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International audience; A series of 35 heteroarylimino-1,3-thiazolidinones with three sites of functionalization were synthesized and their antiproliferative properties were studied. The in vitro screening by MTT assay was performed against five cancer cell lines (human colon cancer cell lines HT29, HCT116 and SW620 and breast cancer cell lines MCF7 and MDA-MB-231). It was observed that N3-substituted thiazolidinones had moderate activities whereas 5-benzylidene thiazolidinones showed promising activities. To investigate the mechanism of action, detailed biological studies of six selected compounds (those presenting the lower mitotic index) were carried out on the human colon cancer HT29 cell line. Cell cycle assay revealed that those compounds induced cell accumulation in G2/M and in subG0/G1 phases of cell cycle. Moreover, dissipation of mitochondria membrane potential was observed as well as redox changes in treated cells. more...

International audience; A selective microwave-assisted mono and bis-annulation of dialkynyl-N-(het)arylpyrrole derivatives is described. These polycyclic aromatic hydrocarbons (PAHs) have been photophysical and computationally characterized. The mono-annulated systems display interesting charge-transfer properties. By contrast, these properties vanish within the more conjugated bis-annulated compounds. more...

International audience; Cell division cycle dual phosphatases (CDC25) are essential enzymes that regulate cell progression in cell cycle. Three isoforms exist as CDC25A, B and C. Over-expression of each CDC25 enzyme is found in cancers of diverse origins. Thiazolidinone derivatives have been reported to display anti-proliferative activities, bactericidal activities and to reduce inflammation process. New 2-(thienothiazolylimino)-1,3-thiazolidin-4-ones were synthesized and evaluated as inhibitors of CDC25 phosphatase. Among the molecules tested, compound 6 inhibited CDC25A with an IC50 estimated at 6.2 +/- 1.0 mu M. The binding of thiazolidinone derivative 6 onto CDC25A protein was reversible. In cellulo, compound 6 treatment led to MCF7 and MDA-MB-231 cell growth arrest. To our knowledge, it is the first time that such 4-thiazolidinone derivatives are characterized as CDC25 potential inhibitor. more...

A two-step synthesis of polyfunctionalized aminothieno[3,2- b ]furans and aminothieno[3,4- b ]furans is described and discussed. It was found that O-alkylated thiophenes bearing electron-withdrawing groups in the ortho -position undergo condensation in the presence of an excess of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Furthermore, selective condensation on an ortho -nitrile substituent in preference to ortho -ester or ortho -ketone substituents was observed. more...

New 2-aminoselenophene-3-carbonitriles and 5-amino-1,3-thiazole-4-carbonitriles were made and reacted with cycloalkanones to give tetrahydros elenolo[2,3-b]quinolines, cycloalkene-fused selenolo[3,2-e]pyridines, [1,3]thiazolo[5,4- b]quinolines, thiazolo[4,5-e]pyridines and tetrahydr o[1,3]thiazolo[5,4-b]quinolines. more...

In this work, we described the synthesis of 3-isothiocyanatoselenophenes starting from 3-aminoselenophenes (using thiophosgene). Those compounds were then converted to the corresponding thioureas in the presence of ammonium hydroxide. Cyclization in 2-aminoselenolo[3,2-d]thiazoles was achieved using DDQ. 2-Aminothieno[3,2-d]thiazoles were obtained from 3-isothiocyanatothiophenes using the same pathway. more...

The preparation of new N-substituted 2-arylimino-1,3-thiazolidin-4-ones from 5-substituted-3-aminothiophenes using an easy three-step procedure is described.

New 4-amino-2-arylthieno[2,3-d]pyrimidines were synthesized by reacting 2-amino-3-cyanothiophenes and aryl nitriles under microwave irradiation. Functionalization of 4-amino group was made by acetic anhydride and several isocyanates. more...

In this work, we described the synthesis of new tetrasubstituted thiophenes and selenophenes achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from ketene dithioacetals. more...

5-Substituted 3-amino-selenophene-2-carbonitriles and 2-substituted 4-amino-1,3-selenazole-5-carbonitriles were reacted with sodium nitrite in hydrochloric acid to give chloroselenolotriazines and chloroselenazolotriazines. These compounds were then subjected to S N Ar reactions with secondary amines under microwave irradiation. more...

In this work, we describe the synthesis of new 2,4,5-trisubstituted-1,3-thiazoles and 1,3-selenazole achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from dimethyl cyanodithioimidocarbonate, which was the common starting material for the preparation of all 1,3-thiazoles and 1,3-selenazoles. Chemical diversity was introduced on thiazole and selenazole rings by varying the amines and the activated halides used. more...

Microwave-assisted synthesis allowed efficient access to 4-chloroselenolo[3,2-d]pyrimidines in short times and very good a yields. Some functionalizations by S N Ar and palladium-catalyzed reactions are also reported. more...

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedlander reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines. more...

DDQ was employed as a dehydrogenation reagent to synthesize polyaromatic compounds from the corresponding tetrahydro derivatives. A microwave-assisted process allows shorter reaction times and easier purification as fewer degradation products were formed. more...

β-Chloroacroleins reacted readily with lactams and several heteroarylamines (aminopyridines, aminoquinoline and azoles) under standard Buchwald-Hartwig amination conditions. Both Pd(OAc) 2 /Binap or Pd(OAc) 2 /Xantphos were efficient catalytic systems in the presence of Cs 2 CO 3 as base. more...

International audience; Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure-activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models' predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors. more...

The N-arylation of hetarylamines by reaction of aminopyridines or aminoquinolines with substituted bromothiophene-2- or -3-carboxylates is described. From 2-aminopyridines and 1-aminoisoquinoline, polycyclic compounds were obtained in one-pot, two-step reactions: C-N coupling is followed by intramolecular cyclization involving the nitrogen atom of the heterocyclic ring and the carboxylate. Steric hindrance seems to be a limitation for the latter reaction, because when 2-amino-6-picoline was used, the corresponding dihetarylamines were obtained. more...

We describe here the palladium-catalyzed amination of polysubstituted bromothiophenes under mild conditions (using Cs 2 CO 3 as base). Anilines bearing electron-donating groups gave good results whereas anilines with electron-withdrawing substituents required greater catalyst loadings and gave lower yields. more...

A wide range of the title compounds (IV) are formed in good yields in two steps starting from thiophen-3-isothiocyanates.

International audience; A series of 5-aryl-2-(3-thienylamino)-1,3,4-thiadiazoles 3a-m were synthesized in good yields in two steps starting from thiophen-3-isothiocyanates. Those compounds as well as the thiosemicarbazide intermediates 2a-m were screened for their antiproliferative activity against a panel of six cancer cell lines. Among them, two 5-aryl-2-(3-thienylamino)-1,3,4-thiadiazoles (3f and 3i) have shown very interesting results with IC50 < 10 mu M on three cell lines. more...

It is demonstrated that base promoted intramolecular condensation occurs preferentially on the adjacent nitrile group rather than at an ester or at a ketone substituent.

International audience; Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure-Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1-3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level. more...

The in vitro growth inhibitory activity of 26 thiazoles (including 4-halogeno-2,5-disubtituted-1,3-thiazoles) and 5 thienothiazoles was assessed on a panel of 6 human cancer cell lines, including glioma cell lines. (4-Chloro-2-(piperidin-1-yl)thiazol-5-yl)(phenyl)methanone ( 12a ) and (4-bromo-2-(piperidin-1-yl)thiazol-5-yl)(phenyl)methanone ( 12b ) displayed ∼10 times greater in vitro growth inhibitory activity than perillyl alcohol (POH), which therapeutically benefits glioma patients through the inhibition of both alpha-1 Na + /K + -ATPase (NAK) and Ras oncogene activity. The in vitro cytostatic activities (as revealed by quantitative videomicroscopy) displayed by 12a and 12b were independent of the intrinsic resistance to pro-apoptotic stimuli associated with cancer cells. Compounds 12a and 12b displayed relatively similar inhibitory activities on purified guinea pig brain preparations that mainly express NAK alpha-2 and alpha-3 subunits, whereas only compound 12b was efficacious against purified guinea pig kidney preparations that mainly express the NAK alpha-1 subunit, which is also expressed in gliomas, melanomas and non-small-cell lung cancers NSCLCs. more...

In this work, we described the synthesis of 3-isothiocyanatoselenophenes starting from 3-aminoselenophenes (using thiophosgene). Those compounds were then converted to the corresponding thioureas in the presence of ammonium hydroxide. Cyclization in 2-aminoselenolo[3,2-d]thiazoles was achieved using DDQ. 2-Aminothieno[3,2-d]thiazoles were obtained from 3-isothiocyanatothiophenes using the same pathway. more...

A four-step preparation of compounds containing a coumarinic moiety is presented. This synthesis involves notably a Suzuki cross-coupling reaction (performed in aqueous media) and a ring closure by formation of δ-lactone. more...

Starting from carboxylic acids, a convenient three-step synthesis of aldehydes is developed as is exemplified for (Va).

In continuation of an ongoing project directed to synthesize novel agonists in the glitazone class, a three-step procedure for the synthesis of title compounds (VII) is described.

Several monographs, series and articles have been published on selenophene [1–4]. These give a general overview of the nucleus synthesis. In this chapter we focus on the synthesis of hydroxy and aminoselenophenes and also describe examples of their reactivity or their transformation to different condensed heterocyclic systems. more...

All pyridine nitriles and esters were metalated at the position next to the directing group using (TMP)3CdLi in tetrahydrofuran at room temperature. The 2-, 3-, and 4-cyanopyridines were treated with 0.5 equiv of base for 2 h to afford, after subsequent trapping with iodine, the corresponding 3-iodo, 2-iodo, and 3-iodo derivatives, respectively, in yields ranging from 30 to 61%. Cyanopyrazine was similarly functionalized at the 3 position in 43% yield. Ethyl 3-iodopicolinate and -isonicotinate were synthesized from the corresponding pyridine esters in 58 and 65% yield. Less stable ethyl 4-iodonicotinate also formed under the same conditions and was directly converted to ethyl 4-(pyrazol-1-yl)nicotinate in a two-step 38% yield. All three ethyl iodopyridinecarboxylates were involved in a one-pot palladium-catalyzed cross-coupling reaction/cyclization using 2-aminopyridine to afford new dipyrido[1,2-a:3′,2′-d]pyrimidin-11-one, dipyrido[1,2-a:4′,3′-d]pyrimidin-11-one, and dipyrido[1,2-a:3′,4′-d]pyrimidin-5-on... more...

A four-step preparation of compounds containing a coumarinic moiety is presented. This synthesis involves notably a Suzuki cross-coupling reaction (performed in aqueous media) and a ring closure by formation of δ-lactone. more...

In this work, we described the synthesis of new tetrasubstituted thiophenes and selenophenes achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from ketene dithioacetals. more...

International audience; A series of thieno[2,3-d]- and thieno[3,2-d]pyrimidines have been easily synthesized using as key step a deproto-cadmiation-trapping sequence. Some of the compounds thus synthesized were screened for anti-cancer (cytotoxic) activities, and (S)-2-(6-iodo-2-phenylthieno[2,3-d]pyrimidin- 4-ylamino)-3-phenylpropanoic acid proved to have a significant activity towards liver, human breast and cervix carcinoma cell lines. more...