Search

A novel pyrazolo-enaminones, bipyrazoles and bipyrazolopyridines from 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)butane-1,3-dione and 4-methyl-2-phenyl-2H-pyrazolo[3,4-b]pyridine-3,6(3aH,7H)-dione have been synthesized by assisted heating with microwave radiation without any catalyst. The pyridine and pyrazole ring formation has been developed from easily accessible enamino keto esters by formylation followed by intramolecular cyclization. The general applicability for the synthesis of the important pyrazolo-enaminones, bipyrazoles and pyrazolo-pyridines heterocycles was attributed to simplicity of operation, synthesis without catalyst, energy efficiency (shorter reaction time under microwave irradiation), good yields, more environmentally friendly and more cost-effective procedure. The antioxidant activity of new heterocyclic compounds was evaluated by free radical scavenging by DPPH assay. Several of these compounds showed good activity against both Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria.

KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the α4-α5 helices of the allosteric domain of KRAS. This region had previously been identified as the binding site for calmodulin (CaM). Using surface plasmon resonance and pulldown analyses, we prove that P14B binds directly to oncogenic KRAS thus competing with CaM. Interestingly, P14B favors oncogenic KRAS interaction with BRAF and phosphorylated C-RAF, and increases downstream Ras signaling in CRC cells expressing oncogenic KRAS. The viability of these cells, but not that of the normal cells, is impaired by P14B treatment. These data support the significance of the α4-α5 helices region of KRAS in the regulation of oncogenic KRAS signaling, and demonstrate that drugs interacting with this site may destine CRC cells to death by increasing oncogenic KRAS downstream signaling.

Background: In this current work, a new synthesis strategy was developed to obtain 1,3,4-trisubstituted pyrazoles derivatives. Methods: A series of 1,3,4-trisubstituted pyrazoles have been prepared via 1,3-dipolar cycloaddition reaction of 3-phenylsydnones with a variety of alkenes derivatives, symmetric and non-symmetric alkynes derivatives, N-phenyl-maleimide, N-benzylmaleimides, and maleic anhydride under conventional manner. Results: Moreover, in this work, it has been demonstrated that the 4-bromopyrazole intermediates can be further functionalized by a combination of Suzuki-Miyaura crosscoupling reactions with aryl-boronic acids and N-arylation reactions of anilines. Conclusion: In summary, we have developed a new method to obtain 1,3,4 triarylated pyrazoles through 3-phenylsydnone 1,3-dipolar cycloadditions. By comparing the different reactions, it is apparent that high temperatures and xylene as solvent are key to achieving pyrazoles derivatives. The best yields were observed for symmetric and non-symmetric alkynes as dipolarophiles.

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors (IC50 between 0.04 and 0.71 M). Also, these highly active methyl sulfones displayed greater COX-2 activity than the parent carboxylic NSAIDs, thus indicating that the replacement of the acetic or propionic acids by a methyl sulfone group enables some of these structures to possess higher COX-2 inhibitory activity than that of the corresponding alkyl carboxylic analogues. The improved inhibitory activity is attributed to the higher flexibility of the sulfone-receptor interaction that enables more profound exploration of the binding site compared with that of acidic analogues. This observation is underpinned by molecular modeling studies that indicates a change in the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.

An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the Kras-Wnt pathway. The lactone 2a also exerted a potent inhibition of Tau protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix α3 and α4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97.

Structural features from the anticancer prodrug nemorubicin (MMDX) and the DNA-binding molecule DRAQ5™ were used to prepare anthraquinone-based compounds, which were assessed for their potential to interrogate cytochrome P450 (CYP) functional activity and localisation. 1,4-disubstituted anthraquinone 8 was shown to be 5-fold more potent in EJ138 bladder cancer cells after CYP1A2 bioactivation. In contrast, 1,5-bis((2-morpholinoethyl)amino) substituted anthraquinone 10 was not CYP-bioactivated but was shown to be fluorescent and subsequently photo-activated by a light pulse (at a bandwidth 532–587 nm), resulting in punctuated foci accumulation in the cytoplasm. It also showed low toxicity in human osteosarcoma cells. These combined properties provide an interesting prospective approach for opto-tagging single or a sub-population of cells and seeking their location without the need for continuous monitoring.

Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro.

Furo[3,4-b]benzodioxin 1 was found to undergo a doubleDiels–Alder reaction with several dienophiles. The diene reacts directly with the suitable dienophile to give the mono-adduct intermediate that unexpectedly leads to a second cycloaddition at the internal, electron-rich, oxabicyclic C4a–C10a double bond. The resulting bis-adducts were formed under relatively mild conditions with dienophiles ranging from maleic anhydride and dimethyl acetylenedicarboxylate to the extremely reactive arynes. With this methodology of two uninterrupted sequential cycloaddition reactions, interesting formation of stable bis-adducts was observed. The dienophile behavior of 1,4-benzodioxin is described for the first time in this work.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Aryl halides and triflates are coupled with primary amides to give the corresponding arylamines in the presence of a palladium catalyst, a suitable ligand, and a base. The catalyst system performs well for a large number of different substrates at 100–150 °C without solvent, and with low catalyst levels (0.12 mol % Pd). Nicotinamide might be useful as a nitrogen source in the Pd-catalyzed amination reaction.

An easy route to the synthesis of 2-substituted-7-azaindole derivatives has been developed. The carbinol intermediate dissolved in DMF undergoes cyclization upon treatment with sodium hydride, trifluoroacetic anhydride, and trifluoroacetic acid at 120 °C in a straightforward and one-pot step. An alternative methodology using (CF3SO2)2O in acetonitrile in basic media followed by the addition of CF3COOH affords the expected 2-substituted azaindole in best yields.

A series of substituted derivatives containing the 1,4-benzodioxine or pyrrole nucleus are described. All the newly synthesized compounds were examined for their in vitro and in vivo anti-inflammatory activity. Several derivatives, including (S)-2, 14 and 17, showed more anti-inflammatory activity in vivo in these assays (rat paw oedema induced by carrageenan) than the known classical anti-inflammatory agent ibuprofen, whereas other compounds like 1 were equipotent to ibuprofen. Compound 17 was the most outstanding derivative because of its remarkable in vivo anti-inflammatory activity. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

A set of disubstituted tetracyclic lactones has been synthesized and tested for potential antitumor activity. Several of them possess a noticeable cytotoxicity against L1210 and HT-29 colon cells in vitro. Relationships between chain nature and biological properties were sought. Lactones with a pentyl or hexyl substituent at C-11 are the most active ones. The introduction of a functional group at the side chain of C-11 modified the potency; carboxylic acid and primary amine decreased the cytotoxicity, whereas a cyano group increased the activity. An extensive structure-activity relationship study of these derivatives, including carbon homologues and bioisosteres has been performed. The synthesis and cytotoxicity of these compounds are discussed. Two lactones are recognized as potential lead compounds.

A series of new acridines has been prepared by cyclodehydration of N-(2,3-dihydro-1,4-benzodioxin-6-yl)anthranilic acid in acidic media following classical procedures. All these compounds have in common a dioxygenated ring fused to the acridine. The tetracyclic system possesses a linear or angular structure formed by intramolecular cyclisation. The last ring and the substituent of the system modify, in an interesting way, the antitumor activity of acridines. Several of the studied compounds displayed significant cytotoxic activity (inhibition of L1210 and HT-29 cell proliferation). The most cytotoxic compound 13a, shows more activity than m-AMSA in inhibiting L1210 and HT-29 cell proliferation and this compound has been selected as a development candidate for further evaluation. The activity results also indicate that the new 11-O-substituted compounds are of considerable interest with high levels of cytotoxic activity. The angular or non-linear dioxinoacridine 10 was equiactive with the linear structure 7. Pentacyclic analogues (14 and 15) were more cytotoxic than the tetracyclic compounds (up to twofold).

Aryl halides and aryl triflates (triflate = trifluoromethanesulfonyl) are coupled with N-compounds to give the corresponding arylamines or arylhydrazines in the presence of a palladium catalyst, a suitable ligand, and a base. Catalyst systems consisting of palladium (II) and BINAP or triphenylphos phine are generally effective for the amination of a wide range of aryl halides and aryl triflates with anilines and hydrazines.

This paper describes extensive research on the activity of more of 100 cytotoxic compounds containing an oxygenated ring in their structure and isolated from natural plants or prepared by semisynthesis or synthesis from available intermediates. Anticancer drugs have been classified according to the chemical structure of the natural products that are considered to lead the series. The origin and mechanism of action involved in each case have been considered. This new family of natural, semisynthetic and synthetic products includes compounds with interesting antitumor activity such as podophyllotoxin derivatives, NK-611 (15), TOP-53 (16), NPF (24) and Tafluposide (28); camptothecin analogs such as 45 with a considerable cytotoxicity against beta-cell chronic lymphocytic leukemia (CLL), and 52 (new piperazinyl-CPT analog). New dioxygenated ellipticine analogs showed more activity and stability than the natural pattern when the structure incorporated a lactone function instead of the pyridine ring. In the acridine series the new tetracyclic derivatives 75 and 76 containing ethylenedioxy groups at the 2- and 3-positions of the acridine system exhibited the same activity as m-AMSA in vivo against murine P-388 leukemia. Other isolated compounds containing a dioxygenated ring in their structure such as 100 and 101 showed antitumor activities related to kinase inhibition, and are attractive candidates for development of new synthetic antitumor agents.

A simple route to the preparation of new heterocyclic systems: pyrazolo [3,4-b]pyridines from the easily available 2-pyrone and 3-aminopyrazolone. The structure of the compounds and the mechanism of their formation are reported.

The 1,4-benzodioxin-2-carboxylic esters or carboxamides react with nucleophilic amines to give access to 3-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxamides and 3-aminomethyn-1,4-benzodioxin-2(3 H )-one precursors of potential therapeutical compounds. The basic environment (K 2 CO 3 or amine) facilitates the process.

B-Raf mutations are identified in 40-50% of patients with melanoma and among them, the substitution of valine for glutamic acid at position 600 ( V600E B-Raf) is the most frequent. Treatment of these patients with B-Raf inhibitors has been associated with a clear clinical benefit. Unfortunately, multiple resistance mechanisms have been identified and new potent and selective inhibitors are currently needed. In this work, five different type II inhibitors, which bind V600E B-Raf in its DFG-out conformation, have been studied using molecular dynamics, free energy calculations and energy decomposition analysis. The ranking of calculated MM-PB/GBSA binding affinities is in good agreement with the experimentally measured ones. The per-residue decomposition of ΔG binding , within the MM-GBSA approach, has been used to identify the key residues governing the allosteric binding of the studied compounds to the V600E B-Raf protein kinase. Results indicate that although van der Waals interactions are key determinants for binding, hydrogen bonds also play an important role. This work also provides a better structural understanding of the binding of DFG-out inhibitors to V600E B-Raf, which can be used in a further step for rational design of a new class of B-Raf potent inhibitors.

A convenient procedure for the synthesis of quinoxalines and pyridopyrazines has been developed from aryldiamines. The condensation of aminocarbamates such as 12 with ethyl 2,3-dibromopropionate provide the quinoxaline 14 directly, in a one-step operation. The methodology reported herein represents an alternative to condensation of o -phenylenediamines with α-dicarbonyl compounds for the quinoxalines formation. The same procedure was applied to the 2,3-diaminopyridine to obtain the corresponding pyridopyrazines.

The pyrrolo[2,1- c ][1,4]benzoxazine system was synthesized from 2-fluoroaniline involving an intramolecular nucleophilic displacement of the fluoride atom. The intermediate alcohols 7a and 10 were treated in basic media under strictly controlled conditions which led to the desired tricyclic structure. The unsubstituted alcohol 10 was more stable than the substituted one.

Summary Racemic (R,S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid (3) has been prepared from 2,3-dihydro-1,4-benzodioxin. R-(−)-Pantolactone has been used as auxiliary for the synthesis of R-3 and S-3. The anti-inflammatory properties of the new carboxylic acids are described and compared with other anti-inflammatory agents. The highest activity is exhibited by compound biS-3.

The naphtho-fused systems 3 and 4 were synthesized from the hydroxy-acetal1 through deacetylation, formation of unstable diene 2 and Diels-Alder cycloaddition with the appropriate dienophile in acidic media.

Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hall- mark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM (the calcein acetoxymethyl-ester) on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phos-phate pathway was significantly altered. To elucidate whe-ther these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.

2,3-dohydro-2,3-dimethylene-1,4-benzodioxin undergoes an easy Diels Alder cycloaddition with a variety of dienophiles. The new products obtained constitute attractive compounds as useful intermediates in the synthesis of tri and tetracyclic systems.

The naphtho-fused systems 3 and 4 were synthesized from the hydroxy-acetal1 through deacetylation, formation of unstable diene 2 and Diels-Alder cycloaddition with the appropriate dienophile in acidic media.

Summary Racemic (R,S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid (3) has been prepared from 2,3-dihydro-1,4-benzodioxin. R-(−)-Pantolactone has been used as auxiliary for the synthesis of R-3 and S-3. The anti-inflammatory properties of the new carboxylic acids are described and compared with other anti-inflammatory agents. The highest activity is exhibited by compound biS-3.

The pyrrolo[2,1- c ][1,4]benzoxazine system was synthesized from 2-fluoroaniline involving an intramolecular nucleophilic displacement of the fluoride atom. The intermediate alcohols 7a and 10 were treated in basic media under strictly controlled conditions which led to the desired tricyclic structure. The unsubstituted alcohol 10 was more stable than the substituted one.

New compounds with naphtho-fused systems were synthesized and evaluated as antitumor agents. The naphtho-fused systems 6 and 7, synthesized from the hydroxy-acetal, exhibit antitumor activity. The bis(phenylthio) derivatives were considered as possible precursors for lignan lactones (11). The hydroxy-naphthalen 6 showed a significant antineoplastic activity.

A convenient procedure for the synthesis of quinoxalines and pyridopyrazines has been developed from aryldiamines. The condensation of aminocarbamates such as 12 with ethyl 2,3-dibromopropionate provide the quinoxaline 14 directly, in a one-step operation. The methodology reported herein represents an alternative to condensation of o -phenylenediamines with α-dicarbonyl compounds for the quinoxalines formation. The same procedure was applied to the 2,3-diaminopyridine to obtain the corresponding pyridopyrazines.

2,3-dohydro-2,3-dimethylene-1,4-benzodioxin undergoes an easy Diels Alder cycloaddition with a variety of dienophiles. The new products obtained constitute attractive compounds as useful intermediates in the synthesis of tri and tetracyclic systems.

Aryl halides and triflates are coupled with primary amides to give the corresponding arylamines in the presence of a palladium catalyst, a suitable ligand, and a base. The catalyst system performs well for a large number of different substrates at 100–150 °C without solvent, and with low catalyst levels (0.12 mol % Pd). Nicotinamide might be useful as a nitrogen source in the Pd-catalyzed amination reaction.

The structure of the title compound, C 16 H 18 O 7 , a key intermediate in the synthesis of antagonist adrenergic agents, is reported. The 1,4-benzodioxin ring shows a half-chair form with a Csp 3 atom out of the plane defined by the remaining atoms. The lactone ring shows an envelope form.

Aryl bromides are coupled with N -compounds to give the corresponding arylamines in the presence of a palladium catalyst, a suitable ligand, and a weak base. The catalysts perform well for a large number of different starting material combinations at 100–150 °C with drops of toluene or without solvent, and with low catalyst levels (0.12 mol % Pd). The low catalyst amount makes the process environment friendly.

The 2-oxofuran moiety in the title compound, C l7 H 18 O 6 , has a skew-envelope form. The heterocycle of the 1,4-benzodioxin-6-yl moiety has the typical half-chair form and steric hindrance between the substituents produces the observed loss of planarity of the 2-arylethanoic acid moiety.

The crystal structure of the title compound has been determined in order to obtain the geometry of one isomer of C 14 H 15 NO 3 . The molecule has the unusual feature of a planar dioxane ring and several bond angles are enlarged due to steric hindrance.

Novel methods for heterocyclic synthesis by metathesis have been developed. Versatile heterocyclic compounds were easily prepared in good yield from intermediate olefins by ring-closing olefin metathesis using the catalyst dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium.

A series of new acridines has been prepared by cyclodehydration of N-(2,3-dihydro-1,4-benzodioxin-6-yl)anthranilic acid in acidic media following classical procedures. All these compounds have in common a dioxygenated ring fused to the acridine. The tetracyclic system possesses a linear or angular structure formed by intramolecular cyclisation. The last ring and the substituent of the system modify, in an interesting way, the antitumor activity of acridines. Several of the studied compounds displayed significant cytotoxic activity (inhibition of L1210 and HT-29 cell proliferation). The most cytotoxic compound 13a, shows more activity than m-AMSA in inhibiting L1210 and HT-29 cell proliferation and this compound has been selected as a development candidate for further evaluation. The activity results also indicate that the new 11-O-substituted compounds are of considerable interest with high levels of cytotoxic activity. The angular or non-linear dioxinoacridine 10 was equiactive with the linear structure 7. Pentacyclic analogues (14 and 15) were more cytotoxic than the tetracyclic compounds (up to twofold).

The spiropiperidine derivatives have considerable importance in pharmaceutical chemistry due to their effects on different biological systems [...]

New compounds with naphtho-fused systems were synthesized and evaluated as antitumor agents. The naphtho-fused systems 6 and 7, synthesized from the hydroxy-acetal, exhibit antitumor activity. The bis(phenylthio) derivatives were considered as possible precursors for lignan lactones (11). The hydroxy-naphthalen 6 showed a significant antineoplastic activity.