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Breast cancer is still considered a high-incidence disease, and numerous are the research efforts for the development of new useful and effective therapies. Among anticancer drugs, carbazole compounds are largely studied for their anticancer properties and their ability to interfere with specific targets, such as microtubule components. The latter are involved in vital cellular functions, and the perturbation of their dynamics leads to cell cycle arrest and subsequent apoptosis. In this context, we report the anticancer activity of a series of carbazole analogues 1–8. Among them, 2-nitrocarbazole 1 exhibited the best cytotoxic profile, showing good anticancer activity against two breast cancer cell lines, namely MCF-7 and MDA-MB-231, with IC50 values of 7 ± 1.0 and 11.6 ± 0.8 μM, respectively. Furthermore, compound 1 did not interfere with the growth of the normal cell line MCF-10A, contrarily to Ellipticine, a well-known carbazole derivative used as a reference molecule. Finally, in vitro immunofluorescence analysis and in silico studies allowed us to demonstrate the ability of compound 1 to interfere with tubulin organization, similarly to vinblastine: a feature that results in triggering MCF-7 cell death by apoptosis, as demonstrated using a TUNEL assay.

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 β-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.

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.

Novel, densely functionalized 2-methylideneazetidines can be obtained in high yields and mild conditions from the reaction of nitropentadienoates with primary amines, most likely through an aza-Michael addition followed by a 4-exo-trig cyclization. The initial, selective trans arrangement for the C3 and C4 ring hydrogens undergoes stereomutation due to the presence of an easily enolisable site at C3, eventually leading to mixtures where the cis isomer generally prevails.

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.

We report herein an original protocol to the indole nucleus, which could contribute to significantly expand the synthetic access to a heterocyclic moiety of undeniable paramount importance. The protocol consists in the construction of the benzene ring onto a pyrrole (benzannulation) starting from 2,3-dinitro-1,3-butadienes. This appealing, metal-free process characterized by high atom economy and mild reaction conditions allows to synthesize indoles possessing nitro group(s) on the benzene ring: a result which cannot be likewise easily obtained by exploiting most common pathways such as functionalization of a preformed indole or heteroannulation of a suitable benzene derivative. From a mechanistic point of view, a stepwise, ionic process is suggested by the identification of a pivot dihydroindole intermediate whose interception facilitates some selectivity in the preparation of different nitroindoles.

A series of atropisomeric molecules containing the indole ring and two stereogenic axes were prepared. The four atropisomers were resolved by enantioselective HPLC. The rotational barriers of the indole–naphthyl axes were evaluated by means of kinetic analysis either by NMR or enantioselective HPLC. The absolute configuration of the ­atropisomers was determined by a combination of X-ray spectroscopy and TD-DFT simulation of electronic circular dichroism spectra.

The initial ring-opening of 3-nitrothiophene and further structural modifications lead to nitrobutadienic building-blocks whose synthetic usefulness in the field of heterocycles has been widely demonstrated. As a further example, the Michael addition of a hydrazone anion to the nitrovinyl moiety of nitrobutadienes generates 1,2-diazaheterocycles as the final result of an overall MIRC process. Depending on the nature of the substituents on the Michael-type acceptor and on the hydrazono nucleophile, an interesting dichotomy is observed that leads to either five-member or six-member N-heterocycles with complete selectivity. The results obtained appear to be both of mechanistic and synthetic interest e.g., in the field of heterocycles endowed with potential pharmacological/biological activity.

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.

The ring opening of 3-nitro-4-(phenylsulfonyl)thiophene with amines and proper modification of the resulting 1,3-diene enables a simple and versatile approach to N-fused pyrroles of both synthetic and biological interest through 1,6-H shift followed by 6π 1,5-electrocyclization. This protocol is effectively driven to the isolated pyrroles by an easy aromatization.

The unusual migration of a nitro group from the - to the -position of a -aryl--nitroethenyl moiety, following a nitrocyclopropane to isoxazoline N-oxide isomerization, has been studied from a mechanistic and synthetic points of view. As a result, two series of isomeric isoxazoline N-oxides could be obtained under controlled conditions. When reacted with diazomethane, a model transposed isoxazoline cleanly furnished a new, interesting pyrazolylisoxazole.

The conjugated bis(sulfonyl)nitrobutadienes 1 undergo, with primary amines, competitive MeSO2 replacement [vinylic substitution at C(1)] versus aza-Michael addition to the nitroethenyl C(3)–C(4) double bond. The latter pathway eventually leads to the trisubstituted pyrroles 2 and conditions have been optimized in order to maximize the yield of such polyfunctionalized heterocycles. Interestingly, in trifluoroethanol tetrasubstituted pyrroles 7 are also formed, thanks to a final aromatization via oxidation by ‘endogenous’ nitrite.

The base-induced cyclization of ( E )-2-aryl-1-[2-(benzylsulfonyl)phenyl]-1-nitroethenes to polysubstituted thiochroman S , S -dioxides exhibits a diastereoselectivity that can be oriented towards a selected isomer by means of appropriate adjustments of the experimental conditions. The interest of such a result also rests on the promising pharmacological activity of the products, whose structure encompasses different well-acknowledged pharmacophores. A conformational 1 H NMR investigation, backed by molecular-mechanics calculations, has also been accomplished.

(1 E ,3 Z )-1-Aryl-4-methanesulfonyl-2-nitro-1,3-butadienes ( 8 ), derived from the initial ring-opening of 3-nitrothiophene ( 5 ), have been found to undergo a facile base-induced cyclization leading to thiopyran S , S -dioxides ( 9 ), thus furnishing a further example of effective ring-enlargement from 5- to 6-membered sulfur heterocycles. Compounds 9 are obtained as single racemic mixtures in satisfactory yields; they still contain a nitrovinylic moiety, which can be exploited for further modifications targeted to new derivatives endowed with either synthetic or pharmacological potentialities e.g., in the field of L-type Ca 2+ -channel blockers.

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.

Reference EPFL-ARTICLE-150326doi:10.2174/157017807781024165 URL: http://www.bentham.org/loc/contabs/loc4-4.htm#13 Record created on 2010-08-06, modified on 2017-05-12

The reaction of nitrobutadienes (I) with indole leads to 1,3,4- and 1,2,4-nitrocarbazoles (III) and (IV).

As a continuation of our research on the synthetic exploitation of the nitrobutadienic building-blocks obtained from the ring-opening of nitrothiophenes, we herein report about their reaction with the π-nucleophilic indole. Thanks to their double Michael-acceptor nature, 2,3-dinitro and 2-nitro-3-phenylsulfonyl substituted 1,3-butadienes produce poly-functionalized carbazoles through a double (inter-+intra-molecular) conjugate addition, followed by aromatization of the newly built ring. Significance is attached to the results obtained in fluorinated solvents such as trifluoroethanol, whereby a mild process, with no need for catalysis, overcomes some practical difficulties otherwise limiting the scope of the reaction. Besides the mechanistic aspects, the reaction encompasses motifs for a synthetic interest, mainly in the field of further-tunable arylcarbazoles endowed with predictable applicative properties, e.g., as fluorescent devices.

The treatment of 3,4-dinitrothiophene with an aryl Grignard reagent results in the reduction of one nitro group accompanied by the ipso-substitution of a hydrogen atom by an ortho-phenolic group on the ring carbon adjacent to the reduced nitro group. A Claisen-type intramolecular rearrangement is proposed as the pivotal step of a rather complex mechanism, followed by proton-transfer aromatizing steps. This work shows yet another facet of the variegated reactivity of 3,4-dinitrothiophene towards nucleophiles. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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 β-elimination of methanesulfinic acid to aromatize the newly formed cyclohexadienic ring.

Static and dynamic stereochemistry of the hydrocarbon comprising a phenyl ring bearing two α-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 (ΔG⧧ = 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 °C allowed the stereolabile diastereoisomers and the corresponding enantiomers to be separated.

The ring opening of 3-nitro-4-(phenylsulfonyl)thiophene with amines and proper modification of the resulting 1,3-diene enables a simple and versatile approach to N-fused pyrroles of both synthetic and biological interest through 1,6-H shift followed by 6π 1,5-electrocyclization. This protocol is effectively driven to the isolated pyrroles by an easy aromatization.

The reactions between 1,2-bis(diethylamino)-2,3-dinitro-1,3-butadiene, easily obtainable by ring-opening of 3,4-dinitrothiophene with diethylamine, and arylmethylmagnesium chlorides in THF at 0°C furnished good yields of (E,E,E)-1,6-diaryl-3-nitro-1,3,5-hexatrienes. To explain the formation of the hexatrienes, a mechanism is advanced which involves, in particular, tautomerisation of the intermediate 1,6-diaryl-3,4-dinitro-2,4-hexadienes followed by base-induced elimination of nitrous acid. The electrocyclic disrotatory conversion of the hexatrienes into the corresponding 5,6-diaryl-2-nitro-1,3-cyclohexadienes was analysed by 1H NMR spectroscopy and exploited for the high-yielding synthesis of 1,2-diaryl-4-nitrobenzenes employing, as oxidants, either DDQ or iodine in the presence of cyclohexene oxide as HI scavenger.

(Z)-4-Nitrophenyl tert-butylsulfide [(Z)-4-NO2−1], upon formation of its radical anion, isomerizes to the (E)-isomer at a very fast rate of 6.3 × 106 s-1, about 103 times faster than azobenzene, while the 4-fluoro tert-butylsulfide (4-F−1) cleaves without isomerization. The particular behavior of 4-NO2−1 is related to the occurrence of a cleavage recombination mechanism, different from the usual inversion rotation mechanism. The existence of a reversible cleavage for the radical anion of 4-NO2−1 bears consequences on the mechanism of SRN1 reactions of azosulfides; the attack of the nucleophile would take place on the intermediate diazenyl radical and not on the ensuing aryl radical as previously proposed.

The reactions between 1,4-bis(diethylamino)-2,3-dinitro-1,3-butadiene (2), easily obtainable by ring-opening of 3,4-dinitrothiophene with diethylamine, and 2-substituted vinylmagnesium bromides gave good yields of the 4,5-dinitro-1,3,5,7-octatetraene derivatives 3a–e. With 1-phenylmagnesium bromide, conversely, only 3,4-dinitro-1,4-diphenyl-1,3,5-cyclooctatriene (4f) was obtained. From the unsubstituted dinitrooctatetraene 3a both the octatriene cycloisomer 4a and the valence tautomer of the latter (6a) could be isolated and characterized. The results obtained evidence an unfavourable effect of the two nitro groups on the cycloisomerization process of the octatetraene system.

1-Aryl-2-(p-tolylazo)alkenes were synthesized starting from alkyl aryl ketones in good overall yield. The employed three-step procedure involves: i) α-p-tolylhydrazonylation of ketone enolates with tert-butyl p-tolylazosulfide 1; ii) selective reduction of the carbonyl function of the obtained α-p-tolylhydrazono ketones 3 with NaBH4; iii) dehydration of the ensuing hydrazono alcohols 4 either in an Et2O/dil. H2SO4 two-phase system or in pyridine/acetic anhydride.

The reactions of arylazosulfones 1 (ArNNSO 2 Ar 1 ) with the potassium salts of ( tert -butoxycarbonyl)methyl 2 and tosylmethyl isocyanide 3 in DMSO afford 4,5-bis( tert -butoxycarbonyl)- 4 and 4-tosyl-1-arylimidazoles 5 , respectively. Yields of imidazoles 4 and 5 vary from moderate to excellent depending on the nature both of Ar in 1 and of the nucleophile ( 2 or 3 ) employed. A comparison of the results obtained with those relevant to the reactions of the same nucleophiles with nitrosobenzene in analogous experimental conditions provides useful mechanistic indications on the transformation of 1 to 4 or 5 .

Different approaches are investigated to the pharmaceutically interesting heterocyclic systems.

The reactions of the enolates of tert-butyl alkanoates2 and N, N-dialkylalkanamides3 with tert-butylp-tolylazo sulfide1 in THF furnish good yields of the correspondingα-p-tolylhydrazonylated esters4 and amides5. Results are reported showing the possible transformation of4 and 5 into theN-methylated derivatives8 and 9 and the subsequent deblocking of the protected carbonyl function to the corresponding 2-oxoalkanoates10 and 2-oxoalkanamides11. Download : Download full-size image

Nucleophilic addition of indole to nitroolefins gives the expected Michael-type adducts (III) and (VI) as well as the carbazoles (IX) and (X).

In prosecution of the synthetic exploitation of nitrobutadienes deriving from the initial ring-opening of nitrothiophenes, their multifaceted behavior finds a further clear-cut example in their Michael-type acceptor reactivity toward the anions of α-oxohydrazones. Thus, depending on the starting diene, new poly-functionalized pyrazoles are obtained. Furthermore, most interestingly, in one occasion a dichotomy has been observed, depending on the nature of the Michael-type donor, leading with complete selectivity to either 5-member or 6-member N-heterocycles. The outcome encompasses motifs for both mechanistic and synthetic interest, for example, in the field of heterocycles endowed with possible pharmacological/biological activity.

The multifaceted behavior of nitrobutadienes deriving from the initial ring-opening of nitrothiophenes finds a further clear-cut example in their Michael-type acceptor reactivity towards indole. Thus, depending on the starting diene, either newly-functionalized indoles or carbazoles are produced, the latter as the result of an appealing double (intermolecular + intramolecular) Michael-type addition to a nitrovinylic moiety. The outcome encompasses motifs for both mechanistic and synthetic interest in the field of heterocycles endowed with possible pharmacological activity.

The title reaction conveniently furnishes, as the sole or main products, α-(p-tolylhydrazono)ketones or their N-methylderivatives (H+ or MeI quenching of the final mixture, respectively). Although the method fails with ketones having a secondary alkyl group bonded to the carbonyl, yields are otherwise more than satisfactory and particular interest is attached to the hydrazonylation of the methyl group in methyl ketones.

Potassium enolates of alkyl aryl ketones react selectively in DMSO with phenylazo 1a and 4 -methylphenylazo tert-butyl sulfide 1b undergoing respectively effective α-phenylation via S RN 1 and α-(4-methylphenyl)hydrazonylation via elimination-addition.

Potassium 2,4-pentanedionate reacts with diazosulfides (E)-1 and (Z)-2 in DMSO to give 3-aryl-2,4-pentanediones 3 via an S RN 1 process. Advantages and drawbacks of such new access to 3 are reported together with relevant mechanistic implications.

The ortho -arylation of phenols by (2-cyanoaryl)azo t -butyl (or phenyl) sulfides in S RN 1 conditions, followed by a silica-gel-catalysed lactonisation of the resulting 2-cyano-2′-hydroxybiphenyls, leads to dibenzo[ b,d ]pyran-6-ones.

Potassium enolates of alkyl aryl ketones react selectively in DMSO with phenylazo 1a and 4 -methylphenylazo tert-butyl sulfide 1b undergoing respectively effective α-phenylation via S RN 1 and α-(4-methylphenyl)hydrazonylation via elimination-addition.

The outcome of the reaction between azosulfides 1 and ketone enolates is influenced by the presence of suitable alkyl substituents on the aryl moiety of 1. The system can thus be conveniently exploited for the selective synthesis of different classes of derivatives of remarkable applicative interest, namely α-aryl ketones, α-arylhydrazono ketones, or indazoles.

Treatment of variously substituted ( o -alkylaryl)azosulfides 1a-n with potassium tert -butoxide in DMSO at room temperature smoothly furnishes 1 H -indazoles 2a-n .