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1.
Molecules ; 26(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494466

RESUMO

Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, N-[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos , DNA de Neoplasias/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Topoisomerase II , Adenocarcinoma de Pulmão/história , Adenocarcinoma de Pulmão/metabolismo , Amsacrina/química , Amsacrina/história , Amsacrina/farmacocinética , Amsacrina/uso terapêutico , Anáfase/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/história , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Cromátides/metabolismo , Segregação de Cromossomos/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , História do Século XX , História do Século XXI , Humanos , Neoplasias Pulmonares/história , Neoplasias Pulmonares/metabolismo , Camundongos , Naftiridinas/química , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacocinética , Inibidores da Topoisomerase II/uso terapêutico
2.
J Biomol Struct Dyn ; 39(15): 5551-5562, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32720578

RESUMO

Coronavirus disease (COVID-19), a life-threatening disease, is caused by SARS-CoV-2. The targeted therapeutics of small molecules helps the scientific community to fight against SARS-CoV-2. In this article, some oxazine substituted 9-anilinoacridines (A1-A48) was designed by docking, MM-GBSA and molecular dynamics (MD) simulation studies for their COVID-19 inhibitory activity. The docking of ligands A1-A48 against SARS-CoV-2 (PDB ID: 5R82) are performed by using Glide module, in silico ADMET screening by QikProp module, binding energy using Prime MM-GB/SA module, MD simulation by Desmond module and atomic charges were derived by Jaguar module of Schrodinger suit 2019-4. Compound A38 has the highest G-score (-7.83) when compared to all the standard compounds which are proposed for COVID-19 treatment such as ritonavir (-7.48), lopinavir (-6.94), nelfinavir (-5.93), hydroxychloroquine (-5.47) and mataquine (-5.37). Compounds A13, A23, A18, A7, A48, A46, A32, A20, A1 and A47 are significantly active against SARS-CoV-2 main protease when compared with hydroxychloroquine and mataquine. The residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN119, ASN142, HIE164, MET165, ASP187, ARG188 and GLN189 of SARS-CoV-2 main protease play a crucial role in binding with ligands. The in silico ADMET properties of the molecules are within the recommended values. The binding free energy was calculated using PRIME MM-GB/SA studies. From the ligands A38, A13, A23, A18, A7, A48 and A46 with significant Glide scores may produce significant COVID-19 activity for further development. Compound A38 was subjected to MD simulation at 100 ns to study the dynamic behaviour of protein-ligand complex.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Simulação de Dinâmica Molecular , Amsacrina/análogos & derivados , COVID-19/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Oxazinas , Inibidores de Proteases , SARS-CoV-2
3.
Chem Biol Drug Des ; 97(2): 237-252, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32772433

RESUMO

The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SN Ar) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/síntese química , Triazenos/química , Amsacrina/química , Amsacrina/metabolismo , Amsacrina/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , DNA/metabolismo , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/metabolismo , Substâncias Intercalantes/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/metabolismo , Triazenos/metabolismo , Triazenos/farmacologia
4.
J Clin Oncol ; 39(7): 768-778, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33373276

RESUMO

PURPOSE: Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS: Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS: There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION: The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.


Assuntos
Amsacrina/administração & dosagem , Bussulfano/administração & dosagem , Citarabina/administração & dosagem , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Amsacrina/efeitos adversos , Bussulfano/efeitos adversos , Citarabina/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Intervalo Livre de Progressão , Recidiva , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Reino Unido , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto Jovem
5.
Resuscitation ; 160: 142-149, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33181229

RESUMO

AIM: Ventricular fibrillation amplitude spectral area (AMSA) and end-tidal carbon dioxide (ETCO2) are predictors of shock success, understood as restoration of an organized rhythm, and return of spontaneous circulation (ROSC). However, little is known about their combined use. We aimed to assess the prediction accuracy when combined, and to clarify if they are correlated in out of hospital cardiac arrest' victims. MATERIALS AND METHODS: Records acquired by external defibrillators in out-of-hospital cardiac arrest patients of the Lombardia Cardiac Arrest registry were processed. The 1-min pre-shock ETCO2 median value (METCO2) was computed from the capnogram and AMSA (2-48 mV.Hz range) computed applying the Fast Fourier Transform to a 2-second pre-shock filtered ECG interval (0.5-30 Hz). Support Vector Machine (SVM) predictive models based on METCO2, AMSA and their combination were fit; results were given as the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. RESULTS: We considered 112 patients with 391 shocks delivered. METCO2 and AMSA were predictors of shock success [AUC (IQR) of the ROC curve: 0.59 (0.56-0.62); 0.68 (0.65-0.72), respectively] and of ROSC [0.56 (0.53-0.59); 0.74 (0.71-0.78),]. Their combination in a SVM model increased the accuracy for predicting shock success [AUC (IQR) of the ROC curve: 0.71 (0.68-0.75)] and ROSC [0.77 (0.73-0.8)]. AMSA and METCO2 were significantly correlated only in patients who achieved ROSC (rho = 0.33 p = 0.03). CONCLUSIONS: AMSA and ETCO2 predict shock success and ROSC after every shock, and their predictive power increases if combined. Notably, they were correlated only in patients who achieved ROSC.


Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca Extra-Hospitalar , Amsacrina , Dióxido de Carbono , Cardioversão Elétrica , Humanos , Parada Cardíaca Extra-Hospitalar/terapia , Fibrilação Ventricular/terapia
6.
Eur Ann Otorhinolaryngol Head Neck Dis ; 138(2): 73-76, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32674996

RESUMO

AIMS: The purpose of repeated application of manosonic nebulizers (AMSA®) is to ensure active Eustachian tube rehabilitation and optimal middle-ear drug diffusion. In response to recent changes in marketing authorizations issued by the French National Drug Safety Agency (ANSM), the present study investigated how AMSA® is used in the Auvergne-Rhône-Alpes Region of France. MATERIAL AND METHODS: A prospective non-interventional regional 1-year survey was conducted in 701 general practitioners and community and hospital ENT physicians in the Auvergne-Rhône-Alpes Region, using a questionnaire sent by mail with a reminder at 2 months. Percentage responses were compared on Chi2 test with alpha risk of 5%. Non-respondents were excluded. ENDPOINTS: The main endpoints were rate of AMSA® prescription, and prescription modalities in a specific geographical territory (Auvergne-Rhône-Alpes Region) in 2018. RESULTS: 93% of the 114 respondents prescribed AMSA®, with 4,000 prescriptions in 1 year. 66.7% prescribed this treatment to avoid recourse to myringotomy. Mean treatment duration was 2 weeks (50.9% of respondents). The most frequent nebulized substance was saline serum (68.4% of respondents), sometimes associated to corticosteroids or mucolytics. CONCLUSION: The majority of physicians in the Auvergne-Rhône-Alpes Region, and notably the ENT physicians, were AMSA® prescribers for the treatment of Eustachian tube dysfunction and its consequences. However, the duration and modalities of use of AMSA® were very heterogeneous, and further studies are needed to standardize prescription.


Assuntos
Amsacrina , Tuba Auditiva , França , Humanos , Nebulizadores e Vaporizadores , Estudos Prospectivos
7.
Int J Biol Macromol ; 165(Pt A): 1410-1421, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33045299

RESUMO

Electrospinning technology was applied for the preparation of polyacrylonitrile (PAN) nanofiber membrane in this work. After hot pressing, alkaline hydrolysis and neutralization treatment, a weak acid cation exchange membrane (P-COOH) was prepared. By the covalent coupling reaction between the acidic membrane and aminomethane sulfonic acid (AMSA), a strong acidic nanofiber membrane (P-SO3H) was obtained. The surface morphology, chemical structure, and thermal stability of the prepared ion exchange membranes were analyzed via SEM, FTIR and TGA. Analytical results showed that the membranes were prepared successfully and thermally stable. The ion exchange membrane (IEX) was conducted with the newly designed membrane reactor, and different operating conditions affecting the adsorption efficiency of Toluidine Blue dye (TBO) were investigated by dynamic flow process. The results showed that dynamic binding capacity (DBC) of weak and strong IEX membranes for TBO dye was ~170 mg/g in a dynamic flow process. Simultaneously, the ion exchange membranes were also used for purifying lysozyme from chicken egg white (CEW). Results illustrated that the recovery yield and purification factor of lysozyme were 93.43% and 29.23 times (P-COOH); 90.72% and 36.22 times (P-SO3H), respectively. It was revealed that two type ion exchange membranes were very suitable as an adsorber for use in dye waste treatment and lysozyme purification process. P-SO3H strong ion-exchange membrane was more effective either removal of TBO dye or purification of lysozyme. The ion exchange membranes not only effectively purified lysozyme from CEW solution, but also effectively removed dye from wastewater.


Assuntos
Amsacrina/química , Corantes/química , Muramidase/química , Nanofibras/química , Resinas Acrílicas/química , Adsorção/efeitos dos fármacos , Cátions/química , Corantes/isolamento & purificação , Troca Iônica , Membranas Artificiais , Muramidase/isolamento & purificação
8.
Anal Chim Acta ; 1133: 48-57, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-32993873

RESUMO

The present research reported a new electrochemical biosensor based on ds-DNA/Eu3+ doped NiO/CPE to detect amsacrine. Therefore, UV-Vis spectrophotometry, docking, and differential pulse voltammetry (DPV) have been used to study the interactions between amsacrine and dsDNA. Then, experimental parameters affected DNA immobilization and interactions between amsacrine and ds-DNA have been optimized. Afterwards, guanine oxidation peak current of ds-DNA has been chosen as a signal to analyze amsacrine in a concentration ranging between 0.1 and 100.0 µM and finally, limit of detection (LOD) of 0.05 µM has been calculated at optimal condition. Ultimately, it was found that the suggested biosensor is able to determine amsacrine in human serum and urine samples successfully.


Assuntos
Amsacrina , Antineoplásicos , Técnicas Biossensoriais , DNA , Técnicas Eletroquímicas , Eletrodos , Humanos
9.
Ann Hematol ; 99(9): 1979-1988, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32594216

RESUMO

The FLAMSA reduced intensity (RIC) concept, also known as "sequential therapy", is a conceptual platform for the treatment of leukemia separated in several parts: induction therapy, a sequence of antileukemic and immunosuppressive conditioning for allogeneic stem cell transplantation, and immune restitution supported by donor lymphocyte transfusions. The antileukemic part consists of fludarabine, cytosine arabinoside, and amsacrine (FLAMSA); non-cross reactive agents like fludarabine and amsacrine have been successfully used in cases of refractoriness and relapse. Immunosuppressive conditioning and transplantation follow after only 3 days of rest. This way, the toxicity of allogeneic transplantation could be reduced and the anti-leukemia effects by using allogeneic immune cells could be optimized. This review summarizes available data on efficacy and toxicity of this approach. Further, possible strategies for improvements are discussed in order to provide better chances for elderly and frail patients and patients with advanced and high-risk disease. Among others, several new agents are available that target molecular changes of leukemia for induction of remission and allow for bridging the time after transplantation until adoptive immunotherapy becomes safe and effective.


Assuntos
Amsacrina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Citarabina/administração & dosagem , Leucemia/terapia , Condicionamento Pré-Transplante/tendências , Vidarabina/análogos & derivados , Antineoplásicos/administração & dosagem , Previsões , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Imunossupressores/administração & dosagem , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Leucemia/imunologia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Transplante Homólogo/tendências , Vidarabina/administração & dosagem
10.
Sci Rep ; 9(1): 19288, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848363

RESUMO

Treatments for refractory glaucoma include trabeculectomy, in which a filtering bleb is created to reduce aqueous pressure. Mitomycin C (MMC) is often used as an adjuvant to reduce post-trabeculectomy bleb scarring and consequent failure. However, scarring sometimes still occurs. Thus, we searched for more effective trabeculectomy adjuvants with high-throughput screening (HTS) of a library of 1,165 off-patent drug compounds. This revealed that amsacrine (AMSA), a DNA topoisomerase II (TOP2) inhibitor, was the top candidate. Compared to MMC, rabbits that underwent trabeculectomy with 10% AMSA had lower IOP at 42, 56, and 70 days (P < 0.01 at all measurement points) and a higher bleb score at 28, 42, 56, and 70 days (P = < 0.01, 0.04, 0.04, and < 0.01, respectively). Compared to saline, rabbits that received 1% AMSA also had lower IOP and better bleb score at all time points, without a sharp drop in IOP just after surgery (all P < 0.01). Both effects were milder than MMC at 7 days (P = 0.02 and <0.01, respectively). Thus, this study showed that HTS may help identify new, promising uses for off-patent drugs. Furthermore, trabeculectomy with AMSA at a suitable concentration may improve the prognosis after trabeculectomy compared to MMC.


Assuntos
Amsacrina/farmacologia , Implantes para Drenagem de Glaucoma/efeitos adversos , Glaucoma/cirurgia , Trabeculectomia/efeitos adversos , Animais , Vesícula/tratamento farmacológico , Vesícula/patologia , Vesícula/cirurgia , Callithrix , Cicatriz/prevenção & controle , Túnica Conjuntiva/efeitos dos fármacos , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA Topoisomerases Tipo II/genética , Modelos Animais de Doenças , Cirurgia Filtrante , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Cultura Primária de Células , Inibidores da Topoisomerase II/farmacologia
11.
Curr Drug Res Rev ; 11(2): 118-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513003

RESUMO

BACKGROUND: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. OBJECTIVE: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. METHODS: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. RESULTS: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. CONCLUSION: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isoxazóis/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Amsacrina/química , Amsacrina/farmacocinética , Amsacrina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Simulação por Computador , Desenho de Fármacos , Etacridina/farmacologia , Feminino , Humanos , Ligação de Hidrogênio , Isoxazóis/química , Isoxazóis/farmacocinética , Modelos Moleculares , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tamoxifeno/farmacologia
12.
Anticancer Agents Med Chem ; 19(11): 1350-1358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961512

RESUMO

BACKGROUND: 9-anilinoacridines are acting as DNA-intercalating agents which plays an important role as antitumor drugs, due to their anti-proliferative properties. Some anticancer agents contain 9- anilinoacridines such as amsacrine (m-AMSA), and nitracrine (Ledakrine) have been already developed. METHODS: In this study, novel 9-anilinoacridines substituted with thiazines 4a-r were designed, synthesized, characterized by physical and spectral data and their cytotoxic activities against DLA cell lines were evaluated. RESULTS: Among those compounds, 4b, c, e, g, i, j, k, m, o, p, q, r exhibited significant short term in vitro cytotoxic activity against Daltons lymphoma ascites (DLA) cells with CTC50 value of 0.18 to 0.31µM. The compounds 4b, c, e, g, i, j, k, m, o, p, q, r are also exhibited significant long term in vitro anti-tumour activity against human tumor cell lines, HEp-2 (laryngeal epithelial carcinoma) by Sulforhodamine B assay with CTC50 value of 0.20 to 0.39µM. The compounds 4b, i, j exhibited significant in vivo antitumor activity with % Increase in Life Span (ILS) 48-82%. CONCLUSION: Results obtained in this study clearly demonstrated that many of the thiazine substituted 9- anilinoacridines exert interesting anti-tumour activity. The compounds 4b, i, j have significant anti-tumour activity and useful drugs after further refinement. The above derivatives will encourage to design future antitumor agents with high therapeutic potentials.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiazinas/farmacologia , Amsacrina/síntese química , Amsacrina/química , Amsacrina/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Tiazinas/química , Células Tumorais Cultivadas
13.
Drug Deliv ; 25(1): 611-622, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29493300

RESUMO

To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as 'micelle pool' drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML-shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre-loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Micelas , Tensoativos/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Amsacrina/administração & dosagem , Amsacrina/análogos & derivados , Amsacrina/farmacocinética , Animais , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Tensoativos/farmacocinética , Resultado do Tratamento , Carga Tumoral/fisiologia
14.
Pharm Res ; 35(1): 13, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29302821

RESUMO

PURPOSE: To enhance therapeutic efficacy and prevent phlebitis caused by Asulacrine (ASL) precipitation post intravenous injection, ASL-loaded hybrid micelles with size below 40 nm were developed to improve drug retention and tumor penetration. METHODS: ASL-micelles were prepared using different weight ratios of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethyleneglycol-2000 (DSPE-PEG2000) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymers. Stability of micelles was optimized in terms of critical micelle concentration (CMC) and drug release properties. The encapsulation efficiency (EE) and drug loading were determined using an established dialysis-mathematic fitting method. Multicellular spheroids (MCTS) penetration and cytotoxicity were investigated on MCF-7 cell line. Pharmacokinetics of ASL-micelles was evaluated in rats with ASL-solution as control. RESULTS: The ASL-micelles prepared with DSPE-PEG2000 and TPGS (1:1, w/w) exhibited small size (~18.5 nm), higher EE (~94.12%), better sustained in vitro drug release with lower CMC which may be ascribed to the interaction between drug and carriers. Compared to free ASL, ASL-micelles showed better MCTS penetration capacity and more potent cytotoxicity. Pharmacokinetic studies demonstrated that the half-life and AUC values of ASL-micelles were approximately 1.37-fold and 3.49-fold greater than that of free ASL. CONCLUSIONS: The optimized DSPE-PEG2000/TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/farmacocinética , Micelas , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Amsacrina/química , Amsacrina/farmacocinética , Amsacrina/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Técnicas de Cultura de Células , Sobrevivência Celular , Preparações de Ação Retardada , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Células MCF-7 , Masculino , Nanopartículas/química , Tamanho da Partícula , Permeabilidade , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Vitamina E/química
15.
J Mol Graph Model ; 72: 209-219, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28110185

RESUMO

Amsacrine is an effective topoisomerase II enzyme inhibitor in acute lymphatic leukemia. Previous experimental studies have successfully identified two important mutations (R487K and E571K) conferring 100 and 25 fold resistance to Amsacrine respectively. Although the reduction of the cleavage ligand-DNA-protein ternary complex has been well thought as the major cause of drug resistance, the detailed energetic, structural and dynamic mechanisms remain to be elusive. In this study, we constructed human topoisomerase II alpha (hTop2α) homology model docked with Amsacrine based on crystal structure of human Top2ß in complex with etoposide. This wild type complex was used to build the ternary complex with R487K and E571K mutants. Three 500ns molecular dynamics simulations were performed on complex systems of wild type and two mutants. The detailed energetic, structural and dynamic analysis were performed on the simulation data. Our binding data indicated a significant impairment of Amsacrine binding energy in the two mutants compared with the wild type. The order of weakening (R487K>E571K) was in agreement with the order of experimental drug resistance fold (R489K>E571K). Our binding energy decomposition further indicated that weakening of the ligand-protein interaction rather than the ligand-DNA interaction was the major contributor of the binding energy difference between R487K and E571K. In addition, key residues contributing to the binding energy (ΔG) or the decrease of the binding energy (ΔΔG) were identified through the energy decomposition analysis. The change in ligand binding pose, dynamics of protein, DNA and ligand upon the mutations were thoroughly analyzed and discussed. Deciphering the molecular basis of drug resistance is crucial to overcome drug resistance using rational drug design.


Assuntos
Amsacrina/química , DNA Topoisomerases Tipo II/genética , Resistencia a Medicamentos Antineoplásicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação/genética , Solventes/química , Homologia Estrutural de Proteína , Amsacrina/farmacologia , DNA/química , Humanos , Proteínas Mutantes/química , Conformação Proteica , Termodinâmica
16.
Bioorg Med Chem Lett ; 27(3): 586-589, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27998679

RESUMO

A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIα. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ∼5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIα in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIα, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons.


Assuntos
Acridinas/química , Acridinas/farmacologia , Antígenos de Neoplasias/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Amsacrina/química , Antineoplásicos/química , Antineoplásicos/farmacologia , DNA/metabolismo , Clivagem do DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Substâncias Intercalantes/química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
17.
J Biomol Struct Dyn ; 35(6): 1260-1271, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27064820

RESUMO

The binding of the anilido aminoacridine derivative amsacrine with the heme proteins, hemoglobin, and myoglobin, was characterized by various spectroscopic and calorimetric methods. The binding affinity to hemoglobin was (1.21 ± .05) × 105 M-1, while that to myoglobin was three times higher (3.59 ± .15) × 105 M-1. The temperature-dependent fluorescence study confirmed the formation of ground-state complexes with both the proteins. The stronger binding to myoglobin was confirmed from both spectroscopic and calorimetric studies. The binding was exothermic in both cases at the three temperatures studied, and was favored by both enthalpy and entropy changes. Circular dichroism results, three-dimensional (3D) and synchronous fluorescence studies confirmed that the binding of amsacrine significantly changed the secondary structure of hemoglobin, while the change in the secondary structure of myoglobin was much less. New insights, in terms of structural and energetic aspects of the interaction of amsacrine with the heme proteins, presented here may help in understanding the structure-activity relationship, therapeutic efficacy, and drug design aspects of acridines.


Assuntos
Amsacrina/química , Calorimetria , Hemoglobinas/química , Mioglobina/química , Análise Espectral , Amsacrina/metabolismo , Calorimetria/métodos , Hemoglobinas/metabolismo , Humanos , Ligantes , Estrutura Molecular , Mioglobina/metabolismo , Ligação Proteica , Análise Espectral/métodos , Termodinâmica
18.
Curr Cancer Drug Targets ; 17(7): 657-668, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27834128

RESUMO

BACKGROUND: DNA topoisomerase II-α (Top2-α), an essential enzyme for the management of DNA during replication, transcription, recombination, and chromatin remodeling, is one of the most important anticancer targets. Numerous molecules have been designed as Top2-α inhibitors. However, several studies have shown that polymorphisms and mutations in Top2 have conferred resistance to most of these anticancer drugs. The aim of this study was to computationally examine the mechanisms by which genomic variations in Top2-α could affect its resistance to Amsacrine and Mitoxantrone as important inhibitors of the enzyme. RESULTS: The results showed that variants K529E, R568H, R568G and T530M could affect Top2-α inhibition by Amsacrine causing possible drug-resistant. Moreover, R487K, and Y481C variants could change the response of the enzyme to Mitoxantrone. CONCLUSION: These results could facilitate the prediction and development of more effective drugs for Top2-α variants, making the cancer chemotherapy more effectiv.


Assuntos
Amsacrina/química , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/genética , Mitoxantrona/química , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/genética , Polimorfismo de Nucleotídeo Único , Amsacrina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação por Computador , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Mitoxantrona/farmacologia , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
19.
Biol Blood Marrow Transplant ; 23(2): 278-284, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27816650

RESUMO

Post-transplant relapse is the leading cause of treatment failure in acute myeloid leukemia (AML) patients after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT). To improve their outcome, we evaluated the outcome of a sequential intermediate-intensity conditioning regimen combining fludarabine, cytosine arabinoside, amsacrine, cyclophosphamide, and either total body irradiation or busulfan (FLAMSA) in patients with intermediate or high-risk AML in first or second complete remission (CR). A total of 265 patients (median age, 55 years; range, 19 to 76) with AML who underwent allo-HSCT using a FLAMSA regimen were included. At the time of transplant, 216 (81.5%) were in CR1 and 49 (18.5%) in CR2. Cytogenetic was intermediate in 114 (43%) and poor in 42 (15.8%) patients, whereas 109 patients (41.1%) had a secondary AML. With a median follow-up of 46 months (range, 1 to 145), the Kaplan-Meier estimate of overall and leukemia-free survival at 2 years were 56.1% (95% CI, 49.7% to 62.6%) and 52.8% (95% CI, 46.4% to 59.2%), respectively. At 2 years, the cumulative incidences of relapse and nonrelapse mortality were 22.8% (95% CI, 17.6% to 28.4%) and 24.0% (95% CI, 18.8% to 29.5%), respectively. In multivariate analysis, patient age and cytogenetics were the only parameters with a significant impact on overall survival. These data suggest that the FLAMSA sequential intermediate conditioning regimen provides an efficient disease control in intermediate- and high-risk AML patients, including those in CR2 and with secondary AML.


Assuntos
Transplante de Medula Óssea , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Aloenxertos , Amsacrina/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Histocompatibilidade , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Modelos de Riscos Proporcionais , Indução de Remissão , Estudos Retrospectivos , Risco , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal Total , Adulto Jovem
20.
Apoptosis ; 22(3): 406-420, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27757735

RESUMO

Previous studies have attributed the anticancer activity of amsacrine to its inhibitory effect on topoisomerase II. However, 9-aminoacridine derivatives, which have the same structural scaffold as amsacrine, induce cancer cell apoptosis by altering the expression of BCL2 family proteins. Therefore, in the present study, we assessed whether BCL2 family proteins mediated the cytotoxic effects of amsacrine on human leukemia U937 cells. Amsacrine-induced apoptosis of U937 cells was characterized by caspase-9 and caspase-3 activation, increased intracellular Ca2+ concentration, mitochondrial depolarization, and MCL1 down-regulation. Amsacrine induced MCL1 down-regulation by decreasing its stability. Further, amsacrine-treated U937 cells showed AKT degradation and Ca2+-mediated ERK inactivation. Blockade of ERK-mediated phosphorylation of MCL1 inhibited the effect of Pin1 on the stabilization of MCL1, and AKT degradation promoted GSK3ß-mediated degradation of MCL1. Restoration of ERK phosphorylation and AKT expression abrogated amsacrine-induced MCL1 down-regulation. Moreover, MCL1 over-expression inhibited amsacrine-induced depolarization of mitochondria membrane and increased the viability of amsacrine-treated cells. Taken together, our data indicate that amsacrine abolishes ERK- and Pin1-mediated stabilization of MCL1 and promotes GSK3ß-mediated degradation of MCL1, leading to activate mitochondria-mediated apoptosis pathway in U937 cells.


Assuntos
Amsacrina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Cálcio/metabolismo , Etoposídeo/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/metabolismo , Células U937
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