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1.
Curr Top Med Chem ; 20(25): 2281-2288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32814527

RESUMO

BACKGROUND: Tamoxifen citrate is a very prevalent drug marketed under several trade names like Apo-Tamox, Nolvadex, Tamec, Tamizam, and Tamoplex. This molecule is approved by the FDA for breast cancer treatment. Some studies have shown that tamoxifen has anti-tuberculosis and antiparasitic activities. Like any drug, tamoxifen possesses side effects, more or less dangerous. AIMS: Basically, this work is a comparative study that aims to: primarily compare the antimicrobial and antitumor activities of tamoxifen and a newly synthesized tamoxifen analog; and to determine the molecule with lesser side effects. METHODS: Three groups of mice were injected with tamoxifen citrate and compound 2(1,1-bis[4-(3- dimethylaminopropoxy)phenyl]-2-phenyl-but-1-ene dihydrochloride) at doses corresponding to C1 (1/10), C2 (1/50), and C3 (1/100) to compound 2 lethal dose (LD50 = 75 mg/kg) administered to adult mice. A group of noninjected mice served as a study control. RESULTS: Experimental results suggest that compound 2 has better antitumor and antimicrobial activity than tamoxifen citrate besides its lower toxicity effects. CONCLUSION: The results obtained from the present study confirmed the antitumor and antimicrobial effect of tamoxifen citrate and its hematological side effects. Compound 2 seems to be more effective than tamoxifen citrate for antitumor and antimicrobial treatment while having less hematological side effects and less disruption of the blood biochemical parameters. These findings encourage us to perform further studies on compound 2 and test it for other therapeutic uses for which tamoxifen was found effective.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Tamoxifeno/farmacologia , Animais , Antibacterianos/efeitos adversos , Antibacterianos/química , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Listeria monocytogenes/efeitos dos fármacos , Células MCF-7 , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Tamoxifeno/análogos & derivados , Tamoxifeno/química
2.
ChemMedChem ; 14(19): 1717-1726, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31483560

RESUMO

The ferrocenyl diphenol complexes 1,1-bis(4'-hydroxyphenyl)-2-ferrocenyl-but-1-ene (1) and 1,2-bis(4'-hydroxyphenyl)-1-ferrocenyl-but-1-ene [(Z)-2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1 is far more cytotoxic than 2). In this study, our goal was to discover the origin of this difference by comparing their reactivity and biological behaviour. In terms of common behaviour, we found that 1 and 2 are both efficient inhibitors of thioredoxin reductase (TrxR) in vitro after oxidation by a horseradish peroxidase/H2 O2 system. However, as 1 is only a moderate inhibitor of TrxR in MDA-MB-231 cells, TrxR is probably not the major target responsible for the cytotoxicity of 1. In terms of differences, we noted that 1 induced a significant redox imbalance characterised by lipid peroxidation and thiol oxidation, and a moderate decrease of the mitochondrial membrane potential in breast cancer cells, whereas 2 has almost no effect. These results underline the importance of the trans configuration in the ferrocenyl-double bond-phenol motif, which is present in 1 but is cis in (Z)-2.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Inibidores Enzimáticos/química , Compostos Ferrosos/química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Oxirredução
3.
Angew Chem Int Ed Engl ; 58(25): 8421-8425, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-30977944

RESUMO

Ferrociphenols, especially those possessing a heterocycle at the terminus of an aliphatic chain, display strong anticancer activity through a novel redox mechanism that generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopy reveal that the specific lone pair (lp)-π interaction between a carbonyl group of the imide and the quinone motif of the QM plays an important role in the exceptional cytotoxic behaviour of their imido-ferrociphenol precursors. This intramolecular lp-π interaction markedly enhanced the stability of the QMs and lowered the pKa values of the corresponding phenol/phenolate couples. As the first example of such a non-covalent interaction that stabilizes QMs remotely, it not only expands the scope of the lp-π interaction in supramolecular chemistry, but also represents a new mode of stabilization of a QM. This unprecedented application of lp-π interactions in imido-ferrociphenol anticancer drug candidates may also have great potential in drug discovery and organocatalyst design.


Assuntos
Antineoplásicos/química , Compostos Ferrosos/química , Imidas/química , Indolquinonas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular
4.
Angew Chem Int Ed Engl ; 58(11): 3461-3465, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30663197

RESUMO

A series of tamoxifen-like metallocifens of the group-8 metals (Fe, Ru, and Os) has strong antiproliferative activity on the triple-negative breast cancer cells (MDA-MB-231). To shed light on the mechanism of action of these molecules, synchrotron radiation X-ray fluorescence nanoimaging studies were performed on cells exposed to osmocenyl-tamoxifen (Oc-OH-Tam) to disclose its intracellular distribution. High-resolution mapping of the lipophilic Oc-OH-Tam in cells revealed its preferential accumulation in the endomembrane system. This is consistent with the ability of the amino nitrogen chain of the compounds to be protonated at physiological pH and responsible for electrostatic interactions between Oc-OH-Tam and membranes. A comprehensive scenario is proposed that provides new insight into the cellular behavior and activation of Oc-OH-Tam and advances the understanding of its mechanism of action.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Compostos Organometálicos/química , Tamoxifeno/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Complexos de Coordenação/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio , Ferro/química , Ligantes , Imagem Molecular/métodos , Sondas Moleculares/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Osmio/química , Radiografia , Rutênio/química , Eletricidade Estática , Síncrotrons , Raios X
5.
Dalton Trans ; 47(29): 9824-9833, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-29993046

RESUMO

Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = η5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6). Complexes 4-6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32-2.5 µM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-hour incubation of cells at 37 °C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 °C for 1 hour with 10 µM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm-1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucleus.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Compostos Ferrosos/química , Compostos Organometálicos/química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Endocitose , Humanos , Concentração Inibidora 50 , Espectroscopia de Infravermelho com Transformada de Fourier
6.
Chem Sci ; 9(1): 70-78, 2018 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-29629075

RESUMO

Organometallic compounds bearing the redox motif [ferrocenyl-ene-phenol] have very promising antiproliferative properties which have been further improved by incorporating pertinent substituents able to engender new mechanisms. Here we show that novel ferrociphenols bearing a hydroxypropyl chain exhibit strong antiproliferative effects, in most cases much better than those of cisplatin, tamoxifen, or of previously described ferrociphenols devoid of this terminal OH. This is illustrated, in the case of one of these compounds, by its IC50 values of 110 nM for MDA-MB-231 triple negative breast cancer cells and of 300 nM for cisplatin-resistant A2780cisR human ovarian cancer cells, and by its GI50 values lower than 100 nM towards a series of melanoma and renal cancer cell lines of the NCI-60 panel. Interestingly, oxidative metabolism of these hydroxypropyl-ferrociphenols yields two kinds of quinone methides (QMs) that readily react with various nucleophiles, such as glutathione, to give 1,6- and 1,8-adducts. Protonation of these quinone methides generates numerous reactive metabolites leading eventually to many rearrangement and cleavage products. This unprecedented and fully characterized metabolic profile involving a wide range of electrophilic metabolites that should react with cell macromolecules may be linked to the remarkable profile of antiproliferative activities of this new series. Indeed, the great diversity of unexpected reactive metabolites found upon oxidation will allow them to adapt to various situations present in the cancer cell. These data initiate a novel strategy for the rational design of anticancer molecules, thus opening the way to new organometallic potent anticancer drug candidates for the treatment of chemoresistant cancers.

7.
Mini Rev Med Chem ; 18(15): 1294-1301, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28183263

RESUMO

BACKGROUND & OBJECTIVE: The inhibitory effects of four series of aryl butene derivatives, active against breast cancer, on the monophenolase activity of tyrosinase, in melanin-free ink from Sepia officinalis, have been studied. Hydroxytamoxifen 1, ferrociphenol 17 and several aryl butene analogs have shown strong antiproliferative activity on hormone-dependent and hormone-independent breast cancer cells and were evaluated in leukemia K562 cell proliferation. Their potential to induce skin depigmentation by evaluating their anti-tyrosinase activity was also estimated. In order to better rationalize the tyrosinase inhibitory action and the binding mode of the compounds, docking studies were carried out. CONCLUSION: Hydroxytamoxifen and some aryl butenes showed strong antiproliferative effects against K562 cells at 1 µM without showing tyrosinase inhibition. If phenolic compounds 16 and 17 showed the best antiproliferative activity on K562, Hydroxytamoxifen and compounds 5, 10, 20 and 21 have been identified as candidates for further development against chronic myeloid leukemia (CML), and are predicted to not induce depigmentation of the skin, a side effect encountered with imatinib, conventionally used for the treatment of CML.


Assuntos
Alcenos/química , Inibidores Enzimáticos/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Alcenos/metabolismo , Alcenos/farmacologia , Alcenos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Ligação de Hidrogênio , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Conformação Molecular , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico
8.
J Med Chem ; 60(20): 8358-8368, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-28895732

RESUMO

Ferrociphenols are known to display anticancer properties by original mechanisms dependent on redox properties and generation of active metabolites such as quinone methides. Recent studies have highlighted the positive impact of oxidative stress on chemosensitivity and prognosis of ovarian cancer patients. Ovarian adenocarcinomas are shown to be an excellent model for defining the impact of selected ferrociphenols as new therapeutic drugs for such cancers. This work describes the syntheses and preliminary mechanistic research of unprecedented multitargeting heterocyclic ferrociphenols bearing either a succinimidyl or phthalimidyl group that show exceptional antiproliferative behavior against epithelial ovarian cancer cells resistant to cisplatin. Owing to the failure of the present pharmaceutical options, such as carboplatin a metallodrug based on Pt coordination chemistry, these species may help to overcome the problem of lethal resistance. Currently, ferrociphenolic entities generally operate via apoptotic and senescence pathways. We present here our first results in this new cyclic-imide series.


Assuntos
Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Compostos Heterocíclicos/farmacologia , Neoplasias Ovarianas/patologia , Fenóis/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos Heterocíclicos/química , Humanos , Fenóis/química , Análise Espectral
9.
Metallomics ; 9(7): 949-959, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28636040

RESUMO

Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of thioredoxin reductase after enzymatic oxidation with HRP/H2O2 while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in the accumulation of oxidized thioredoxin 2 and cell redox imbalance. Overproduction of ROS resulted in a strong decrease in the mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal, as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with the induction of apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Tamoxifeno/farmacologia , Tiorredoxinas/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Células Jurkat , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Selenocisteína/metabolismo , Frações Subcelulares/metabolismo , Tamoxifeno/química , Tiorredoxina Dissulfeto Redutase/metabolismo
10.
Angew Chem Int Ed Engl ; 55(35): 10431-4, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27276169

RESUMO

Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC-SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC-SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC-QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC-SR-QM. These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to a new series of organometallic antitumor compounds.

11.
Dalton Trans ; 45(33): 13126-34, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27276499

RESUMO

In order to examine whether the length of the bridging chain in ansa-ferrocenes affects their antiproliferative activity against MDA-MB-231 triple negative breast cancer cell lines (TNBC), we synthesized derivatives of the type 1-[bis-(4-hydroxyphenyl)]methylidene-[n]ferrocenophane and 1-[(4-hydroxyphenyl)-phenyl]methylidene-[n]ferrocenophane with n = 3, 4, 5. We found that the derivatives of [3]ferrocenophane, the compounds with the shortest bridging chains, are the most active. IC50 values were 0.09 ± 0.01, 2.41 ± 0.10, and 1.85 ± 0.25 µM for the dihydroxyphenyl derivatives, with n = 3, 4, 5, respectively. These differences can be explained in terms of modification of the key metabolites (radical versus quinone methides) within the ansa series depending on the length of the bridging chain. The derivative of [5]ferrocenophane, possessing two -[bis-(4-hydroxyphenyl)]methylidene groups, was also prepared. Surprisingly, this relatively large molecule is also active (IC50 = 2.7 ± 0.3 µM). Two ruthenocenophane analogs were also synthesized. These ruthenium compounds are practically inactive against MDA-MB-231 cells. The unusual chemistry of these different compounds is discussed in terms of elucidating the mechanism underlying their diverse antiproliferative activity, and their specific advantages are evaluated.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Metalocenos/química , Metalocenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
12.
J Inorg Biochem ; 160: 296-304, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27130146

RESUMO

The synthesis and the biological effects of two ferrocifen analogs in the osmium series, namely the monophenolic complex 1, the tamoxifen-like complex 2 and their oxidized quinone methide (QM) derivatives, 1-QM and 2-QM, are reported. Inhibition of purified thioredoxin reductase (TrxR) is observed with 1 and 2 only after their enzymatic oxidation by the hydrogen peroxide/horseradish peroxidase (H2O2/HRP) system with IC50 of 2.4 and 1.2µM respectively. However, this inhibition is larger than that obtained with the corresponding quinone methides (IC50=5.4µM for 1-QM and 3.6µM for 2-QM). The UV-Vis spectra of 1 or 2 incubated in the presence of H2O2/HRP show that the species generated is not a quinone methide, but probably the corresponding cation. In Jurkat cells, 2 shows high toxicity (IC50=7.4µM), while 1 is less effective (IC50=42µM). Interestingly, a significant inhibition of TrxR activity is observed in cells incubated with 2 (about 70% inhibition with 15µM) while the inhibition induced by 1 is much weaker (about 30% inhibition with 50µM). This strong inhibition of TrxR by 2 leads to accumulation of thioredoxin and peroxiredoxin 3 in oxidized form and to a decrease of the mitochondrial membrane potential (MMP). These results show that cytotoxicity of the osmocifens depends on their oxidation within the cell and that inhibition of thioredoxin reductase by oxidized species is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Ferrosos/farmacologia , Compostos Organometálicos/farmacologia , Tamoxifeno/química , Tiorredoxina Redutase 1/antagonistas & inibidores , Antineoplásicos/síntese química , Morte Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Compostos Ferrosos/síntese química , Expressão Gênica , Glutationa/metabolismo , Humanos , Indolquinonas/química , Células Jurkat , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organometálicos/síntese química , Osmio/química , Oxirredução , Estresse Oxidativo , Peroxirredoxina III/química , Peroxirredoxina III/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/química , Tiorredoxinas/metabolismo
13.
Mem. Inst. Oswaldo Cruz ; 110(8): 981-988, Dec. 2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-769827

RESUMO

This work reports the in vitro activity against Plasmodium falciparumblood forms (W2 clone, chloroquine-resistant) of tamoxifen-based compounds and their ferrocenyl (ferrocifens) and ruthenocenyl (ruthenocifens) derivatives, as well as their cytotoxicity against HepG2 human hepatoma cells. Surprisingly with these series, results indicate that the biological activity of ruthenocifens is better than that of ferrocifens and other tamoxifen-like compounds. The synthesis of a new metal-based compound is also described. It was shown, for the first time, that ruthenocifens are good antiplasmodial prototypes. Further studies will be conducted aiming at a better understanding of their mechanism of action and at obtaining new compounds with better therapeutic profile.


Assuntos
Animais , Humanos , Antimaláricos/farmacologia , Complexos de Coordenação/síntese química , Compostos Ferrosos/farmacologia , Compostos Organometálicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Rutênio/farmacologia , Antimaláricos/síntese química , Linhagem Celular , Cromatografia em Camada Fina , Complexos de Coordenação/farmacologia , Citotoxinas/farmacologia , Compostos Ferrosos/síntese química , Haplorrinos , /parasitologia , Técnicas In Vitro , Compostos Organometálicos/síntese química , Rutênio/química , Tamoxifeno/química
14.
Mem Inst Oswaldo Cruz ; 110(8): 981-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26602875

RESUMO

This work reports the in vitro activity against Plasmodium falciparum blood forms (W2 clone, chloroquine-resistant) of tamoxifen-based compounds and their ferrocenyl (ferrocifens) and ruthenocenyl (ruthenocifens) derivatives, as well as their cytotoxicity against HepG2 human hepatoma cells. Surprisingly with these series, results indicate that the biological activity of ruthenocifens is better than that of ferrocifens and other tamoxifen-like compounds. The synthesis of a new metal-based compound is also described. It was shown, for the first time, that ruthenocifens are good antiplasmodial prototypes. Further studies will be conducted aiming at a better understanding of their mechanism of action and at obtaining new compounds with better therapeutic profile.


Assuntos
Antimaláricos/farmacologia , Complexos de Coordenação/síntese química , Compostos Ferrosos/farmacologia , Compostos Organometálicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Rutênio/farmacologia , Animais , Antimaláricos/síntese química , Linhagem Celular , Cromatografia em Camada Fina , Complexos de Coordenação/farmacologia , Citotoxinas/farmacologia , Compostos Ferrosos/síntese química , Haplorrinos , Células Hep G2/parasitologia , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Compostos Organometálicos/síntese química , Rutênio/química , Tamoxifeno/química
15.
Chem Soc Rev ; 44(24): 8802-17, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26486993

RESUMO

Despite current developments in therapeutics focusing on biotechnologically-oriented species, the unflagging utility of small molecules or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small molecules, while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chemistry. Medicinal organometallic chemistry can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clinical development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable aromatic, with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concentration of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.


Assuntos
Antineoplásicos/farmacologia , Compostos Ferrosos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Compostos Ferrosos/química , Humanos , Estrutura Molecular
16.
Angew Chem Int Ed Engl ; 54(35): 10230-3, 2015 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-26179051

RESUMO

The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH2 )3 C(Fc)=C(C6 H4 OH)2 (3 b) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC, with IC50 values of 0.07 and 0.11 µM, respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran-substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH3 CH2 -C(Fc)=C(C6 H4 OH)2 merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox "antenna", but also as a stabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3 b-QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.


Assuntos
Proliferação de Células/efeitos dos fármacos , Compostos Ferrosos/farmacologia , Indolquinonas/química , Compostos Organometálicos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Ciclização , Compostos Ferrosos/química , Células Hep G2 , Humanos , Compostos Organometálicos/química , Oxirredução , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
17.
ChemMedChem ; 10(6): 981-90, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25882581

RESUMO

Ferrociphenols have been found to have high antiproliferative activity against estrogen-independent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied. Three main metabolite classes were identified: quinone methides (QMs) deriving from two-electron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH2 group of FCs leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA-MB-231 hormone-independent breast cancer cells.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Compostos Ferrosos/metabolismo , Tamoxifeno/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Metalocenos , Microssomos/metabolismo , Oxirredução
18.
J Med Chem ; 57(21): 8849-59, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25313665

RESUMO

Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 ≈ 2.5 µM) than the hydroxyferrocifens (IC50 ≈ 15 µM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells.


Assuntos
Compostos Ferrosos/química , Indolquinonas/química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Cistamina/análogos & derivados , Cistamina/química , Compostos Ferrosos/uso terapêutico , Glutationa/metabolismo , Glutationa Redutase/antagonistas & inibidores , Glutationa Redutase/metabolismo , Humanos , Indolquinonas/síntese química , Concentração Inibidora 50 , Células Jurkat , Metalocenos , Neoplasias/tratamento farmacológico , Compostos Organosselênicos/química , Ratos , Selenocisteína/química
19.
J Inorg Biochem ; 141: 144-151, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25261808

RESUMO

Platinum coordination complexes represent an important class of anti-tumor agents. Due to recognized drawbacks, research into other types of metallodrugs has been diversified with the aim of finding new chemical entities with alternative mechanisms of action to overcome classical chemoresistance. P5 and DP1, two closely related ferrocenyl complexes bearing a similar ferrocenyl-ene-phenyl motif and displaying marked differences in their conformations and oxidation state versatility, were assayed in cancer cell models characterized by various sensitivities to pro-apoptotic stimuli. P5 and DP1 exert growth inhibitory effects between 0.5 and 10 µM against glioma and melanoma cells including pluripotent stem-like cells. These effects are due, at least partly, to senescence induction with typical SA-ß-galactosidase staining and senescence-associated secretory phenotype (SASP) as measured by the secretion of IL-1α, IL-1ß, IL-6, IL-8 and TNF-α. Regulation of these cytokines' secretion may be related to AP-1 and other transcription factors unrelated to senescence. An in vivo graft of B16F10 cells after in vitro pre-incubation with DP1 or P5 led to increased survival in mice. In conclusion, P5 and DP1 ferrocenyl complexes induce senescence in various cancer cell models associated with distinct sensitivity to pro-apoptotic stimuli.


Assuntos
Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Compostos Ferrosos/farmacologia , Regulação Neoplásica da Expressão Gênica , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Compostos Ferrosos/síntese química , Humanos , Interferon gama/biossíntese , Interferon gama/metabolismo , Interleucina-6/biossíntese , Interleucina-6/metabolismo , Interleucina-8/biossíntese , Interleucina-8/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Camundongos , Transplante de Neoplasias , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
20.
Molecules ; 19(7): 10350-69, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-25036149

RESUMO

In the course of the preparation of a series of ferrocenyl derivatives of diethylstilbestrol (DES), in which one of the 4-hydroxyphenyl moieties was replaced by a ferrocenyl group, the McMurry reaction of chloropropionylferrocene with a number of mono-aryl ketones unexpectedly yielded the hydroxylated ferrocenyl DES derivatives, 5a-c, in poor yields (10%-16%). These compounds showed high activity on the hormone-independent breast cancer cell line MDA-MB-231 with IC50 values ranging from 0.14 to 0.36 µM. Surprisingly, non-hydroxylated ferrocenyl DES, 4, showed only an IC50 value of 1.14 µM, illustrating the importance of the hydroxyethyl function in this promising new series. For comparison, McMurry reactions of the shorter chain analogue chloroacetylferrocene were carried out to see the difference in behaviour with mono-aryl ketones versus a diaryl ketone. The effect of changing the length of the alkyl chain adjacent to the phenolic substituent of the hydroxylated ferrocenyl DES was studied, a mechanistic rationale to account for the unexpected products is proposed, and the antiproliferative activities of all of these compounds on MDA-MB-231 cells lines were measured and compared. X-ray crystal structures of cross-coupled products and of pinacol-pinacolone rearrangements are reported.


Assuntos
Antineoplásicos/química , Compostos Ferrosos/química , Fenol/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Combinatória , Humanos , Concentração Inibidora 50 , Metalocenos , Estrutura Molecular
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