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1.
Drug Deliv ; 26(1): 34-44, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30744436

RESUMO

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Glioma/terapia , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Radiossensibilizantes/administração & dosagem , Temozolomida/administração & dosagem , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/metabolismo , Linhagem Celular Tumoral , Terapia Combinada/métodos , Sistemas de Liberação de Medicamentos/métodos , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Nanopartículas/química , Nanopartículas/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Radiossensibilizantes/síntese química , Radiossensibilizantes/metabolismo , Radioterapia/métodos , Temozolomida/síntese química , Temozolomida/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
J Pharm Sci ; 107(11): 2927-2937, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29960026

RESUMO

(2S,3S)-1,2:3,4-diepoxybutane (DEB) cross-links DNA guanines by forming the intermediate epoxy-adduct ((2'S,3'S)-N-7-(3',4'-epoxy-2'-hydroxybut-1'-yl)guanine [EHBG]). This process is presently considered a primary mechanism for the action of treosulfan (TREO), the prodrug that transforms to DEB via the monoepoxide intermediate (2S,3S)-1,2-epoxybutane-3,4-diol 4-methanesulfonate (EBDM). In this article, the N-7-guanine adduct of EBDM ((2'S,3'S)-N-7-(2'3'-dihydroxy-4'-methylsulfonyloxybut-1'-yl)guanine [HMSBG]) was synthesized for the first time, and its stability was investigated at physiological in vitro conditions. To synthesize HMSBG, EBDM, formed in-situ from TREO, was treated with guanosine in glacial acetic acid at 60°C followed by ribose cleavage in 1 M HCl at 80°C. HMSBG was stable during the synthesis, which showed that a ß-hydroxy group protects the sulfonate moiety against hydrolysis in acid environment. At pH 7.2 and 37°C, HMSBG exclusively underwent first-order epoxidation to EHBG with a half-life of 5.0 h. EHBG further decomposed to trihydroxybutyl-guanine, chlorodihydroxybutyl-guanine (major products), phosphodihydroxy-guanine, and a structural isomer (minor products). The isomeric derivative was identified as guanine with a fused 7-membered ring, which provided a new insight into the EHBG stability. To conclude, the exclusive conversion of HMSBG to EHBG indicates that EBDM might contribute to DNA cross-linking independently from DEB and play a more important role in the TREO action than expected before.


Assuntos
Antineoplásicos Alquilantes/química , Bussulfano/análogos & derivados , Guanina/análogos & derivados , Substâncias Intercalantes/química , Pró-Fármacos/química , Antineoplásicos Alquilantes/síntese química , Bussulfano/síntese química , Bussulfano/química , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Guanina/síntese química , Concentração de Íons de Hidrogênio , Hidrólise , Substâncias Intercalantes/síntese química , Cinética , Espectroscopia de Ressonância Magnética , Pró-Fármacos/síntese química
3.
Curr Drug Deliv ; 15(9): 1230-1244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29929464

RESUMO

BACKGROUND: Bendamustine HCl, an antineoplastic drug, has a very short life of about 40 minutes which necessitates administration of large doses which leads to increased side effects as well as costs. OBJECTIVE: The present work describes the fabrication, optimization, and evaluation of bioactive hydroxyapatite nanoparticles to achieve sustained delivery of bendamustine HCl. METHODS: Hydroxyapatite nanoparticles (NPs) were prepared by the wet chemical precipitation method by reacting a calcium and phosphate precursor and the reaction was optimized via Box-Behnken DOE. The drug was loaded on particles by physical adsorption. Various analytical studies were performed on the fabricated nanoparticles in addition to biodistribution studies to establish the physicochemical and biological characteristics of the designed formulation. RESULTS: pH of the reactant solution was found to have a more profound effect on the particle size and size distribution in comparison to reactant concentration. The particles were found to have a spherical morphology by SEM. Size of the blank and drug-loaded nanoparticles was found to be 130±20 nm by TEM. Energy Dispersive X-ray Spectroscopy (EDS) studies confirmed the presence of hydroxyapatite as the dominant phase while DSC studies indicated the presence of the drug in its amorphous form after its adsorption on NPs. Tissue distribution studies further suggested that the majority of drug concentration was released in blood rather than the other organs implying low organ toxicity. CONCLUSION: Bendamustine loaded hydroxyapatite nanoparticles were successfully optimized and fabricated. Favorable results were obtained in in vitro, in vivo, and analytical studies.


Assuntos
Antineoplásicos Alquilantes/farmacocinética , Cloridrato de Bendamustina/farmacocinética , Durapatita/farmacocinética , Nanopartículas/química , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/química , Cloridrato de Bendamustina/síntese química , Cloridrato de Bendamustina/química , Composição de Medicamentos , Durapatita/química , Concentração de Íons de Hidrogênio , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar , Propriedades de Superfície , Distribuição Tecidual
4.
Pak J Pharm Sci ; 31(3(Supplementary)): 1081-1085, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29731447

RESUMO

This research work revolves around synthesis of antineoplastic alkylating sulfonate esters with dual alkylating sites for crosslinking of the DNA strands. These molecules were evaluated as potential antineoplastic cross linking alkylating agents by reaction with the nucleoside of Guanine DNA nucleobase at both ends of the synthesized molecule. Synthesis of the alkylating molecules and the crosslinking with the guanosine nucleoside was monitored by MALDITOF mass spectroscopy. The synthesized molecule's crosslinking or adduct forming rate with the nucleoside was compared with that of 1,4 butane disulfonate (busulfan), in form of time taken for the appearance of [M+H]+. It was found that aryl sulfonate leaving group was causing higher rate of nucleophilic attack by the Lewis basic site of the nucleobase. Furthermore, the rate was also found to be a function of electron withdrawing or donating nature of the substituent on the aryl ring. Compound with strong electron withdrawing substituent on the para position of the ring reacted fastest. Hence, new alkylating agents were synthesized with optimized or desired reactivity.


Assuntos
Antineoplásicos Alquilantes/síntese química , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/química , Bussulfano/química , Reagentes para Ligações Cruzadas/síntese química , Reagentes para Ligações Cruzadas/química , Desoxiguanosina/química
5.
Chem Commun (Camb) ; 54(3): 256-259, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29231931

RESUMO

It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by H2O2 and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA.


Assuntos
Antineoplásicos Alquilantes/química , DNA/química , Guanina/química , Lactamas Macrocíclicas/química , Pró-Fármacos/química , Alquilação , Antineoplásicos Alquilantes/síntese química , Dano ao DNA , Compostos Férricos/química , Peróxido de Hidrogênio/química , Lactamas Macrocíclicas/síntese química , Oxirredução , Pró-Fármacos/síntese química , Xantina/química , Xantina Oxidase/química
6.
ACS Chem Neurosci ; 8(1): 50-59, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-27665765

RESUMO

Glioblastoma (GBM) is the most common and aggressive type of brain tumor in adults. The triazene Temozolomide (TMZ), an alkylating drug, is the classical chemotherapeutic agent for gliomas, but has been disappointing against the highly invasive and resistant nature of GBM. Hybrid compounds may open new horizons within this challenge. The multicomponent therapeutic strategy here used resides on a combination of two repurposing drugs acting by different but potentially synergistic mechanisms, improved efficacy, and lower resistance effects. We synthesized a new hybrid compound (HYBCOM) by covalently binding a TMZ analogue to valproic acid, a histone deacetylase inhibitor drug that was shown to sensitize TMZ-resistant glioma cells. Advantages of this new molecule as compared to TMZ, in terms of chemotherapeutic efficacy, were investigated. Our results evidenced that HYBCOM more efficiently decreased the viability and proliferation of the GL261 glioma cells, while showing to better target the tumor cells than the functionally normal astrocytes. Increased cytotoxicity by HYBCOM may be a consequence of the improved autophagic process observed. Additionally, HYBCOM changed the morphology of GL261 cells into a nonpolar, more rounded shape, impairing cell migration ability. Most interesting, and in opposite to TMZ, cells exposed to HYBCOM did not enhance the expression of drug resistance proteins, a major issue in the treatment of GBM. Overall, our studies indicate that HYBCOM has promising chemotherapeutic benefits over the classical TMZ, and future studies should assess if the treatment translates into efficacy in glioblastoma experimental models and reveal clinical benefits in GBM patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/química , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Glioma/patologia , Humanos , Temozolomida
7.
Biochemistry ; 56(2): 421-440, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28000448

RESUMO

DNA-alkylating drugs continue to remain an important weapon in the arsenal against cancers. However, they typically suffer from several shortcomings because of the indiscriminate DNA damage that they cause and their inability to specifically target cancer cells. We have developed a strategy for overcoming the deficiencies in current DNA-alkylating chemotherapy drugs by designing a site-specific DNA-methylating agent that can target cancer cells because of its selective uptake via glucose transporters, which are overexpressed in most cancers. The design features of the molecule, its synthesis, its reactivity with DNA, and its toxicity in human glioblastoma cells are reported here. In this molecule, a glucosamine unit, which can facilitate uptake via glucose transporters, is conjugated to one end of a bispyrrole triamide unit, which is known to bind to the minor groove of DNA at A/T-rich regions. A methyl sulfonate moiety is tethered to the other end of the bispyrrole unit to serve as a DNA-methylating agent. This molecule produces exclusively N3-methyladenine adducts upon reaction with DNA and is an order of magnitude more toxic to treatment resistant human glioblastoma cells than streptozotocin is, a Food and Drug Administration-approved, glycoconjugated DNA-methylating drug. Cellular uptake studies using a fluorescent analogue of our molecule provide evidence of uptake via glucose transporters and localization within the nucleus of cells. These results demonstrate the feasibility of our strategy for developing more potent anticancer chemotherapeutics, while minimizing common side effects resulting from off-target damage.


Assuntos
Antineoplásicos Alquilantes/síntese química , Adutos de DNA/biossíntese , DNA de Neoplasias/antagonistas & inibidores , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glicoconjugados/síntese química , Neuroglia/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/química , Adenina/metabolismo , Alcanossulfonatos/química , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Adutos de DNA/química , Dano ao DNA , Metilação de DNA , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Expressão Gênica , Glucosamina/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Glicoconjugados/metabolismo , Glicoconjugados/farmacologia , Humanos , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Neuroglia/metabolismo , Neuroglia/patologia , Conformação de Ácido Nucleico , Pirróis/química , Estreptozocina/farmacologia
8.
Med Chem ; 13(1): 28-39, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27396904

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is often associated with a poor survival prognostic for patients. The main reason seems to be the acquired or inherent resistance to the chemotherapeutic agent used to treat the tumor, temozolomide (TMZ). To this day, the most recognized pathway of resistance is the DNA Direct Repair pathway by the means of the protein O6- methylguanine DNA-methyltransferase (MGMT). OBJECTIVES: To design and synthesize a series of MGMT inhibitors that can sensitize GBM cells to TMZ. METHODS: Twenty-five O6-alkyl, O6-aryl and O6-substituted-aryl guanine analogs including nine novel compounds were synthesized, characterized, analyzed by molecular docking and tested on the T98G GBM cells viability. RESULTS: Following molecular modeling with MGMT, the newly designed compounds 19, 22, and 24 emerged as the most promising MGMT ligands and displayed modest cytotoxicity. Guanine analog (19), bearing a p-nitrobenzyl moiety, reduced considerably the O6-methylguanine DNAmethyltransferase expression level. When combined with TMZ (1), which is used as first line treatment for brain tumors, compounds 19, 22, and 24 decreased T98G cells proliferation by 32%, 68% and 50%, respectively. TMZ (1) displayed negligible effect on the proliferation of these cells further supporting the notion that this cell model is resistant to this alkylating agent. CONCLUSION: Overall, these results notably highlight a group of MGMT inhibitors that warrants further exploration in the development of therapeutic options to circumvent TMZ resistance in brain tumors.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Glioblastoma/tratamento farmacológico , Guanina/farmacologia , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Metilases de Modificação do DNA , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Guanina/análogos & derivados , Guanina/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
9.
Annu Rev Biochem ; 85: 375-404, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27145840

RESUMO

Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. We trace the structural evolution of the p53 pathway, from germ-line surveillance in simple multicellular organisms to its pluripotential role in humans.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Proteína Supressora de Tumor p53/agonistas , Animais , Antineoplásicos Alquilantes/síntese química , Proteínas de Ciclo Celular , Ensaios Clínicos como Assunto , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Multimerização Proteica , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Anticancer Agents Med Chem ; 16(1): 20-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25980817

RESUMO

Chemotherapy may still be an essential component to treat cancer in combination with new targeted therapies. But chemotherapy needs to get smarter in order to make those combination regimens more effective and also more tolerable, particularly for an aging population. We describe the first time the synthesis and pharmacological testing of a fusion molecule comprising of the alkylator bendamustine and the HDAC-inhibitor vorinostat. The drug was designed to allow for the exploitation of both mechanisms of action simultaneously with the goal to provide a molecule with superior efficacy over the single agents. The pharmacological testing confirms the full functional capacity of both moieties and encouraging pharmacological data raises the hope that the drug may turn out to be a great addition to the armentarium of anticancer agents.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Cloridrato de Bendamustina/farmacologia , Benzimidazóis/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/química , Cloridrato de Bendamustina/síntese química , Cloridrato de Bendamustina/química , Benzimidazóis/síntese química , Benzimidazóis/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vorinostat
11.
Molecules ; 20(7): 12412-35, 2015 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-26184130

RESUMO

A new route to 3-(4-arylmethylamino)butyl-5-arylidene-2-thioxo-1,3-thiazolidine-4-one 9 was developed in six steps from commercial 1,4-diaminobutane 1 as starting material. The key step of this multi-step synthesis involved a solution phase "one-pot two-steps" approach assisted by microwave dielectric from N-(arylmethyl)butane-1,4-diamine hydrochloride 6a-f (as source of the first point diversity) and commercial bis-(carboxymethyl)-trithiocarbonate reagent 7 for construction of the rhodanine platform. This platform was immediately functionalized by Knoevenagel condensation under microwave irradiation with a series of aromatic aldehydes 3 as second point of diversity. These new compounds were prepared in moderate to good yields and the fourteen synthetic products 9a-n have been obtained with a Z-geometry about their exocyclic double bond. These new 5-arylidene rhodanines derivatives 9a-n were tested for their kinase inhibitory potencies against four protein kinases: Human cyclin-dependent kinase 5-p25, HsCDK5-p25; porcine Glycogen Synthase Kinase-3, GSK-3α/ß; porcine Casein Kinase 1, SsCK1 and human HsHaspin. They have also been evaluated for their in vitro inhibition of cell proliferation (HuH7 D12, Caco 2, MDA-MB 231, HCT 116, PC3, NCI-H727, HaCat and fibroblasts). Among of all these compounds, 9j presented selective micromolar inhibition activity on SsCK1 and 9i exhibited antitumor activities in the HuH7 D12, MDA-MBD231 cell lines.


Assuntos
Antineoplásicos Alquilantes/síntese química , Inibidores de Proteínas Quinases/síntese química , Tiazolidinas/síntese química , Aldeídos/química , Animais , Antineoplásicos Alquilantes/farmacologia , Células CACO-2 , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Expressão Gênica , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HCT116 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Micro-Ondas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Putrescina/química , Relação Estrutura-Atividade , Suínos , Tiazolidinas/farmacologia , Tionas/química
12.
Bioorg Med Chem ; 23(13): 3481-9, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25963825

RESUMO

Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydrobenzo[e]indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (ΔTm=13°C) and cytotoxicity against LNCaP human prostate cancer cells (IC50=18nM).


Assuntos
Antineoplásicos Alquilantes/síntese química , Ciclopropanos/síntese química , DNA de Neoplasias/antagonistas & inibidores , Indóis/síntese química , Pró-Fármacos , Acetamidas , Alquilação , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Óxidos N-Cíclicos/química , Ciclização , Ciclopropanos/farmacologia , DNA de Neoplasias/química , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Fluoracetatos , Humanos , Concentração de Íons de Hidrogênio , Indóis/farmacologia , Modelos Moleculares , Naftalenos/química , Desnaturação de Ácido Nucleico , Relação Estrutura-Atividade
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 Drogas , Humanos , Ifosfamida/metabolismo , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia
14.
Anticancer Agents Med Chem ; 15(5): 616-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25511515

RESUMO

The duocarmycins and CC-1065 are members of a class of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity none of the analogs have passed clinical evaluation. As a result, the intensity in the design, synthesis, and development of novel analogs of the duocarmycins has continued. Accordingly, in this review, which covers a period from the 1990s through the present time, the design and synthesis of duocarmycin SA are described along with the synthesis of novel and highly cytotoxic analogs that lack the chiral center. Examples of achiral analogs of duocarmycin SA described in this review include seco-DUMSA (39 and 40), seco-amino-CBI-TMI (13, Centanamycin), and seco-hydroxy-CBI-TMI (14). In addition, another novel class of biologically active duocarmycin SA analogs that contained the seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) DNA alkylating submit was also designed and synthesized. The synthesis of seco-iso-CFI-TMI (10, Tafuramycin A) and seco-CFQ-TMI (11, Tafuramycin B) is included in this review.


Assuntos
Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacologia , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Indóis/química , Animais , Antineoplásicos Alquilantes/química , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Humanos , Indóis/farmacologia , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Pirróis/química , Pirróis/farmacologia
15.
Mol Cancer Ther ; 14(1): 111-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25351918

RESUMO

The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell-cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced antiglioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.


Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacocinética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/farmacocinética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/metabolismo , Temozolomida , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Eur J Med Chem ; 83: 695-708, 2014 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-25014640

RESUMO

We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure-activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a-o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a-d) in inhibiting the cell growth of various human tumor cell lines in vitro. However, the methylamino or aniline substituents at C4 of quinoline did not influence the cytotoxic effects. The title conjugates were capable of inducing DNA cross-linking and promoting cell-cycle arrest at the G2/M phase. This study demonstrates that phenyl N-mustard-4-anilinoquinoline conjugates are generally more potent than phenyl N-mustard-4-anilinoquinazoline conjugates against the cell growth of various tumor cell-lines.


Assuntos
Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacologia , DNA/metabolismo , Quinolinas/química , Ureia/química , Antineoplásicos Alquilantes/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Solubilidade , Relação Estrutura-Atividade
17.
ChemMedChem ; 9(9): 2099-103, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24931822

RESUMO

The bisalkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), used in cancer chemotherapy to hinder cellular proliferation, forms lethal interstrand cross-links (ICLs) in DNA. BCNU generates an ethylene linkage connecting the two DNA strands at the N1 atom of 2'-deoxyguanosine and N3 atom of 2'-deoxycytidine, which is a synthetically challenging probe to prepare. To this end, an ICL duplex linking the N1 atom of 2'-deoxyinosine to the N3 atom of thymidine via an ethylene linker was devised as a mimic. We have solved the structure of this ICL duplex by a combination of molecular dynamics and high-field NMR experiments. The ethylene linker is well-accommodated in the duplex with minimal global and local perturbations relative to the unmodified duplex. These results may account for the substantial stabilization of the ICL duplex observed by UV thermal denaturation experiments and provides structural insights of a probe that may be useful for DNA repair studies.


Assuntos
Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacologia , Carmustina/farmacologia , DNA/química , DNA/farmacologia , Etilenos/química , Reagentes para Ligações Cruzadas , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Termodinâmica
18.
Molecules ; 19(7): 8803-19, 2014 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-24968335

RESUMO

A series of N-mustards, which was conjugated to mono- or bis-naphthalimides with a flexible amine link, were synthesized and evaluated for cytotoxicity against five cancer cell lines (HCT-116, PC-3, U87 MG, Hep G2 and SK-OV-3). Several compounds displayed better activities than the control compound amonafide. Further evaluations by fluorescence spectroscopy studies and DNA-interstrand cross-linking assays revealed that the derivatives showed both alkylating and intercalating properties. Among the derivatives, the bis-naphthalimide N-mustard derivative 11b was found to exhibit the highest cytotoxic activity and DNA cross-linking ability. Both 11b and 7b induce HCT-116 cell apoptosis by S phase arrest.


Assuntos
Antineoplásicos Alquilantes/síntese química , Naftalimidas/síntese química , Mostardas de Fosforamida/síntese química , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Naftalimidas/farmacologia , Mostardas de Fosforamida/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo
19.
ChemMedChem ; 9(9): 2178-85, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24616300

RESUMO

Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.


Assuntos
Alquilantes/síntese química , Alquilantes/farmacologia , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacologia , Clivagem do DNA/efeitos dos fármacos , Compostos de Mostarda Nitrogenada/síntese química , Compostos de Mostarda Nitrogenada/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Alquilação , Ciclização , Conformação Molecular , Piperazinas/síntese química , Piperazinas/farmacologia , Plasmídeos/efeitos dos fármacos
20.
Cent Nerv Syst Agents Med Chem ; 13(2): 114-21, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23745622

RESUMO

Tumors of the central nervous system are the third most common type of childhood cancers. Brain tumors occur in children and adults; however pediatric patients require a different treatment process. Thirteen drugs similar to mechlorethamine are analyzed in this study. These drugs possess molecular properties enabling substantial and successful access to tumors of the central nervous system. All drugs exhibit zero violations of the Rule of 5, which indicate favorable bioavailability. Ranges in Log P, formula weight, and polar surface area for these drugs are: 1.554 to 3.52, 156.06 to 460.45, and 3.238 Angstroms(2) to 45.471 Angstroms(2), respectively. Hierarchical cluster analysis determined that agents 7 and 12 are most similar to the parent compound mechlorethamine. The mean values of Log P, formula weight, polar surface area, and molecular volume are 2.25, 268.51, 16.57 Angstroms(2), and 227.01 Angstroms(3), respectively. Principal component analysis indicates that agents 7 and 12 are most similar to mechlorethamine and multiple regression analysis of molecular properties produced a model to enable the design of similar alkylating agents. Values of Log (Cbrain/Cblood) indicate these agents will have very high permeation into the central nervous system.


Assuntos
Antineoplásicos Alquilantes/química , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Mecloretamina/química , Algoritmos , Antineoplásicos Alquilantes/síntese química , Neoplasias do Sistema Nervoso Central/epidemiologia , Análise por Conglomerados , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Análise de Componente Principal , Relação Estrutura-Atividade
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