactions within the cascade structure. Sustainable metal-free routes such as the Staudinger reaction or Schiff-base condensation, involving only water and nitrogen as byproducts, allow access to several dendritic macromolecules bearing up to seven different phosphorus units in their backbone, each of them featuring specific reactivity. The presence of the highly aurophilic P=N-P=S fragment enables selective ligation of Au(I) within the dendritic framework.

Investigations on dendrimer space reveal solid and liquid tumor growth-inhibition by original phosphorus-based dendrimers and the corresponding monomers and dendrons with ethacrynic acid motifs.

The well-known reactive diuretic ethacrynic acid (EA, Edecrin), with low antiproliferative activities, was chemically modified and grafted onto phosphorus dendrimers and the corresponding simple branched phosphorus dendron-like derivatives affording novel nanodevices showing moderate to strong antiproliferative activities against liquid and solid tumor cell lines, respectively.

Bis[1-benzyl-2-(1,3-thia-zol-4-yl)-1H-benzimidazole-κ(2) N (2),N (3)]dichloridocobalt(II).

In the title compound, [CoCl2(C17H13N3S)2], the Co(II) atom exhibits a distorted octa-hedral coordination geometry involving two chloride ligands, one of which is split over two positions [refined site-occupancy ratio = 0.847 (18):0.153 (18)], and four N-atom donors from two 1-benzyl-2-(1,3-thia-zol-4-yl)-1H-benzimidazole ligands. The two chelate rings including the Co(II) atom are essentially planar, the maximum deviations from the mean planes being 0.080 (2) and 0.046 (2) Å; the dihedral angle between them is 74.1 (1)°. In both ligands, the thia-zole and benzimidazole rings are nearly coplanar, as indicated by the dihedral angles between their planes of 1.16 (8) and 6.29 (7)°. Each pendant benzene ring is almost perpendicular to the benzimidazole mol-ecule to which it is attached; the dihedral angles between their planes are 75.94 (9) and 75.55 (10)°. The crystal structure is stabilized by non-classical C-H⋯Cl hydrogen bonding forming a three-dimensional network.