Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 66(4): 2477-2497, 2023 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-36780426

RESUMO

Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are a new family of antimitotic prodrugs bioactivated in breast cancer cells expressing CYP1A1. In this study, we report that the 14C-labeled prototypical PAIB-SO [14C]CEU-818 and its antimitotic counterpart [14C]CEU-602 are distributed in whole mouse body and they show a short half-life in mice. To circumvent this limitation, we evaluated the effect of the homologation of the alkyl side chain of the imidazolidin-2-one moiety of PAIB-SOs. Our studies evidence that PAIB-SOs bearing an n-pentyl side chain exhibit antiproliferative activity in the nanomolar-to-low-micromolar range and a high selectivity toward CYP1A1-positive breast cancer cells. Moreover, the most potent n-pentyl PAIB-SOs were significantly more stable toward rodent liver microsomes. In addition, PAIB-SOs 10 and 14 show significant antitumor activity and low toxicity in chorioallantoic membrane (CAM) assay. Our study confirms that homologation is a suitable approach to improve the rodent hepatic stability of PAIB-SOs.


Assuntos
Antimitóticos , Neoplasias , Pró-Fármacos , Camundongos , Animais , Antimitóticos/química , Pró-Fármacos/química , Citocromo P-450 CYP1A1 , Roedores , Microssomos Hepáticos , Benzenossulfonatos/química
2.
Eur J Med Chem ; 229: 114003, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34839998

RESUMO

We recently discovered a new family of prodrugs deriving from phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) bioactivatable by cytochrome P450 1A1 (CYP1A1) into potent antimitotics referred to as phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs). PAIB-SOs display significant selectivity toward human breast cancer cells based on the N-dealkylation of PAIB-SOs into their corresponding PIB-SOs by CYP1A1. In this study, we have evaluated the molecular mechanism of the bioactivation of PAIB-SOs into PIB-SOs by branching the linear alkyl chain on the imidazolidin-2-one (IMZ) moiety of PAIB-SOs by branched alkyl groups such as isopropyl, isobutyl and sec-butyl. Our results show that PAIB-SOs bearing an isobutyl group on the IMZ moiety and either a methoxy, a chloro or a bromo group at positions 3, 3,5 or 3,4,5 on the aromatic ring B exhibit antiproliferative activity ranging from 0.13 to 6.9 µM and selectivity toward MCF7 and MDA-MB-468 mammary cancer cells comparatively to other cell lines tested. Moreover, the most potent and selective PAIB-SOs bearing an isobutyl group and either a 3,5-Cl (44), 3,5-Br (45) or a 3,4,5-OMe (46) on the IMZ moiety exhibit antiproliferative activity in the sub-micromolar range and high selectivity ratios toward mammary cancer cells. They stop the cell cycle of MCF7 cells in the G2/M phase and disrupt their cytoskeleton. Furthermore, our studies evidenced that PAIB-SOs bearing either an isopropyl, a sec-butyl or an isobutyl group are hydroxylated on the carbon atom adjacent to the IMZ (Cα-OH) but only PAIB-SOs bearing an isobutyl group are bioactivated into PIB-SOs. Finally, PAIB-SOs 45 and 46 exhibit low toxicity toward normal cells and chick embryos and are thus promising antimitotic prodrugs highly selective toward CYP1A1-expressing breast cancer cells.


Assuntos
Antimitóticos/química , Benzenossulfonatos/química , Citocromo P-450 CYP1A1/metabolismo , Pró-Fármacos/química , Animais , Antimitóticos/síntese química , Antimitóticos/farmacologia , Benzenossulfonatos/síntese química , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Galinhas , Citocromo P-450 CYP1A1/química , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato
3.
J Immunol ; 206(3): 505-514, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33361205

RESUMO

High concentrations of the damage-associated molecular patterns S100A8 and S100A9 are found in skin and serum from patients suffering from psoriasis, an IL-17-related disease. Notably, although the expression of these proteins correlates with psoriatic disease severity, the exact function of S100A8 and S100A9 in psoriasis pathogenesis remains unclear. In this study, we investigated the role of S100A8 and S100A9 in psoriasis-associated skin hyperplasia and immune responses using S100a8-/- and S100a9-/- mice in an imiquimod-induced model of psoriasis. We found that S100a8-/- and S100a9-/- psoriatic mice exhibit worsened clinical symptoms relative to wild-type mice and increased expression of S100A9 and S100A8 proteins in keratinocytes, respectively. In addition, the loss of S100A8 enhances proliferation of keratinocytes and disrupts keratinocyte differentiation. We further detected elevated production of IL-17A and -F from CD4+ T cells in the absence of S100A8 and S100A9, as well as increased infiltration of neutrophils in the skin. In addition, treatment with anti-IL-17A and -F was found to reduce psoriasis symptoms and skin hyperplasia in S100a8-/- and S100a9-/- mice. These data suggest that S100A8 and S100A9 regulate psoriasis by inhibiting production of IL-17A and -F, thereby, to our knowledge, providing new insights into their biological functions.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Interleucina-17/metabolismo , Psoríase/metabolismo , Psoríase/patologia , Pele/patologia , Células Th17/imunologia , Animais , Anticorpos Bloqueadores/metabolismo , Calgranulina A/genética , Calgranulina B/genética , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hiperplasia , Imiquimode , Interleucina-17/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Psoríase/induzido quimicamente
4.
Eur J Med Chem ; 179: 660-666, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279298

RESUMO

Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80-90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and -independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 µM on LNCaP (AR+) in comparison to 13.3 µM on PC3 (AR-) and 8.8 µM on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 µM, 0.5 µM and 1.0 µM, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 µM. This is not the case for CDDP showing IC50 of 1.3 µM and 5.1 µM on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Testosterona/química
5.
Bioorg Med Chem ; 26(18): 5045-5052, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30201525

RESUMO

The role and the importance of the sulfonate moiety in phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were assessed using its bioisosteric sulfonamide equivalent leading to new cytochrome P450 1A1 (CYP1A1)-activated prodrugs designated as 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs). PAIB-SAs are active in the submicromolar to low micromolar range showing selectivity toward CYP1A1-expressing MCF7 cells as compared to cells devoid of CYP1A1 activity such as MDA-MB-231 and HaCaT cells. The most potent, PAIB-SA 13, bearing a trimethoxyphenyl group on ring B blocks the cell cycle progression in G2/M phase, disrupts the microtubule dynamics and is biotransformed by CYP1A1 into CEU-638, its potent antimicrotuble counterpart. Structure-activity relationships related to PAIB-SOs and PAIB-SAs evidenced that PAIB-SOs and PAIB-SAs are true bioisosteric equivalents fully and selectively activatable by CYP1A-expressing cells into potent antimitotics.


Assuntos
Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP1A1/metabolismo , Pró-Fármacos/farmacologia , Antimitóticos/síntese química , Antimitóticos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
6.
ACS Nano ; 12(3): 2482-2497, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29498821

RESUMO

Gold nanoparticles (Au NPs) distributed in the vicinity of low-dose rate (LDR) brachytherapy seeds could multiply their efficacy thanks to the secondary emissions induced by the photoelectric effect. Injections of radioactive LDR gold nanoparticles (LDR Au NPs), instead of conventional millimeter-size radioactive seeds surrounded by Au NPs, could further enhance the dose by distributing the radioactivity more precisely and homogeneously in tumors. However, the potential of LDR Au NPs as an emerging strategy to treat cancer is strongly dependent on the macroscopic diffusion of the NPs in tumors, as well as on their microscopic internalization within the cells. Understanding the relationship between interstitial and intracellular distribution of NPs, and the outcomes of dose deposition in the cancer tissue is essential for considering future applications of radioactive Au NPs in oncology. Here, LDR Au NPs (103Pd:Pd@Au-PEG NPs) were injected in prostate cancer tumors. The particles were visualized at time-points by computed tomography imaging ( in vivo), transmission electron microscopy ( ex vivo), and optical microscopy ( ex vivo). These data were used in a Monte Carlo-based dosimetric model to reveal the dose deposition produced by LDR Au NPs both at tumoral and cellular scales. 103Pd:Pd@Au-PEG NPs injected in tumors produce a strong dose enhancement at the intracellular level. However, energy deposition is mainly confined around vesicles filled with NPs, and not necessarily close to the nuclei. This suggests that indirect damage caused by the production of reactive oxygen species might be the leading therapeutic mechanism of tumor growth control, over direct damage to the DNA.


Assuntos
Ouro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Paládio/administração & dosagem , Neoplasias da Próstata/radioterapia , Animais , Braquiterapia/métodos , Ouro/farmacocinética , Ouro/uso terapêutico , Humanos , Injeções Intralesionais , Masculino , Nanopartículas Metálicas/análise , Nanopartículas Metálicas/uso terapêutico , Camundongos , Método de Monte Carlo , Células PC-3 , Paládio/farmacocinética , Paládio/uso terapêutico , Fótons , Neoplasias da Próstata/patologia , Radioisótopos/administração & dosagem , Radioisótopos/farmacocinética , Radioisótopos/uso terapêutico , Radiometria
7.
J Med Chem ; 60(12): 4963-4982, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28535350

RESUMO

Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) that are antimicrotubule prodrugs activated by CYP1A1. Although PAIB-SOs are inert in most cells tested, they are highly cytocidal toward several human breast cancer cells, including hormone-independent and chemoresistant types. PAIB-SOs are N-dealkylated into cytotoxic phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) in CYP1A1-positive cancer cells, both in vitro and in vivo. In conclusion, PAIB-SOs are novel chemotherapeutic prodrugs with no equivalent among current antineoplastics and whose selective action toward breast cancer is tailored to the characteristic pattern of CYP1A1 expression observed in a large percentage of human breast tumors.


Assuntos
Antimitóticos/farmacologia , Benzenossulfonatos/química , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP1A1/metabolismo , Pró-Fármacos/farmacologia , Animais , Antimitóticos/farmacocinética , Benzenossulfonatos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Embrião de Galinha , Citocromo P-450 CYP1A1/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Pró-Fármacos/farmacocinética
8.
Adv Healthc Mater ; 6(4)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28116855

RESUMO

Prostate cancer (PCa) is one of the leading causes of death among men. Low-dose brachytherapy is an increasingly used treatment for PCa, which requires the implantation of tens of radioactive seeds. This treatment causes discomfort; these implants cannot be removed, and they generate image artifacts. In this study, the authors report on intratumoral injections of radioactive gold nanoparticles (Au NPs) as an alternative to seeds. The particles (103 Pd:Pd@Au-PEG and 103 Pd:Pd@198 Au:Au-PEG; 10-14 nm Pd@Au core, 36-48 nm hydrodynamic diameter) are synthesized by a one-pot process and characterized by electron microscopy. Administrated as low volume (2-4 µL) single doses (1.6-1.7 mCi), the particles are strongly retained in PCa xenograft tumors, impacting on their growth rate. After 4 weeks, a tumor volume inhibition of 56% and of 75%, compared to the controls, is observed for 103 Pd:Pd@Au-PEG NPs and 103 Pd:Pd@198 Au:Au-PEG NPs, respectively. Skin necrosis is observed with 198 Au; therefore, Au NPs labeled with 103 Pd only are a more advisable choice. Overall, this is the first study confirming the impact of 103 Pd@Au NPs on tumor growth. This new brachytherapy procedure could allow tunable doses of radioactivity, administered with smaller needles than with the current technologies, and leading to fewer image artifacts.


Assuntos
Braquiterapia/métodos , Ouro , Nanopartículas , Paládio , Neoplasias da Próstata/radioterapia , Animais , Linhagem Celular Tumoral , Ouro/química , Ouro/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Paládio/química , Paládio/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Bioorg Med Chem Lett ; 27(2): 299-302, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27903409

RESUMO

The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI50<6µM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity.


Assuntos
Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Sulfonamidas/química
10.
J Vis Exp ; (114)2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27585303

RESUMO

Mammalian cell culture in monolayers is widely used to study various physiological and molecular processes. However, this approach to study growing cells often generates unwanted artifacts. Therefore, cell culture in a three-dimensional (3D) environment, often using extracellular matrix components, emerged as an interesting alternative due to its close similarity to the native in vivo tissue or organ. We developed a 3D cell culture system using two compartments, namely (i) a central compartment containing cancer cells embedded in a collagen gel acting as a pseudo-primary macrospherical tumor and (ii) a peripheral cell-free compartment made of a fibrin gel, i.e. an extracellular matrix component different from that used in the center, in which cancer cells can migrate (invasion front) and/or form microspherical tumors representing secondary or satellite tumors. The formation of satellite tumors in the peripheral compartment is remarkably correlated to the known aggressiveness or metastatic origin of the native tumor cells, which makes this 3D culture system unique. This cell culture approach might be considered to assess cancer cell invasiveness and motility, cell-extracellular matrix interactions and as a method to evaluate anti-cancer drug properties.


Assuntos
Técnicas de Cultura de Células/métodos , Movimento Celular/fisiologia , Matriz Extracelular , Invasividade Neoplásica , Animais , Colágeno , Fibrina , Humanos , Imageamento Tridimensional , Neoplasias
11.
Sci Rep ; 6: 23302, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-27001483

RESUMO

2-Ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) is a novel anticancer agent that arrests cell cycle in S-phase and causes DNA replication stress leading to the phosphorylation of H2AX into γ-H2AX. First, using the M21, HT29, HT-1080 and HeLa cell lines, we confirmed that S-phase cell cycle arrest and γ-H2AX foci induction by SFOM-0046 is a general mechanism occurring in diverse cancer cell lines. In addition to γ-H2AX, SFOM-0046 activates preferentially ATR-Chk1 in M21 and HT29 cells while both ATR-Chk1 and ATM-Chk2 pathways are activated in HCT116 cells. Co-localization of SFOM-0046-induced 53BP1 foci with γ-H2AX foci validates that the DNA damage generated corresponds to double-strand-breaks (DSBs). Consistent with an S-phase arrest, SFOM-0046 treatment induces RAD51 foci formation but not DNA-PKcs foci, confirming that homologous recombination is the major DSB repair pathway targeted by the drug. Furthermore, using isogenic HCT116 p53+/+ and HCT116 p53-/- cells, we showed that p53 plays a key role in the survival mechanism to SFOM-0046. Finally, SFOM-0046 exhibits a dose-dependent antitumor activity on human fibrosarcoma HT-1080 tumours grafted onto chick chorioallantoic membranes without showing embryo toxicity even at high doses. Altogether, our results highlight SFOM-0046 as a very promising drug that induces a replication stress response.


Assuntos
Benzenossulfonatos/farmacologia , Dano ao DNA , Reparo do DNA , Compostos de Fenilureia/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Replicação do DNA , Humanos
12.
J Mater Chem B ; 4(39): 6413-6427, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32263450

RESUMO

In recent years, pulsed laser ablation in liquids (PLAL) has emerged as a new green chemistry method to produce different types of nanoparticles (NPs). It does not require the use of reducing or stabilizing agents, therefore enabling the synthesis of NPs with highly-pure surfaces. In this study, pure Au NPs were produced by PLAL in aqueous solutions, sterically stabilized using minimal PEG excess, and functionalized with manganese chelates to produce a dual CT/MRI contrast agent. The small hydrodynamic size (36.5 nm), low polydispersity (0.2) and colloidal stability of Au NPs@PEG-Mn2+ were demonstrated by DLS. The particles were further characterized by TEM, XPS, FTIR and 1H NMR to confirm the purity of the Au surfaces (i.e. free from the common residual chemicals found after NP synthesis) and the presence of the different surface molecules. The potential of these particles as contrast agents for CT/MRI was assessed in vivo (e.g. chicken embryo). Au NPs@PEG-Mn2+ also demonstrated strong blood retention for at least 90 minutes following intravenous injection in mouse models. The promising performance of PEGylated PLAL-synthesized Au NPs containing manganese chelates could open new possibilities for the production of purer dual imaging contrast agents based on Au colloids.

13.
Eur J Med Chem ; 103: 563-73, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26408815

RESUMO

DNA double strand-breaks (DSBs) are the most deleterious lesions that can affect the genome of living beings and are lethal if not quickly and properly repaired. Recently, we discovered a new family of anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs) that are blocking the cells cycle progression in S-phase and inducing DNA DSBs. Previously, we have studied the effect of several modifications on the molecular scaffold of PUB-SOs on their cytocidal properties. However, the effect of the nature and the position of substituents on the aromatic ring B is still poorly studied. In this study, we report the preparation and the biological evaluation of 45 new PUB-SO derivatives substituted by alkyl, alkoxy, halogen and nitro groups at different positions on the aromatic ring B. All PUB-SOs were active in the submicromolar to low micromolar range (0.24-20 µM). The cell cycle progression analysis showed that PUB-SOs substituted at position 2 by alkyl, halogen or nitro groups or substituted at position 4 by a hydroxyl group arrest the cell cycle progression in S-phase. Interestingly, all others PUB-SOs substituted at positions 3 and 4 arrested the cell cycle in G2/M-phase. PUB-SOs arresting the cell cycle progression in S-phase also induced the phosphorylation of H2AX (γH2AX) which is indicating the generation of DNA DSBs. We evidenced that few modifications on the ring B of PUB-SOs scaffold lead to cytocidal derivatives arresting the cell cycle in S-phase and inducing γH2AX and DSBs. In addition, this study shows that these new anticancer agents are promising and could be used as alternative to circumvent some of the biopharmaceutical complications that might be encountered during the development of PUB-SOs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Eur J Med Chem ; 100: 34-43, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26069928

RESUMO

Combretastatin A-4 (CA-4) is a well-studied and attractive molecular template to develop new antimitotics. Several thousand of modifications were performed on the ring B and the ethenyl bridge of CA-4 but only a few involved the trimethoxyphenyl moiety (TMP, ring A) often considered essential to the antiproliferative and antimicrotubule activities. In this study, we described the design, the preparation, the characterization and the biological evaluation of three new series of CA-4 analogs namely styryl-N-phenyl-N'-ethylureas (SEUs), styryl-N-phenyl-N'-(2-chloroethyl)ureas (SCEUs) and styrylphenylimidazolidin-2-ones (SIMZs) bearing a 3-Cl (series a), 3,5-Me (series b) and TMP (series c) substituents, respectively. All SCEU and SIMZ Z-isomers were active in the high and the low nanomolar range, respectively. Conversely to SEUs and their E-isomers that were significantly less active or inactive. Interestingly, the TMP moiety is giving rise to derivatives exhibiting the lowest antiproliferative activity in the SCEU series (10c) and the most active compound in the SIMZ series (12c). Moreover, SIMZ Z-isomers bearing either a 3-Cl (12a) or a 3,5-Me (12b) exhibited antiproliferative activities that are also in the same order of magnitude as 12c. All SCEU and SIMZ Z-isomers also arrested the cell cycle progression in G2/M phase, bound to the colchicine-binding site and disrupted the cytoskeleton of cancer cells. In addition to the promising and innovative microtubule-disrupting properties of SCEUs and SIMZs, these results show that the TMP moiety is not essential for the cytocidal activity of these new CA-4 analogs.


Assuntos
Antineoplásicos/farmacologia , Imidazolidinas/farmacologia , Microtúbulos/efeitos dos fármacos , Estilbenos/farmacologia , Ureia/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Células MCF-7 , Estrutura Molecular , Estilbenos/química , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacologia
15.
Mol Cell Biol ; 33(11): 2285-301, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23547259

RESUMO

Stress granules (SG) are cytoplasmic multimeric RNA bodies that form under stress conditions known to inhibit cap-dependent translation. SG contain translation initiation factors, RNA binding proteins, and signaling molecules. SG are known to inhibit apoptotic pathways, thus contributing to chemo- and radioresistance in tumor cells. However, whether stress granule formation involves oncogenic signaling pathways is currently unknown. Here, we report a novel role of the mTORC1-eukaryotic translation initiation factor 4E (eIF4E) pathway, a key regulator of cap-dependent translation initiation of oncogenic factors, in SG formation. mTORC1 specifically drives the eIF4E-mediated formation of SG through the phosphorylation of 4E-BP1, a key factor known to inhibit formation of the mTORC1-dependent eIF4E-eIF4GI interactions. Disrupting formation of SG by inactivation of mTOR with its specific inhibitor pp242 or by depletion of eIF4E or eIF4GI blocks the SG-associated antiapoptotic p21 pathway. Finally, pp242 sensitizes cancer cells to death in vitro and inhibits the growth of chemoresistant tumors in vivo. This work therefore highlights a novel role of the oncogenic mTORC1-eIF4E pathway, namely, the promotion of formation of antiapoptotic SG.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Grânulos Citoplasmáticos/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Fosfoproteínas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Ácidos Borônicos/farmacologia , Bortezomib , Proteínas de Ciclo Celular , Embrião de Galinha , Fator de Iniciação 4E em Eucariotos/genética , Células HeLa/efeitos dos fármacos , Humanos , Indóis/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos , Fosforilação , Purinas/farmacologia , Pirazinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética
16.
J Med Chem ; 55(13): 6194-208, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22694057

RESUMO

Twenty-eight new substituted N-phenyl ureidobenzenesulfonate (PUB-SO) and 18 N-phenylureidobenzenesulfonamide (PUB-SA) derivatives were prepared. Several PUB-SOs exhibited antiproliferative activity at the micromolar level against the HT-29, M21, and MCF-7 cell lines and blocked cell cycle progression in S-phase similarly to cisplatin. In addition, PUB-SOs induced histone H2AX (γH2AX) phosphorylation, indicating that these molecules induce DNA double-strand breaks. In contrast, PUB-SAs were less active than PUB-SOs and did not block cell cycle progression in S-phase. Finally, PUB-SOs 4 and 46 exhibited potent antitumor activity in HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membranes, which was similar to cisplatin and combretastatin A-4 and without significant toxicity toward chick embryos. These new compounds are members of a promising new class of anticancer agents.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Fase S/efeitos dos fármacos , Animais , Anticarcinógenos/síntese química , Benzenossulfonatos/síntese química , Ciclo Celular , Linhagem Celular Tumoral , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Cisplatino/farmacologia , Células HT29 , Histonas/metabolismo , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Imidazolidinas/farmacologia , Células Jurkat , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/síntese química , Fosforilação , Estilbenos/farmacologia , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 46(11): 5327-42, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21920638

RESUMO

The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G(2)/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Antimitóticos/química , Antimitóticos/farmacologia , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Inibidores da Angiogênese/metabolismo , Animais , Antimitóticos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/patologia , Colchicina/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Sulfonamidas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Benzenossulfonamidas
18.
Contrast Media Mol Imaging ; 6(4): 209-18, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21861281

RESUMO

The majority of contrast agents used in magnetic resonance imaging (MRI) is based on the rare-earth element gadolinium. Gadolinium-based nanoparticles could find promising applications in pre-clinical diagnostic procedures of certain types of cancer, such as glioblastoma multiforme. This is one of the most malignant, lethal and poorly accessible forms of cancer. Recent advances in colloidal nanocrystal synthesis have led to the development of ultra-small crystals of gadolinium oxide (US-Gd(2)O(3), 2-3 nm diameter). As of today, this is the smallest and the densest of all Gd-containing nanoparticles. Cancer cells labeled with a sufficient quantity of this compound appear bright in T(1)-weighted MRI images. Here we demonstrate that US-Gd(2)O(3) can be used to label GL-261 glioblastoma multiforme cells, followed by localization and visualization in vivo using MRI. Very high amounts of Gd are efficiently internalized and retained in cells, as confirmed with TEM and ICP-MS. Labeled cells were visualized in vivo at 1.5 T using the chicken embryo model. This is one more step toward the development of "positively contrasted" cell tracking procedures with MRI.


Assuntos
Neoplasias Encefálicas/diagnóstico , Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética/métodos , Nanopartículas/química , Animais , Embrião de Galinha , Meios de Contraste/química , Gadolínio/química , Humanos , Microscopia Eletrônica de Transmissão
19.
J Med Chem ; 54(13): 4559-80, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21604746

RESUMO

Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G(2)/M phase and bind to the colchicine-binding site on ß-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships.


Assuntos
Sulfonatos de Arila/síntese química , Derivados de Benzeno/síntese química , Imidazolidinas/síntese química , Estilbenos/química , Moduladores de Tubulina/síntese química , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Sulfonatos de Arila/química , Sulfonatos de Arila/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Colchicina/metabolismo , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Modelos Moleculares , Mimetismo Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Estilbenos/farmacologia , Transplante Heterólogo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
20.
Can J Physiol Pharmacol ; 88(11): 1102-14, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21076498

RESUMO

Aryl chloroethyl ureas (CEUs) are new protein alkylating agents exhibiting anticancer activity both in vitro and in vivo. We report herein that 14C-labeled CEU derivatives, designated CEU-025 and CEU-027, covalently bind to thioredoxin-1 (TRX1). Covalent binding of these molecules slightly decreases the disulfide-reducing activity of recombinant TRX1, when compared with the effect of strong thioalkylating agents such as N-ethylmaleimide. Moreover, site-directed mutagenesis and diamide competition assays demonstrated that TRX1 cysteinyl residues are not the prime targets of CEUs. CEU-025 abrogates the nuclear translocation of TRX1 in human cancer cells. In addition, we show that CEU-025 can block TRX1 nuclear translocation induced by cisplatin. Unexpectedly, pretreatment with sublethal CEU-025 concentrations that block TRX1 nuclear translocation protected the cells against cisplatin cytotoxicity. Overexpression of TRX1 in HT1080 fibrosarcoma cells attenuated CEU-025 cytotoxicity, while its suppression using TRX1-specific siRNA increased the effects of CEU-025, suggesting that loss of function of TRX1 is involved, at least in part, in the cytotoxic activity of CEU-025. These results suggest that CEU-025 and CEU-027 exhibit anticancer activity through a novel, unique mechanism of action. The importance of TRX1 and the dependence of the cytotoxicity of CEU-025 and CEU-027 on TRX1 intracellular localization are also discussed.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Tiorredoxinas/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Catálise , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Transporte Proteico/efeitos dos fármacos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...