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1.
Molecules ; 27(10)2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35630623

RESUMO

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.


Assuntos
Carbono , Furanos , Álcoois , Aminas , Carbono/química , Furanos/química , Tiofenos
2.
Molecules ; 25(5)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120861

RESUMO

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.


Assuntos
Antineoplásicos/farmacologia , Canais de Cálcio/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromanos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Cromanos/síntese química , Cromanos/química , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Cobaias , Átrios do Coração/metabolismo , Humanos , Concentração Inibidora 50 , Músculo Liso/fisiologia , Piranos/síntese química , Piranos/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Tiamina/análogos & derivados , Tiamina/síntese química , Tiamina/química , Tiamina/farmacologia
3.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652581

RESUMO

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.


Assuntos
Carbazóis/química , Indóis/química , Pirróis/química , Carbazóis/síntese química , Indóis/síntese química , Estrutura Molecular , Pirróis/síntese química
4.
Org Biomol Chem ; 8(24): 5674-81, 2010 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-20936232

RESUMO

Different nitronaphthylbutadienes have been previously proved to have antitumour activity. The main drawback of these derivatives is their low water solubility. With the aim of facilitating the administration of these new drugs we have synthesized the hexyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate analogue (1-Naph-NHCB) which is demonstrated to be easily included into cyclodextrins and/or entrapped into liposomes. Its antitumour activity was revealed to be almost comparable with that of the previously studied methyl analogue ester (1-Naph-NMCB). On the other hand, in vitro studies with different cancer cell lines showed that the cytotoxic activity of both 1-Naph-NMCB and 1-Naph-NHCB were fully preserved and in some cases also enhanced when entrapped into liposomal carriers.


Assuntos
Antineoplásicos/química , Butadienos/química , Nitrocompostos/química , Água/química , Antineoplásicos/farmacologia , Butadienos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Nitrocompostos/farmacologia , Solubilidade
5.
Chemistry ; 16(4): 1312-8, 2010 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-20024991

RESUMO

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.

6.
Eur J Pharmacol ; 588(1): 47-51, 2008 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-18495109

RESUMO

The inhibition of cell proliferation by methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) has been studied in vitro against four cell lines selected for their resistance to doxorubicin, cisplatin, taxol and 5-fluorouracil. In previous experiments both compounds showed good in vitro antiproliferative, cytotoxic and pro-apoptotic activities against cell lines of different histologic origin. The results of the experiments presented here suggest that 1-Naph-NMCB is able to overcome all of the different mechanisms of resistance showed by the resistant cell lines used for our experiments. On the contrary, when we used the taxol-resistant A549-T12 cell line, characterized by a mechanism of resistance due to a mutation of the target site of taxol on microtubules, it displayed a partial but significant cross-resistance to 2-Naph-DNB. Although the actual mechanism of this cross-resistance has not yet been definitively elucidated, our results from immunostaining of microtubules suggest that it may be linked to the presence of a shared target site for taxol and 2-Naph-DNB on microtubules.


Assuntos
Antineoplásicos/farmacologia , Butadienos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Naftalenos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Imunofluorescência , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Sais de Tetrazólio , Tiazóis
7.
Bioorg Med Chem ; 16(1): 240-7, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17936630

RESUMO

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.


Assuntos
Antineoplásicos/síntese química , Butadienos/síntese química , Butadienos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Interfase/efeitos dos fármacos , Naftalenos , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
8.
J Org Chem ; 72(24): 9067-73, 2007 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-17975926

RESUMO

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.

9.
Pharmacol Res ; 56(4): 318-28, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17827031

RESUMO

Our interesting results on the antiproliferative (in vitro) and antitumour (in vivo) activities of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) have more recently induced us to design and synthesize some new 1,4-diaryl-2,3-dinitro-1,3-butadienes characterized by a common arylnitrobutadiene array but with different geometric and/or functional properties. This task was undertaken with the aim to obtain new compounds with an enhanced antiproliferative activity and, possibly, a different specificity with respect to the original (lead) compound. (1E,3E)-1,4-Bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) is one of the molecules so obtained, a structural isomer of 1-Naph-DNB provided with a different spatial arrangement. When analyzed in vitro for its inhibition of cell proliferation 2-Naph-DNB showed a remarkable activity in the range of micromolar concentrations, with significant differences, with respect to 1-Naph-DNB, against some cell lines. Furthermore, it was able to significantly trigger apoptosis, to up-regulate p53, to block cells in the G2/M phase of the cell cycle and, finally, to slightly bind to DNA forming interstrand cross-links (ISCL). 2-Naph-DNB was then analyzed for its toxic activity in vivo in CD1 mice. This allowed the determination of toxicity parameters such as the lethal doses (LD) and the maximal tolerated dose (MTD) together with the definition of the spectrum of tissue alterations due to its administration i.v. Altogether our data suggest that the idea of modifying the geometry of the lead compound 1-Naph-DNB deserves further investigation aimed at synthesizing new molecules with similar chemical functionalities but with different spatial requirements, hopefully characterized by still enhanced activities in terms of inhibition of cell proliferation and apoptosis.


Assuntos
Antineoplásicos/síntese química , Butadienos/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose , Western Blotting , Butadienos/farmacologia , Butadienos/toxicidade , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/farmacologia , Reagentes de Ligações Cruzadas/toxicidade , DNA/química , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Naftalenos/síntese química , Naftalenos/farmacologia , Naftalenos/toxicidade , Baço/efeitos dos fármacos , Baço/patologia , Estereoisomerismo , Proteína Supressora de Tumor p53/biossíntese , Regulação para Cima
10.
Invest New Drugs ; 25(6): 535-44, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17572851

RESUMO

On the basis of our previous interesting results in vitro on the antiproliferative activity of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) we have designed and synthesized the new molecule methyl (2Z,4E)-2-methylsulphanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) characterized by the same naphthylnitrobutadiene array but with a different functional group at one end of the diene system. This new molecule showed an in vitro antiproliferative activity more significant than that found for the original 1-Naph-DNB. In order to verify in vivo our in vitro results we have tested the antitumour activity of 1-Naph-DNB and 1-Naph-NMCB in several murine tumour models, namely the myelomonocytic P388 and the Lewis lung carcinoma 3LL in BDF1 mice, the melanoma B16 in C57Bl mice, the fibrosarcoma WEHI 164 in nude mice and, finally, the C51 colon cancer in Balb/c mice. In the case of 1-Naph-NMCB the analysis of the antitumour activity has been preceded by toxicological experiments on CD-1 mice, in order to determine the lethal (LD) and the maximal tolerated (MTD) doses together with the spectrum of histological alterations caused by its iv administration. The results obtained show that the modification of the original structure of 1-Naph-DNB according to the molecular-simplification strategy has led to an asymmetric nitrobutadiene array, i.e. that of 1-Naph-NMCB, endowed with an antitumour activity which is in some cases even better than that showed by the parental compound itself, together with differences in tumour selectivity and negligible histological toxic effects.A promising, versatile route to new, more active and/or safe nitrobutadiene derivatives has thus been positively tested.


Assuntos
Antineoplásicos/farmacologia , Butadienos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Naftalenos/farmacologia , Animais , Antineoplásicos/toxicidade , Butadienos/toxicidade , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Testes de Toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Org Chem ; 72(15): 5771-7, 2007 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-17595137

RESUMO

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.

12.
J Org Chem ; 70(22): 8734-8, 2005 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-16238303

RESUMO

[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.

13.
Oncol Rep ; 12(1): 91-6, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15201965

RESUMO

The inhibition of cell proliferation by 1,4-bis (1-naphthyl)-2,3-dinitro-1,3-butadiene (Naph-DNB) was evaluated in vitro against 4 cell lines (L1210/DDP, A2780/DX3, HCT-8/FU7dR, A549-T12) selected for their resistance to cisplatin, doxorubicin, 5-fluorouracil and taxol, and their wild-type counterparts. Naph-DNB is a novel anti-cancer compound obtained years ago within a research project of Organic Chemistry aimed at synthesizing 2,3-dinitrobutadiene derivatives. Because of its chemical structure, Naph-DNB was suggested to interact with nucleic acids, in particular DNA, and the other cellular macromolecules. This hypothesis made us consider Naph-DNB as a candidate for studies concerning its antitumour activity. We used the MTT assay to test the inhibition of cell proliferation after incubation of the cell lines with Naph-DNB for 72 h. For comparison, resistant and wild-type cell lines were also tested against those anticancer drugs used in vitro for their selection. In these culture conditions Naph-DNB retained its inhibiting activity against all resistant cells with IC50 values similar to those obtained in corresponding wild-type cell lines. Moreover, Naph-DNB was twice as effective as 5-fluorouracil against wild-type HCT-8 cells. Our previous findings about the interaction of Naph-DNB with DNA through the formation of interstrand cross-links suggested a mechanism of action similar to that of platinum/alkylating agents or topoisomerase inhibitors (intercalating agents). Our present data obtained by the K-SDS precipitation assay in A2780 and A549 cells showed that Naph-DNB is not able to form a stable topoisomerase-DNA complex as is the case for topoisomerase inhibitors. In conclusion, our results indicate that Naph-DNB is able to overcome some of the classical mechanisms of resistance selected by some anticancer drugs mainly used in clinical setting.


Assuntos
Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Butadienos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Fluoruracila/farmacologia , Humanos , Cinética , Paclitaxel/farmacologia
14.
J Org Chem ; 68(13): 5254-60, 2003 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-12816486

RESUMO

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.

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