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.

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, Photophysical Properties, and Aromaticity of Pyrazine-Fused Tetrazapentalenes.

Pyrazine-fused 1,2,6,6a-tetrazapentalenes (PyTeAP) are zwitterionic tricyclic compounds exhibiting an original pattern with four consecutive nitrogen atoms. They were obtained by a challenging cyclization through the formation of a N-N bond under thermolytic conditions. Ten derivatives were synthesized, and the original scaffold of PyTeAP was confirmed by single-crystal X-ray diffraction analysis of one derivative. Examination of their photophysical properties in solution revealed blue fluorescence with λem = 416-426 nm. Theoretical investigations of the aromaticity in these compounds through magnetic criteria evidenced the presence of a dominant 14-electron circuit at the periphery.

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.

Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors.

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.

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.

Pyridazino-1,3a,6a-Triazapentalenes as Versatile Fluorescent Probes: Impact of Their Post-Functionalization and Application for Cellular Imaging.

Pyridazino-1,3a,6a-triazapentalenes (PyTAP) are compact fused 6/5/5 tricyclic scaffolds which exhibit promising fluorescent properties. Chemically stable, they can be post-functionalized using standard Pd-catalyzed cross-coupling chemistry. Several original PyTAP bearing additional unsaturated substituents in positions 2 and 8 were synthetized and their spectroscopic properties analyzed. They have been successfully tested as fluorescent probes for cellular imaging.

Access and modulation of substituted 1-methyl-1,6-dihydropyrazolo[3,4-c]pyrazoles.

Despite the pharmacological potential of the pyrazolo[3,4-c]pyrazoles, only a few methods of preparation and direct functionalization of this moiety have been described. We report herein a convenient design of new pyrazolo[3,4-c]pyrazoles with a high therapeutic impact. The effective chosen strategy consists of hydrazine condensations and C-N Ullmann-type cross-coupling reactions with microwave activation. Moreover, chemoselective bromination of the newly formed bipyrazoles followed by Suzuki-Miyaura cross-coupling reactions allowed the synthesis of a variety of modulated heterobicycles.

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.

Intramolecular Metal-Free N-N Bond Formation with Heteroaromatic Amines: Mild Access to Fused-Triazapentalene Derivatives.

Formation of N-N bonds may offer an original approach to various nitrogen-containing heterocycles with numerous applications. For this purpose, we found that readily available heteroaromatic amines are appropriate substrates for providing an efficient and innovative approach for the formation of N-N bonds in the presence of iodine (III) reagent in very mild conditions. This method makes it possible to synthesize nitrogen rich triazapentalene derivatives exhibiting fluorescent properties, inaccessible with existing approaches.

Organocatalytic aza-Michael Reaction to 3-Vinyl-1,2,4-triazines as a Valuable Bifunctional Platform.

An unprecedented catalytic aza-Michael addition to substituted 3-vinyl-1,2,4-triazines, as original bifunctional platforms for the domino conjugate addition inverse-electron-demand hetero-Diels-Alder/retro-Diels-Alder ( ihDA/ rDA) reaction, was achieved using the highly acidic triflimide as an organocatalyst. Based on the use of alkoxyamine nucleophiles, this sequence not only highlights a rare example of the catalytic aza-Michael reaction to alkenylazaarenes but also proves to be useful for the elaboration of an array of biorelevant tetrahydro-[1,6]-naphthyridines.

Domino Aza-Michael-ih-Diels-Alder Reaction to Various 3-Vinyl-1,2,4-triazines: Access to Polysubstituted Tetrahydro-1,6-naphthyridines.

A straightforward domino aza-Michael-inverse-electron-demand-hetero-Diels-Alder/retro-Diels-Alder reaction between primary and secondary propargylamine derivatives and 3-vinyl-1,2,4-triazines is developed highlighting not only the uniqueness of this dual-heterocyclic platform but also a novel and unprecedented path to polysubstituted tetrahydro-1,6-naphthyridine scaffolds.

Efficient metal-free synthesis of various pyrido[2',1':2,3]imidazo- [4,5-b]quinolines.

Dancing with diversity: The synthesis of diverse pyrido[2',1':2,3]imidazo[4,5-b]quinolines bearing several substitution patterns was developed based on combining a multicomponent reaction (Groebke-Blackburn-Bienaymé reaction) with an original cyclization as a secondary transformation (see scheme; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene).

Total synthesis of bistramide†A and its 36(Z)†isomers: differential effect on cell division, differentiation, and apoptosis.

The total synthesis of bistramide A and its 36(Z),39(S) and 36(Z),39(R) isomers shows that these compounds have different effects on cell division and apoptosis. The synthesis relies on a novel enol ether-forming reaction for the spiroketal fragment, a kinetic oxa-Michael cyclization reaction for the tetrahydropyran fragment, and an asymmetric crotonylation reaction for the amino acid fragment. Preliminary biological studies show a distinct pattern of influence of each of the three compounds on cell division, differentiation, and apoptosis in HL-60 cells, thus suggesting that these effects are independent activities of the natural product.

Efficient synthesis of unprotected C-5-aryl/heteroaryl-2'-deoxyuridine via a Suzuki-Miyaura reaction in aqueous media.

Following our previous results on an environmentally benign one-pot Sonogashira-cyclization protocol to obtain substituted furopyrimidine nucleosides under aqueous conditions, we investigate herein the Suzuki-Miyaura cross-coupling reactions of aryl and heteroaryl derivatives at the C5 position of unprotected 2'-deoxyuridine in the same media with a common catalyst system avoiding exotic ligands, since palladium acetate and triphenylphosphine afforded the expected products in moderate to good yields.

Synthesis and cross-coupling of sulfonamidomethyltrifluoroborates.

Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to access such structurally interesting motifs.

Synthesis of amidomethyltrifluoroborates and their use in cross-coupling reactions.

Amidomethyltrifluoroborates were successfully synthesized in a one-pot fashion and used in cross-coupling reactions with a wide variety of aryl and heteroaryl chlorides.