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1.
Angew Chem Int Ed Engl ; 60(45): 24043-24047, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34487611

RESUMO

Pharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity. Here, we report a platform able to generate the cytotoxic agent by intramolecular cyclization. Using phenanthridines as cytotoxic model compounds, we designed ring-opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid inside living cells of KB cancer spheroids so as to circumvent drug action.


Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Fenantridinas/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células KB , Estrutura Molecular , Fenantridinas/síntese química , Fenantridinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química
2.
Bioorg Chem ; 91: 103158, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376782

RESUMO

This study describes the synthesis of arylboronate-based ROS-responsive prodrugs of doxorubicin and their biological evaluation as anticancer agents. The determination of the most sensitive cancer type toward arylboronate prodrugs is crucial for further consideration of these molecules in clinical phase. To address this goal, an arylboronate-based profluorescent probe was used to compare the capacity of various cancer cell lines to efficiently convert the precursor into the free fluorophore. On the selected MiaPaCa-2 pancreatic cancer cells, a benzeneboronate prodrug exhibited 67% of the cytotoxicity obtained with the free doxorubicin. The prodrug was also able to induce tumor regression on MiaPaCa-2 pancreatic tumor model in ovo. Using this model, the amount of free doxorubicin liberated from this prodrug into the tumor was equivalent to the quantity measured after direct intratumoral injection of the same concentration of doxorubicin.


Assuntos
Ácidos Borônicos/química , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Compostos Heterocíclicos/química , Neoplasias Pancreáticas/tratamento farmacológico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Embrião de Galinha , Membrana Corioalantoide , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
5.
JVS Vasc Sci ; 5: 100213, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39257386

RESUMO

Objective: Implantation of an endovascular device disrupts the homeostatic CD31:CD31 interactions among quiescent endothelial cells (ECs), platelets, and circulating leukocytes. The aim of this study was to design an endothelial-mimetic coating of nitinol and cobalt-chromium (CoCr) surfaces and stents using synthetic CD31 peptides, to promote device endothelialization and pacific integration within the arterial wall. Methods: Peptides mimicking the domains 1 (D1) and 2 (D2) of CD31 were synthetized and immobilized onto experimental nitinol and CoCr surfaces using a three-step, dip-coating, mussel-inspired protocol using copper-free click chemistry. Human aortic EC phenotype and endothelialization assessment using parallel scratch tests were carried out using five synthetic CD31 peptides coated on 4.8-mm nitinol and CoCr flat disks and were compared with control disks. The CD31 peptide exhibiting the best results in vitro was then immobilized on clinical-grade 3 × 40-mm self-expanding nitinol and 2.5 × 20.0-mm balloon-expandable CoCr stents. Such devices were implanted in native arteries of White New Zealand rabbits, and compared with control uncoated bare metal stents (BMS) and drug-eluting stents 7 and 30 days after implantation using resin cross-sections and scanning electron microscopy (n = 2-3 per group at each time point). Results: Membrane-distal CD31 D1 and D2 peptides exhibited a distinct capability to foster a healthy endothelial phenotype and to promote endothelialization in vitro. By day 7 after implantation, CD31 nitinol and CoCr stents were evenly covered by wholesome ECs, devoid of thromboinflammatory signs, in contrast with both BMS and drug-eluting stents. Such results were consistent until day 30. Conclusions: Membrane-distal CD31 biomimetic peptides seem to camouflage the device surface effectively, preventing local reactions and promoting rapid and seamless endovascular integration.

6.
J Neurointerv Surg ; 15(12): 1207-1211, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36878688

RESUMO

BACKGROUND: The first-pass complete recanalization by mechanical thrombectomy (MT) for the treatment of stroke remains limited due to the poor integration of the clot within current devices. Aspiration can help retrieval of the main clot but fails to prevent secondary embolism in the distal arterial territory. The dense meshes of extracellular DNA, recently described in stroke-related clots, might serve as an anchoring platform for MT devices. We aimed to evaluate the potential of a DNA-reacting surface to aid the retention of both the main clot and small fragments within the thrombectomy device to improve the potential of MT procedures. METHODS: Device-suitable alloy samples were coated with 15 different compounds and put in contact with extracellular DNA or with human peripheral whole blood, to compare their binding to DNA versus blood elements in vitro. Clinical-grade MT devices were coated with two selected compounds and evaluated in functional bench tests to study clot retrieval efficacy and quantify distal emboli using an M1 occlusion model. RESULTS: Binding properties of samples coated with all compounds were increased for DNA (≈3-fold) and decreased (≈5-fold) for blood elements, as compared with the bare alloy samples in vitro. Functional testing showed that surface modification with DNA-binding compounds improved clot retrieval and significantly reduced distal emboli during experimental MT of large vessel occlusion in a three-dimensional model. CONCLUSION: Our results suggest that clot retrieval devices coated with DNA-binding compounds can considerably improve the outcome of the MT procedures in stroke patients.


Assuntos
Acidente Vascular Cerebral , Trombose , Humanos , Resultado do Tratamento , Trombectomia/métodos , Trombose/terapia , Acidente Vascular Cerebral/cirurgia , Ligas , DNA
7.
Environ Sci Pollut Res Int ; 29(4): 6060-6071, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34431057

RESUMO

Methotrexate is an antineoplastic folate analog of high environmental concern, due to its low biodegradability and toxicological properties. This study focused on its photodegradation under two irradiation conditions, aiming to be representative of environment (300-450 nm) and drinking water treatment (254 nm). The photodegradation experiments were conducted at two pH, to vary the methotrexate ionization state and to produce a large variety of transformation products (TPs). The degradation kinetics determined through LC-UV monitoring were contrasted according to pH and irradiation wavelength. However, the quantum yields were independent of ionization state at 254 nm and the changes in kinetics at higher wavelengths were attributed to a change in the degradation mechanism. The TPs formed during the reactions were identified by UHPLC-MS/MS, using both the positive and negative modes. Among the eleven proposed structures, five were described as methotrexate TPs for the first time. The TPs result from N-demethylation, glutamic acid oxidation, and C-N cleavage, all of them leading to further degraded photoproducts presenting modified or lost glutamic acid part. This was made possible thanks to the negative mode, which allowed the exploration of the glutamic acid moiety modifications. Cytotoxicity assessment on A549 cancer cells demonstrated that all photoproducts formed at pH 7 were less toxic than the parent compound.


Assuntos
Espectrometria de Massas em Tandem , Poluentes Químicos da Água , Cinética , Metotrexato , Fotólise , Poluentes Químicos da Água/análise
8.
Chemosphere ; 306: 135616, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35810859

RESUMO

Environmental emission of pharmaceutical pollutants notably causes the contamination of aquatic ecosystems and drinking water. Typically, reduction of these pollutants in the environment is mostly managed by ameliorated wastewater treatments. Here, we report a method for the eco-design of drugs through the introduction within the molecular structure of a sensitive chemical group responsive to water treatments. The new drugs are thus programmed to fragment more easily and quickly than the original drugs. In this "retro catabolic drug design" strategy, methotrexate was used as drug model and an ether analog displaying a similar pharmacological profile was selected. Using photo-irradiation experiments at 254 nm, a representative drinking water treatment process, the identified transformation products were predominantly obtained from the expected molecular scission. Moreover, a faster kinetics of degradation was measured for the ether analog as compared to methotrexate and its transformation products were far less cytotoxic.


Assuntos
Água Potável , Poluentes Ambientais , Poluentes Químicos da Água , Ecossistema , Éteres , Metotrexato/toxicidade , Preparações Farmacêuticas , Fotólise , Águas Residuárias , Poluentes Químicos da Água/análise
9.
Eur J Med Chem ; 207: 112670, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858470

RESUMO

Boronic acid (and ester) prodrugs targeting the overexpressed level of reactive oxygen species within tumor microenvironment represent a promising area for the discovery of new selective anticancer chemotherapy. This strategy that emerged only ten years ago is exponentially growing and could demonstrate its clinical usefulness in the near future. Herein, the previously described small-molecule and macromolecular anticancer prodrugs activated by carbon-boron oxidation are gathered. This review reports on the most interesting derivatives mentioned in the literature based on the in vitro and in vivo activity when available. Eventually, the pharmacological applicability of this strategy is discussed, in particular, the kinetic aspect of the prodrug oxidation and the selectivity of this reaction towards certain ROS from the tumor microenvironment are specified.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Compostos de Boro/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
10.
J Immunother Cancer ; 8(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32784216

RESUMO

BACKGROUND: Oxazaphosphorines (cyclophosphamide (CPA), ifosfamide (IFO)) are major alkylating agents of polychemotherapy protocols but limiting their toxicity and increasing their efficacy could be of major interest. Oxazaphosphorines are prodrugs that require an activation by cytochrome P450 (CYP). CPA is mainly metabolized (>80%) to phosphoramide mustard while only 10%-50% of IFO is transformed in the alkylating entity, isophosphoramide mustard and 50%-90% of IFO release chloroacetaldehyde, a nephrotoxic and neurotoxic metabolite. Geranyloxy-IFO (G-IFO) was reported as a preactivated IFO to circumvent the toxic pathway giving directly the isophosphoramide mustard without CYP metabolization. The similarity in structure of CPA and IFO and the similarity in metabolic balance of CPA and G-IFO have led us to explore immunomodulatory effect of these components in mice and to investigate the combination of these oxazaphosphorines with immune checkpoint blockers (ICB). METHODS: The investigation of the immunomodulatory properties of IFO and G-IFO compared with CPA has been conducted through immune cell phenotyping by flow cytometry and analysis of the cytokine profile of T cells after ex-vivo restimulation. T cell-mediated antitumor efficacy was confirmed in CD4+ and CD8+ T cell-depleted mice. A combination of oxazaphosphorines with an anti-programmed cell death 1 (PD-1) antibody has been studied in MCA205 tumor-bearing mice. RESULTS: Studies on a MCA205 mouse model have demonstrated a dose-dependent effect of IFO and G-IFO on T cell immunity. These components in particular favored Th1 polarization when used at low dose (150 and eq. 100 mg/kg, respectively). Antitumor activity at low dose was abolished in mice depleted in CD4+ and CD8+ T cells. G-IFO at low dose (eq. 100 mg/kg) in combination with anti-PD-1 antidody showed high synergistic antitumor efficacy compared with IFO. CONCLUSION: Oxazaphosphorines are characterized by a dual mechanism of antitumor action; low-dose schedules should be preferred in combination with ICB, and dose escalation was found to have better utility in polychemotherapy protocols where a conventional direct cytotoxic anticancer effect is needed. G-IFO, the novel oxazaphosphorine drug, has shown a better metabolic index compared with IFO as its metabolization gives mainly the alkylating mustard as CPA (and not IFO) and a best potential in combination with ICB.


Assuntos
Antineoplásicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Mostardas de Fosforamida/uso terapêutico , Animais , Antineoplásicos/farmacologia , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Mostardas de Fosforamida/farmacologia
11.
Int J Pharm ; 532(2): 748-756, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28546071

RESUMO

Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Ifosfamida/análogos & derivados , Ifosfamida/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Antineoplásicos Alquilantes/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ifosfamida/química , Ifosfamida/farmacocinética , Masculino , Dose Máxima Tolerável , Camundongos Nus , Nanoestruturas/química , Prenilação
12.
Artigo em Inglês | MEDLINE | ID: mdl-25939095

RESUMO

The antitumor drug, ifosfamide (IFO), requires activation by cytochrome P450 (CYP) to form the active metabolite, 4-hydroxyisfosfamide (4-OHIFO), leading to toxic by-products at high dose. In order to overcome these drawbacks, preactivated ifosfamide derivatives (RXIFO) were designed to release 4-OHIFO without CYP involvement. A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the simultaneous quantification of 4-OHIFO, IFO and four derivatives RXIFO in mouse plasma using multiple reaction monitoring. Because of its instability in plasma, 4-OHIFO was immediately converted to the semi-carbazone derivative, 4-OHIFO-SCZ. For the six analytes, the calibration curves were linear from 20 to 5000ng/mL in 50µL plasma and the lower limit of quantitation was determined at 20ng/mL with accuracies within ±10% of nominal and precisions less than 12%. Their recoveries ranged from 62 to 96% by using liquid-liquid extraction. With an improved assay sensitivity compared to analogues, the derivative 4-OHIFO-SCZ was stable in plasma at 4°C for 24h and at -20°C for three months. For all compounds, the assay was validated with accuracies within ±13% and precisions less than 15%. This method was applied to a comparative pharmacokinetic study of 4-OHIFO from IFO and three derivatives RXIFO in mice. This active metabolite was produced by some of the novel conjugates with good pharmacokinetic properties.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ifosfamida/análogos & derivados , Ifosfamida/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Feminino , Ifosfamida/química , Ifosfamida/farmacocinética , Modelos Lineares , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
J Med Chem ; 58(2): 705-17, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25494842

RESUMO

Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported.


Assuntos
Antineoplásicos Alquilantes/síntese química , Ifosfamida/análogos & derivados , Mostardas de Fosforamida/metabolismo , Pró-Fármacos/síntese química , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Ifosfamida/metabolismo , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia
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