RESUMEN
Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMOheterodiene-HOMOdienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4',3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.
RESUMEN
Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed by, e.g., intramolecular replacement of the nitro group) with the possibility to exploit a conjugated system of double bonds within an electrocyclization process. Herein, nitrostilbenes are reacted with different aromatic enols provided by a double (carbon and oxygen) nucleophilicity, leading to novel, interesting naphthodihydrofurans. From these, as a viable application, aromatization and electrocyclization lead in turn to valuable polycondensed, fully aromatic O-heterocycles.
Asunto(s)
Carbono , Furanos , Alcoholes , Aminas , Carbono/química , Furanos/química , TiofenosRESUMEN
Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.
Asunto(s)
Antibacterianos , Azetidinas , Enterococcus faecalis/crecimiento & desarrollo , Staphylococcus aureus/crecimiento & desarrollo , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Azetidinas/síntesis química , Azetidinas/química , Azetidinas/farmacología , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Células Hep G2 , Humanos , Relación Estructura-ActividadRESUMEN
Our research groups have been involved for many years in studies aimed at identifying new active organic compounds endowed with pharmacological properties. In this work, we focused our attention on the evaluation of cardiovascular and molecular drug resistance (MDR) reverting activities of some nitrosubstituted sulphur-containing heterocycles. Firstly, we have examined the effects of 4-nitro-3-(4-methylphenyl)-3,6-dihydro-2H-thiopyran S,S-dioxide 5, and have observed no activity. Then we have extended our investigation to the 3-aryl-4-nitrobenzothiochromans S,S-dioxide 6 and 7, and have observed an interesting biological profile. Cardiovascular activities were assessed for all compounds using ex vivo studies, while the MDR reverting effect was evaluated only for selected compounds using tumor cell lines. All compounds were shown to affect cardiovascular parameters. Compound 7i exerted the most effect on negative inotropic activity, while 6d and 6f could be interesting molecules for the development of more active ABCB1 inhibitors. Both 6 and 7 represent structures of large possible biological interest, providing a scaffold for the identification of new ABCB1 inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Canales de Calcio/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromanos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Canales de Calcio/metabolismo , Línea Celular Tumoral , Cromanos/síntesis química , Cromanos/química , Doxorrubicina/farmacología , Sinergismo Farmacológico , Cobayas , Atrios Cardíacos/metabolismo , Humanos , Concentración 50 Inhibidora , Músculo Liso/fisiología , Piranos/síntesis química , Piranos/química , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/química , Tiamina/análogos & derivados , Tiamina/síntesis química , Tiamina/química , Tiamina/farmacologíaRESUMEN
Herein we report a significant, valuable extension of a recently implemented pyrrole benzannulation methodology that, employing versatile nitrodienes from our lab as useful C4 building blocks, led to indole derivatives characterized by unusual patterns of substitution. The 6-nitro-7-arylindoles resulting from suitably derivatized, non-symmetric dienes are of foreseeable synthetic interest in search for new polyheterocyclic systems. As an example, pyrrolocarbazoles with a rarely reported ring fusion were synthesized with the classical Cadogan protocol. Furthermore, the proven easy reducibility of the nitro group to amine will surely open the way to further interesting elaborations.
Asunto(s)
Carbazoles/química , Indoles/química , Pirroles/química , Carbazoles/síntesis química , Indoles/síntesis química , Estructura Molecular , Pirroles/síntesis químicaRESUMEN
A series of 1-[(methylsulfonyl)methyl]-2-nitro-5,6,7,8-tetrahydroindolizines and homologs were designed, prepared, and evaluated as non-sugar-type α-glucosidase inhibitors. The inhibitory activity appeared to be related to cyclo homologation with the best congeners being tetrahydroindolizines. The introduction of a methoxycarbonyl group as an additional hydrogen bond acceptor into the exocyclic methylene group was beneficial affording the most potent congener 3e (half maximal inhibitory concentration, IC50=8.0±0.1µM) which displayed 25-fold higher inhibitory activity than 1-deoxynojirimycin (2, IC50=203±9µM)-the reference compound. Kinetic analysis indicated that compound 3e is a mixed inhibitor with preference for the free enzyme over the α-glucosidase-substrate complex (Ki,free=3.6µM; Ki,bound=7.6µM). Molecular docking experiments were in agreement with kinetic results indicating reliable interactions with both the catalytic cleft and other sites. Circular dichroism spectroscopy studies suggested that the inhibition exerted by 3e may involve changes in the secondary structure of the enzyme. Considering the relatively low molecular weight of 3e together with its high fraction of sp3 hybridized carbon atoms, this nitro-substituted tetrahydroindolizine may be considered as a good starting point towards new leads in the area of α-glucosidase inhibitors.
Asunto(s)
Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas/farmacología , Indolizinas/farmacología , Nitrocompuestos/farmacología , alfa-Glucosidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Humanos , Indolizinas/síntesis química , Indolizinas/química , Cinética , Simulación del Acoplamiento Molecular , Estructura Molecular , Nitrocompuestos/química , Relación Estructura-ActividadRESUMEN
When Ar is a low-aromaticity homo- or heterosystem, the sulfonyl-stabilized anion of nitrobutadienes 4 (which derive from the initial ring opening of 3-nitrothiophene) undergoes a rather surprising addition onto the aromatic ring itself, thereby leading to the construction of an unusual eight-membered sulfur heterocycle condensed with the original Ar ring. The competitiveness of such a pathway with respect to the formation of the thiopyran ring (i.e., addition onto the nitrovinyl moiety) is favored at low temperatures, thus revealing its nature as a kinetically controlled process.
RESUMEN
On the grounds of previous encouraging results on the antitumor activity of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1), we have designed and synthesized two new molecules [(1E,3E)-1,4-bis(4-carboxy-1-naphthyl)-2,3-dinitro-1,3-butadiene (2) and methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (3)] characterized by a common naphthylnitrobutadiene array but with different structural properties, with the aim of approaching to some structure-activity correlation. When 2 and 3 were analyzed in vitro for their inhibition of cell proliferation and pro-apoptotic properties, the carboxyderivative 2 did not furnish appreciable results. In contrast, 3 (which contains only one of the two naphthylnitroethenyl moieties of the original compound 1) showed remarkable activities in the range of micromolar concentrations (in six over eight cell lines its IC(50)s are in the 1-3 microM range), with a significant improvement compared to 1. In particular, 3 proved able to bind to DNA, to upregulate p53, to block cells in the G2/M phase of their cycle, and to induce apoptosis. Thus, very interestingly, the performance of 3 with respect to 1 shows that a single 1-(1-naphthyl)-2-nitroethene moiety is able to ensure better (on four out of eight of the cell lines tested) or comparable levels of activity. This result suggests that the 'molecular-simplification strategy' could furnish a useful instrument for future design in our antitumor research.
Asunto(s)
Antineoplásicos/síntesis química , Butadienos/síntesis química , Butadienos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/metabolismo , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Interfase/efectos de los fármacos , Naftalenos , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
With the goal of their exploitation for the synthesis of heterocycles, sulfides 10 and sulfones 11, derived from the initial ring-opening of 2-nitrothiophene (5) with pyrrolidine/AgNO3 in EtOH, were reacted with diazomethane. Interesting dichotomic behavior was found to yield pyrazolines 17 from 10 and isoxazolines 18 (as the main products) from 11. Intriguingly enough, in the latter case, an unexpected apparent C-C methylene insertion was also observed, leading to the homologous cyclopropanes 19 as secondary products.
RESUMEN
4-Alkyl-2-nitrothiophenes [10: R = CH3, CH(OH)CH3, CH(OCH3)CH3] react with secondary aliphatic amines, in the presence of AgNO3, to give 3-alkyl-2-amino-5-nitrothiophenes (12) through an oxidative nucleophilic substitution of hydrogen (ONSH) of synthetic interest. This behavior is in striking contrast with that of the parent 2-nitrothiophene (6), which was found to undergo ring-opening in analogous reaction conditions. A possible rationale for the crucial effect of alkyl groups is suggested, grounded also on a study of the corresponding Meisenheimer-like adducts.
RESUMEN
We have recently evidenced an interesting differential behavior in the reactivity in dioxane/water between the (Z)-2,4-dinitrophenylhydrazone (1a) and the (Z)-phenylhydrazone (1b) of 5-amino-3-benzoyl-1,2,4-oxadiazole. The former rearranges into the relevant triazole 2a only at pS+ > 4.5 while undergoing hydrolysis at high proton concentration (pS+ < 3.5); on the contrary, the latter rearranges into 2b in the whole pS+ range examined (0.1 < or = pS+ < or = 14.9). Thus, for a deeper understanding of these differences we have now collected kinetic data on the rearrangement in dioxane/water of a series of 3- or 4-substituted (Z)-phenylhydrazones (1c-l) of 5-amino-3-benzoyl-1,2,4-oxadiazole in a wide range of proton concentrations (pS+ 0.1-12.3) with the aim of gaining information about the effect of the substituent on the course of the reaction. All of the (Z)-arylhydrazones studied rearrange via three different reaction routes (specific-acid-catalyzed, uncatalyzed, and general-base-catalyzed), and the relevant results have been examined by means of free energy relationships.
Asunto(s)
Dioxanos/química , Hidrazonas/química , Oxadiazoles/química , Triazoles/síntesis química , Agua/química , Catálisis , Cinética , Estructura Molecular , Termodinámica , Triazoles/químicaRESUMEN
[reaction: see text] In prosecution of previous work on the thermal cyclization of 1-aryl-4-methanesulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (7), the 3-unsubstituted derivatives 8, deriving from the initial ring opening of 3-nitrothiophene (2), have been likewise found herein to undergo cyclization, followed by aromatization, in analogous mild experimental conditions, leading to the ring-fused homo- or heteroaromatic nitro derivatives 10. The concerted electrocyclic nature of the process is strongly supported by the outcome of tests based on the variation of the polarity of the solvent or of the electron density on the aryl of 8. Thus, the successful application of the process to the non-phenylsulfonyl-activated 8 significantly widens the scope of a synthetically valuable overall ring-opening/ring-closing procedure from nitrothiophenes. Support to the recently renewed interest in thermal 6pi electrocyclizations as a tool for the construction of the benzene ring is furthermore provided.
RESUMEN
Within an overall ring-opening/ring-forming protocol, the (E,E)-4-methylthio-2-nitro-3-phenylsulfonyl-1-pyrrolidino-1,3-butadiene (7) [derived from the initial opening of 3-nitro-4-(phenylsulfonyl)thiophene (6) with pyrrolidine and silver nitrate in EtOH] is revealed to be an excellent precursor of nitro(phenylsulfonyl) derivatives of ring-fused aromatic (naphthalene, phenanthrene) or heteroaromatic (benzothiophene) compounds whose substitution pattern cannot be easily achieved by conventional methods. The key step is represented by a thermal electrocyclic rearrangement of (E,E)-1-aryl-4-methylsulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (9), which, thanks to proper geometric and electronic factors, occurs in unprecedentedly mild conditions and is followed by an irreversible, concerted syn beta-elimination of methanesulfinic acid to aromatize the newly formed cyclohexadienic ring.
RESUMEN
Static and dynamic stereochemistry of the hydrocarbon comprising a phenyl ring bearing two alpha-naphthyl substituents in the ortho positions, i.e., 1,2-di-(4-methyl-naphth-1-yl)-benzene 1, has been studied by a combination of variable temperature NMR, cryogenic HPLC, and MM calculations. Whereas in solution both syn (meso) and anti (chiral) forms were observed and the corresponding interconversion barrier was determined (Delta G(++) = 19.5 kcal mol(-1)), only the diastereoisomer anti was found to be present in the crystalline state (X-ray diffraction). When the molecule is rendered asymmetric by introduction of a nitro group in the phenyl ring as in 1,2-di-(4-methyl-naphth-1-yl)-4-nitrobenzene 2, the chiral syn and anti diastereoisomers are simultaneously present both in solution and in the solid state, albeit in different proportions. Cryogenic chromatography on a HPLC chiral stationary phase at 20 degrees C allowed the stereolabile diastereoisomers and the corresponding enantiomers to be separated.