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1.
Int J Nanomedicine ; 14: 6231-6247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496683

RESUMO

Purpose: A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug's half-life, antiretroviral activities and biodistribution. Methods: A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC's chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated. Results: MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and -20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile. Conclusion: NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.


Assuntos
Composição de Medicamentos , Emtricitabina/farmacologia , Nanopartículas/química , Pró-Fármacos/farmacologia , Animais , Antirretrovirais/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Emtricitabina/sangue , Emtricitabina/síntese química , Emtricitabina/química , Humanos , Cinética , Macrófagos/efeitos dos fármacos , Masculino , Nanopartículas/ultraestrutura , Pró-Fármacos/síntese química , Pró-Fármacos/química , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley
2.
Int J Nanomedicine ; 14: 5201-5213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371956

RESUMO

Background: SN38 (7-ethyl-10-hydroxy camptothecin), as a potent metabolite of irinotecan, is highly efficacious in cancer treatment. However, the clinical utility of SN38 has been greatly limited due to its undesirable properties, such as poor solubility and low stability. Materials and methods: In order to overcome these weaknesses, moeixitecan, a lipophilic SN38 prodrug containing a SN-38, a trolox, a succinic acid linker, and a hexadecanol chain, was loaded into liposomal nanoparticles by ethanol injection method. Results: Experiments showed that the moeixitecan-loaded liposomal nanoparticles (MLP) with a diameter of 105.10±1.49 nm have a satisfactory drug loading rate (90.54±0.41%), high solubility and stability, and showed sustained release of SN38. Notably, MLP exhibited better antitumor activity against human colon adenocarcinoma cells than irinotecan, a FDA-approved drug for the treatment of advanced colorectal cancer. Furthermore, xenograft model results showed that MLP outperformed irinotecan in terms of pharmacokinetics, in vivo therapeutic efficacy and safety. Finally, we used molecular dynamic simulations to explore the association between the structure of MLP and the physical and functional properties of MLP, moeixitecan molecules in MLP folded themselves inside the hydrocarbon chain of the lipid bilayer, which led an increased acyl chain order of the lipid bilayer, and therefore enhanced the lactone ring stability protecting it from hydrolysis. Conclusion: Our MLP constructing strategy by liposome engineering technology may serve a promising universal approach for the effective and safe delivery of lipophilic prodrug.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Irinotecano/uso terapêutico , Lipídeos/química , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Células HT29 , Humanos , Irinotecano/sangue , Irinotecano/farmacocinética , Lipossomos , Camundongos Nus , Simulação de Dinâmica Molecular , Nanopartículas/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Chem Commun (Camb) ; 55(68): 10142-10145, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31389424

RESUMO

Hydrogen sulfide, an endogenous signalling molecule, is central to several pathophysiological processes in mammalian systems. It scavenges reactive oxygen species and is known to ameliorate dopaminergic neuronal degeneration in neurotoxin-induced Parkinson's disease models. The rapid volatilization of H2S from spontaneously releasing sulfide salts being a challenge, we describe peptide conjugates which exhibit tris(2-carboxyethyl)phosphine mediated "slow and sustained" H2S release. These conjugates reduced hydrogen peroxide-induced oxidative stress and significantly increased dopamine levels in transgenic C. elegans.


Assuntos
Dopamina/metabolismo , Sulfeto de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/farmacologia , Tionas/farmacologia , Tiofenos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Liberação Controlada de Fármacos , Oxirredução , Peptídeos/síntese química , Peptídeos/química , Fosfinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tionas/síntese química , Tionas/química , Tiofenos/síntese química , Tiofenos/química , alfa-Sinucleína/genética
4.
Inorg Chem ; 58(16): 11076-11084, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31393117

RESUMO

Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Platina/farmacologia , Pró-Fármacos/farmacologia , Receptores LHRH/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta à Radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores LHRH/metabolismo , Relação Estrutura-Atividade
5.
AAPS PharmSciTech ; 20(6): 245, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286294

RESUMO

Highly water-soluble prodrug micelle (50-fold compared with free MTX) of methotrexate-polyethyleneglycol-rhodamine (MTX-PEG-rhodamine) and MTX-mPEG was synthesized by the esterification reaction. The stability of the prodrug micelles was evaluated in phosphate buffer saline (PBS) with 10% fetal bovine serum (FBS). The tumor volume of the saline, MTX, and MTX-PEG-rhodamine groups was increased 3.7-fold, 2.8-fold, and 1.8-fold, respectively, compared with the initial tumor volume. TUNEL and drug distribution results further confirmed that the micelle of MTX-PEG-rhodamine possessed fewer side effects on the normal tissue compared with MTX. The prodrug micelle showed four advantages: retention of the drug activity site, higher water solubility of methotrexate (MTX), ease of preparation and application, and preferential accumulation in tumor tissues. These advantages of MTX-mPEG make it a promising drug delivery system (DDS) for clinical use.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Metotrexato/farmacologia , Micelas , Polietilenoglicóis/química , Pró-Fármacos/farmacologia , Rodaminas/química , Água/química , Animais , Antimetabólitos Antineoplásicos/química , Sistemas de Liberação de Medicamentos , Feminino , Metotrexato/química , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Solubilidade , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Med Chem ; 178: 515-529, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207463

RESUMO

Carvacrol (CAR), a natural monoterpene particularly abundant in plants belonging to the Lamiaceae family, has recently attracted much attention for its many biological properties (antioxidant, anti-inflammatory, neuroprotective, antitumour, antibacterial, and several others). However, CAR has poor chemical-physical properties (low water solubility and high volatility), which hamper its potential pharmacological uses. In this paper, the synthesis and antimicrobial evaluation of 23 carvacrol derivatives (WSCP1-23) against a panel of selected gram-positive and gram-negative bacteria are reported. Using the prodrug approach, CAR hydrophilic (WSCP1-17) and lipophilic prodrugs (WSCP18-23) were prepared. Notably, CAR water solubility was increased by using polar neutral groups (such as natural amino acids) with the aim of improving oral drug delivery. On the other hand, CAR lipophilic prodrugs, obtained by prenylation of CAR hydroxyl group, were designed to promote membrane permeation and oral absorption. Our results revealed that WSCP1-3, showing the highest water solubility (>1700-fold compared to that of CAR), possessed good antibacterial activity against gram-negative bacteria with MIC values comparable to those of CAR and antifungal properties against different species of Candida. WSCP18-19 were the most promising prodrugs, showing good antibacterial profiles against gram-positive bacteria by interfering with the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis. Moreover, WSCP18-19 resulted more stable in simulated fluids and human plasma than WSCP1-3. Toxicity studies performed on human erythrocytes and HaCaT cells revealed that all WSCPs were not toxic at the tested concentrations.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Monoterpenos/farmacologia , Pró-Fármacos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida/efeitos dos fármacos , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Solubilidade , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 177: 448-456, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174062

RESUMO

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 µM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.


Assuntos
Antineoplásicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Feminino , Células HCT116 , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ligação Proteica/efeitos dos fármacos , Solubilidade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Chem Commun (Camb) ; 55(53): 7683-7686, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204739

RESUMO

An easy access to topical gels (both hydro- and organogels) derived from an anti-cancer prodrug namely 5-fluorouracil acetic acid (5-FuA) achieved by exploiting a simple salt formation strategy is reported for the first time. Nearly 85% of the salts synthesized were gelators. Single crystal structures of some of the gelator salts revealed an intriguing hydrogen bonding network including double stranded 1D chains stabilized through uracil-uracil complementary interactions and the crystal structures of the gelator salts corroborated well with the hypothesis based on which the gelators were designed. Studies indicated that both the hydrogel and the methyl salicylate gel of the gelator salt FuA-15 were suitable for self-drug-delivery application.


Assuntos
Ácido Acético/farmacologia , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Fluoruracila/farmacologia , Pró-Fármacos/farmacologia , Ácido Acético/síntese química , Ácido Acético/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fluoruracila/síntese química , Fluoruracila/química , Géis/síntese química , Géis/química , Géis/farmacologia , Humanos , Ligações de Hidrogênio , Estrutura Molecular , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Propriedades de Superfície
9.
Chem Commun (Camb) ; 55(52): 7474-7477, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31184664

RESUMO

Inspired by clinical studies on alcohol abuse induced endoplasmic reticulum disruption, we designed a N-hydroxylethyl peptide assembly to regulate the ER stress response in cancer cells. Upon coupling with a coumarin derivative via an ester linkage, a prodrug was synthesized to promote esterase-facilitated self-delivery of N-hydroxylethyl peptide assemblies around the ER, inducing ER dilation. Following this, ER-specific apoptosis was effectively and efficiently activated in various types of cancer cells including drug resistant and metastatic ones.


Assuntos
Citosol/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Peptídeos/farmacologia , Apoptose/efeitos dos fármacos , Carboxilesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Humanos , Microscopia de Fluorescência , Peptídeos/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia
10.
Eur J Med Chem ; 179: 84-99, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247375

RESUMO

The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 µM and EMAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells.


Assuntos
Antineoplásicos/farmacologia , Ciclofosfamida/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/síntese química , Ciclofosfamida/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
11.
Carbohydr Polym ; 216: 224-230, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047061

RESUMO

γ-Cyclodextrin-based metal-organic framework (γCD-MOF) crystals were successfully synthesized using a vapor diffusion method. An applicability of γCD-MOF for encapsulation of immunosuppressive disease-modifying antirheumatic drug leflunomide (LEF) was examined. Loading of LEF in γCD-MOF was performed by impregnation and co-crystallization. The empty and loaded γCD-MOFs were characterized using X-ray powder diffraction, N2 adsorption/desorption, thermogravimetric analysis, 1H NMR and FTIR spectroscopy. It was shown that in the presence of γCD-MOF leflunomide is transformed into its pharmacologically active form - teriflunomide that can be also applied alone in the treatment of multiple sclerosis. It was demonstrated that teriflunomide released from γCD-MOF has improved pharmacologically relevant properties such as solubility, dissolution rate and membrane permeability. It can be proposed that γCD-MOF can be considered as novel strategy for delivery of leflunomide.


Assuntos
Antirreumáticos/química , Crotonatos/síntese química , Leflunomida/química , Estruturas Metalorgânicas/química , Pró-Fármacos/química , Toluidinas/síntese química , gama-Ciclodextrinas/química , Liberação Controlada de Fármacos , Cinética , Estruturas Metalorgânicas/síntese química , Oxirredução , Permeabilidade , Porosidade , Solubilidade , gama-Ciclodextrinas/síntese química
12.
Int J Mol Sci ; 20(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060339

RESUMO

The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood-brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation. The PL-prodrug design includes various structural modalities-different conjugation strategies and/or the use of linkers between the PL and the drug moiety, which considerably influence the prodrug characteristics and the consequent effects. In this article, we describe how molecular modeling can guide the structural design of PL-based prodrugs. Computational simulations can predict the extent of phospholipase A2 (PLA2)-mediated activation, and facilitate prodrug development. Several computational methods have been used to facilitate the design of the pro-drugs, which will be reviewed here, including molecular docking, the free energy perturbation method, molecular dynamics simulations, and free density functional theory. Altogether, the studies described in this article indicate that computational simulation-guided PL-based prodrug molecular design correlates well with the experimental results, allowing for more mechanistic and less empirical development. In the future, the use of molecular modeling techniques to predict the activity of PL-prodrugs should be used earlier in the development process.


Assuntos
Desenho de Drogas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosfolipídeos/química , Pró-Fármacos/química , Animais , Antígenos de Plaquetas Humanas/química , Humanos , Estrutura Molecular , Especificidade por Substrato
13.
Org Lett ; 21(10): 3649-3652, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31063383

RESUMO

A high-content bioorthogonal prodrug with multiple outputs using the "click, cyclize, and release" concept is described. The proof of concept is established by the co-delivery of a gasotransmitter carbon monoxide, an anticancer drug floxuridine, and an in situ generated fluorescent reporter molecule for real-time monitoring of the prodrug activation. Bioorthogonal prodrugs as such are invaluable tools for the co-delivery of other drug payloads for multimodal therapy.


Assuntos
Antineoplásicos/química , Pró-Fármacos/química , Antineoplásicos/farmacologia , Monóxido de Carbono/química , Ciclização , Humanos , Estrutura Molecular
14.
Chem Commun (Camb) ; 55(43): 6106-6109, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31070201

RESUMO

We developed a spermine-conjugated lipophilic Pt(iv) prodrug that is able to reduce the cancer stem cell population in ovarian cancer. The therapeutic effect is attributed to the hydrophobic tail and cationic spermine head group, the combination of which allows the Pt(iv) prodrug to localize in mitochondria and induce corresponding damage.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Compostos de Platina/farmacologia , Pró-Fármacos/farmacologia , Espermina/química , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Pró-Fármacos/química , Espectrofotometria Atômica , Espermina/farmacologia
15.
Chem Biol Interact ; 307: 91-104, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31047917

RESUMO

Tumor hypoxia is the low tissue oxygen levels seen characteristically in rapidly proliferating and expanding neoplasms. It affects both malignant tumor cells and its microenvironment, resulting in dysfunctional neovascularization. This leads to epithelial-to-mesenchymal transition phenotype, facilitating tumor progression through cell mobility, invasion, and metastasis. The hypoxic condition in solid tumors is thus an indicator of the process of cancer progression towards an aggressive malignant phenotype with an enhanced possibility of metastasis and resistance to treatment. Advancements in the detection of tumor hypoxia and its utilization as a treatment modality in solid tumors are highly imperative. The use of fluorescent probes is an evolving field for detecting hypoxic tumors in biological systems. The present review is an attempt to provide a contextual knowledge on the prominent role of tumor hypoxia in cancer progression and dissemination. The use of azodyes in detecting tumor hypoxia aiding in cancer diagnosis through fluorescence off-on imaging and azodye-based hypoxia selective pro-drugs for assisting cancer therapy are presented. The limitations of fluorescence based hypoxia imaging and further investigations desired for clinical usage of azodye based hypoxic probes for fluorescence imaging are also considered.


Assuntos
Compostos Azo/química , Biomarcadores Tumorais/metabolismo , Corantes Fluorescentes/química , Neoplasias/diagnóstico , Hipóxia Tumoral , Compostos Azo/farmacologia , Compostos Azo/uso terapêutico , Biomarcadores Tumorais/química , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Hipóxia Tumoral/efeitos dos fármacos , Microambiente Tumoral
16.
ACS Appl Mater Interfaces ; 11(18): 16391-16401, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31002492

RESUMO

Nanomedicine has emerged as a promising strategy for effective cancer treatment. A useful approach is to develop carrier-free nanodrugs via a facile supramolecular self-assembly process. To achieve high therapeutic effect, integrating photodynamic therapy with chemotherapy has been sought after. In this work, we designed a nanocarrier (PEG-Por-CD: oxliPt(IV)-ada) assembled with oxaliplatin prodrug (oxliPt(IV)-ada) and porphyrin photosensitizer (PEG-Por-CD) through host-guest interaction to achieve stimulus-responsive combination therapy. Contributed by excellent spatial control of the binding ratio between host and guest molecules, porphyrin and oxaliplatin were separately modified with ß-cyclodextrin and adamantane to prepare the amphiphilic host-guest complex for subsequent self-assembly into therapeutic nanoparticles. The obtained PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited good colloidal stability with an average hydrodynamic size of 164 nm while undergoing the disassembly under reductive environment to release active therapeutic species. Confocal imaging demonstrated the ability of PEG-Por-CD: oxliPt(IV)-ada to effectively accumulate in the cells and produce reactive oxygen species in vitro upon 630 nm light irradiation. As compared with the monotherapy, the PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited 3-fold enhanced cytotoxicity and 2-fold increase in the apoptosis. In vivo experiments using 4T1 tumor-bearing mice confirmed that the nanoparticles were efficient in suppressing the tumor growth without eliciting systemic toxicity. The present self-delivery nanosystem constructed from the self-assembly approach not only allows precise control over the drug and photosensitizer loading ratio but also eliminates systemic toxicity concern of the drug carriers, providing a solution for further development of combinational cancer treatment.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Neoplasias/terapia , Oxaliplatina/administração & dosagem , Apoptose/efeitos dos fármacos , Terapia Combinada , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Tratamento Farmacológico , Humanos , Células MCF-7 , Nanopartículas/química , Neoplasias/patologia , Oxaliplatina/química , Fotoquimioterapia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Espécies Reativas de Oxigênio/química , Nanomedicina Teranóstica/tendências
17.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010230

RESUMO

Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible "trigger" to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/química , Cromatografia Líquida , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Pró-Fármacos/química , Quinazolinas/química
18.
Molecules ; 24(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939771

RESUMO

Despite their side effects, cholinesterase (ChE) inhibitors remain the only approved drugs to treat Alzheimer's disease patients, along with the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. In the last few years, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has also been studied as a promising target for the development of new drugs for this pathology. In this context, and based on our previous characterization of bio-oxidizable prodrugs of potent acetylcholinesterase (AChE) inhibitors, we envisioned a strategy involving the synthesis of a bio-oxidizable prodrug of both ChE and DYRK1A inhibitors. To this end, we fixed our interest on a known potent inhibitor of DYRK1A, namely INDY. The designed prodrug of both ChE and DYRK1A inhibitors was successfully synthesized, connecting both inhibitors by a carbonate link. This prodrug and its corresponding drug were then evaluated as ChEs and DYRK1A inhibitors. Remarkably, in vitro results were in accordance with the starting hypothesis, showing a relative inactivity of the prodrug against DYRK1A and ChEs and a potent inhibition of ChEs by the oxidized form. Molecular docking and kinetic studies of ChE inhibition by the active compound are also discussed in this report.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Inibidores da Colinesterase/química , Humanos , Técnicas In Vitro , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica
19.
Inorg Chem ; 58(9): 6507-6516, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31013065

RESUMO

Cancer is characterized by abnormal cellular energy metabolism, which preferentially switches to aerobic glycolysis rather than oxidative phosphorylation as a means of glucose metabolism. Many key enzymes involved in the abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV) complexes are potential anticancer prodrugs and kinetically more inert than the platinum(II) counterparts, which offer an opportunity to be modified by functional ligands for activation or targeted delivery. A novel platinum(IV) complex, c, c, t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the effects of axial ligands on the reactivity and bioactivity of the complex as well as on tumor energy metabolism. The complex was characterized by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy. The introduction of dichloroacetate (DCA) markedly increases the lipophilicity, reactivity, and cytotoxicity of the complex and blocks the growth of cancer cells having active glycolysis, and the introduction of biotin (C10H16N2O3S) enhances the tumor-targeting potential of the complex. The cytotoxicity of DPB is increased dramatically in a variety of cancer cell lines as compared with the platinum(IV) complex PB without the DCA group. DPB alters the mitochondrial membrane potential and disrupts the mitochondrial morphology. The levels of mitochondrial and cellular reactive oxygen species are also decreased. Furthermore, the mitochondrial function of tumor cells was impaired by DPB, leading to the inhibition of both glycolysis and glucose oxidation and finally to the death of cancer cells via a mitochondria-mediated apoptotic pathway. These findings demonstrate that DPB suppresses cancer cells mainly through altering metabolic pathways and highlight the importance of dual-targeting for the efficacy of anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
20.
Nat Commun ; 10(1): 1675, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975988

RESUMO

Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules.


Assuntos
Acetais/química , Antineoplásicos/química , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Pró-Fármacos/química , Antineoplásicos/farmacologia , Catálise , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Estrutura Molecular , Ácidos Ftálicos/química , Pró-Fármacos/farmacologia , Estereoisomerismo
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