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1.
Parasitol Int ; 91: 102647, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35985636

RESUMO

A series of 1-aryl-4-(phthalimidoalkyl) piperazines and 1-aryl-4-(naphthalimidoalkyl) piperazines were retrieved from a proprietary library based on their high structural similarity to haloperidol, an antipsychotic with antiparasitic activity, and assessed as potential antileishmanial scaffolds. Selected compounds were tested for antileishmanial activity against promastigotes of Leishmania major and Leishmania mexicana in dose-response assays. Two of the 1-aryl-4-(naphthalimidoalkyl) piperazines (compounds 10 and 11) were active against promastigotes of both Leishmania species without being toxic to human fibroblasts. Their activity was found to correlate with the length of their alkyl chains. Further analyses showed that compound 11 was also active against intracellular amastigotes of both Leishmania species. In promastigotes of both Leishmania species, compound 11 induced collapse of the mitochondrial electrochemical potential and increased the intracellular Ca2+ concentration. Therefore, it may serve as a promising lead compound for the development of novel antiparasitic drugs.


Assuntos
Antiprotozoários , Leishmania major , Leishmania mexicana , Antiparasitários , Antiprotozoários/química , Antiprotozoários/farmacologia , Humanos , Piperazinas/farmacologia
2.
Eur J Med Chem ; 242: 114641, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36027862

RESUMO

Schistosomiasis is a neglected tropical disease with more than 200 million new infections per year. It is caused by parasites of the genus Schistosoma and can lead to death if left untreated. Currently, only two drugs are available to combat schistosomiasis: praziquantel and, to a limited extent, oxamniquine. However, the intensive use of these two drugs leads to an increased probability of the emergence of resistance. Thus, the search for new active substances and their targeted development are mandatory. In this study the substance class of "dithiocarbamates" and their potential as antischistosomal agents is highlighted. These compounds are derived from the basic structure of the human aldehyde dehydrogenase inhibitor disulfiram (tetraethylthiuram disulfide, DSF) and its metabolites. Our compounds revealed promising activity (in vitro) against adults of Schistosoma mansoni, such as the reduction of egg production, pairing stability, vitality, and motility. Moreover, tegument damage as well as gut dilatations or even the death of the parasite were observed. We performed detailed structure-activity relationship studies on both sides of the dithiocarbamate core leading to a library of approximately 300 derivatives (116 derivatives shown here). Starting with 100 µm we improved antischistosomal activity down to 25 µm by substitution of the single bonded sulfur atom for example with different benzyl moieties and integration of the two residues on the nitrogen atom into a cyclic structure like piperazine. Its derivatization at the 4-nitrogen with a sulfonyl group or an acyl group led to the most active derivatives of this study which were active at 10 µm. In light of this SAR study, we identified 17 derivatives that significantly reduced motility and induced several other phenotypes at 25 µm, and importantly five of them have antischistosomal activity also at 10 µm. These derivatives were found to be non-cytotoxic in two human cell lines at 100 µm. Therefore, dithiocarbamates seem to be interesting new candidates for further antischistosomal drug development.


Assuntos
Esquistossomose , Esquistossomicidas , Adulto , Aldeído Desidrogenase/farmacologia , Animais , Dissulfiram/farmacologia , Humanos , Doenças Negligenciadas , Nitrogênio/farmacologia , Oxamniquine/química , Oxamniquine/farmacologia , Piperazinas/farmacologia , Praziquantel/farmacologia , Schistosoma mansoni , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Enxofre/farmacologia
3.
Bioorg Chem ; 128: 106071, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35932498

RESUMO

The Bcr-Abl tyrosine kinase (TK) is the molecular hallmark of chronic myeloid leukemia (CML). Src is another TK kinase whose involvement in CML was widely demonstrated. Small molecules active as dual Src/Bcr-Abl inhibitors emerged as effective targeted therapies for CML and a few compounds are currently in clinical use. In this study, we applied a target-oriented approach to identify a family of pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl inhibitors as anti-leukemia agents. Considering the high homology between Src and Bcr-Abl, in-house Src inhibitors 8a-l and new analogue compounds 9a-n were screened as dual Src/Bcr-Abl inhibitors. The antiproliferative activity on K562 CML cells and the ADME profile were determined for the most promising compounds. Molecular modeling studies elucidated the binding mode of the inhibitors into the Bcr-Abl (wt) catalytic pocket. Compounds 8j and 8k showed nanomolar activities in enzymatic and cellular assays, together with favorable ADME properties, emerging as promising candidates for CML therapy. Finally, derivatives 9j and 9k, emerging as valuable inhibitors of the most aggressive Bcr-Abl mutation, T315I, constitute a good starting point in the search for compounds able to treat drug-resistant forms of CML. Overall, this study allowed us to identify more potent compounds than those previously reported by the group, marking a step forward in searching for new antileukemic agents.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/química
4.
Bioorg Chem ; 127: 105999, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35809513

RESUMO

New monomethine, unsymmetrical styryl dyes consisting of benzothiazole and N-methylpiperazine or N-phenylpiperazine scaffolds were synthesized, and their binding affinities for different ds-polynucleotides and G-quadruplex were studied. Substitution of piperazine unit with methyl or phenyl group strongly influenced their binding modes, binding affinities, spectroscopic responses and antiproliferative activities. Compounds with N-methylpiperazine substituents showed a significant preference for AT-DNA polynucleotides and demonstrated AT-minor groove binding, which manifested in strong fluorescence increase, significant double helix stabilization, and positive induced circular dichroism spectra. These compounds formed complexes with G-quadruplex by π-π stacking interactions of dye with the top or bottom G-tetrad. Bulkier compounds with N-phenylpiperazine function are probably bound to ds-polynucleotide by partial intercalation between base pairs. On the other hand, they showed stronger stabilization of G-quadruplex compared to methyl-substituted compounds. Fluorimetric titrations pointed to possible mixed stoichiometry's: 1:1 complex with π-π stacking interactions of dye on the top or bottom G-tetrad and 1:2 complex with dye positioned between two G-quadruplex molecules. Bulkier dyes with N-phenylpiperazine fragments demonstrated micromolar and submicromolar antiproliferative activity that was especially pronounced for leukaemia and lymphoma. Flow cytometric assay shows dose- and time-dependent increase in SubG0/G1 phase. Furthermore, the compounds enter the cells readily and accumulate in the mitochondrial space, co-localize with the standard mitochondrial markers.


Assuntos
Corantes , Quadruplex G , DNA/química , Ligantes , Piperazinas/farmacologia , Polinucleotídeos , Medicina de Precisão
5.
Antimicrob Agents Chemother ; 66(8): e0018522, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35862743

RESUMO

Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns. Healthy volunteers from Papua New Guinea received a 3-day course of DHA-PQP (2.1/17.1 mg/kg) monthly for 3 consecutive months in a single arm longitudinal study. Plasma PQP concentrations were measured after the third dose of each course (at 52-54 h) and at 0 h of course 3. Twelve-lead electrocardiographic readings were conducted at 0 h, 48 h, 52 h, and day 7 of each course. QT interval corrected by Fridericia's formula (QTcF) was measured at each time point. A pharmacokinetic-pharmacodynamic model using nonlinear mixed effects models was developed to correlate PQP concentrations with QTcF. Ten thousand female and 10,000 male individuals were simulated at each treatment course. Eighty-two participants were included; mean age was 28.3 years (standard deviation [SD] ±12.3 years), and 36 (44%) were female. Pharmacokinetic-pharmacodynamic models were determined with 290 PQP concentrations and 868 QTcF observations. The average baseline QTcF was 392 ms with a between-subject variability SD ±14.4 ms and between-occasion variability SD ±3.64 ms. From the population modeled, only 0.08% of males and 0.45% of females would be at risk of an absolute QTcF of >500 ms. DHA-PQP is safe at standard doses in consecutive months, and the likelihood of severe cardiac events occurring during an MDA campaign is very low. This study has been registered at ClinicalTrials.gov under identifier NCT02605720.


Assuntos
Antimaláricos , Malária Falciparum , Piperazinas , Quinolinas , Adulto , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Artemisininas/efeitos adversos , Artemisininas/farmacocinética , Artemisininas/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Síndrome do QT Longo/induzido quimicamente , Estudos Longitudinais , Malária Falciparum/tratamento farmacológico , Masculino , Papua Nova Guiné , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Quinolinas/farmacologia
6.
Int J Oncol ; 61(1)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35642662

RESUMO

Poly (ADP­ribose) polymerase (PARP)­inhibitors (PARPi) such as olaparib and niraparib are currently used as a treatment option for BRCA­deficient tumors and also show efficacy in platinum­sensitive tumors. However, resistance to PARPi occurs in numerous patients and in particular acquired PARPi resistance presents a major obstacle in the treatment of these tumors. In the present study, it was investigated whether stepwise exposure of ovarian cancer cells to escalating concentrations of olaparib produced subcells with acquired resistance to PARPi and/or acquired cross­resistance to platinum compounds, paclitaxel, and doxorubicin. To this aim, the sensitivity of fourteen ovarian cancer cell lines, including nine with TP53­mutations and five carrying BRCA­mutations, to olaparib and niraparib was determined and a subset of seven cell lines was selected to investigate the potential of olaparib to produce resistance. It was identified that escalating olaparib did neither produce subcells with acquired PARPi­resistance nor did it produce acquired cross­resistance to platinum compounds, doxorubicin, and paclitaxel. This finding was independent of the cells' TP53 and BRCA mutation status. CRISPR­Cas9 mediated deletion of PARP1 did not affect sensitivity to PARPi, platinum compounds, doxorubicin, and paclitaxel. In addition, olaparib sensitivity correlated with niraparib sensitivity, but BRCA­mutated cells were not more sensitive to PARPi. Moreover, PARPi sensitivity associated with cross­sensitivity not only to platinum compounds but also to anthracylines, paclitaxel, and inhibitors of histone deacetylases. These in vitro data indicated that olaparib exposure is unlikely to produce an acquired resistance phenotype and that PARPi­sensitive ovarian cancer cells are also cross­sensitive to non­platinum and even to compounds not directly interacting with the DNA.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Compostos de Platina/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
7.
J Mol Neurosci ; 72(9): 1797-1808, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35727524

RESUMO

Propofol is a short-acting intravenous anesthetic that is widely used in clinical treatment. Previous articles have indicated that propofol is a therapeutic target for anti-apoptosis, anti-inflammation, anti-lipid peroxidation, and anti-reactive oxygen species (ROS). Moreover, cell ferroptosis is strongly correlated with cellular ROS, inflammatory responses, and lipid peroxidation. However, the mechanisms by which propofol attenuates neuronal injury by reducing ferroptosis remain unknown. Hence, we hypothesized that propofol could protect neurons by reducing ferroptosis. To test this hypothesis, HT-22 cells were treated with a specific ferroptosis activator (erastin) in the presence of propofol (50 µM). We found that propofol reduced erastin-induced high Fe2+ concentrations, lipid peroxides, and excess ROS. Western blotting results also suggested that propofol could rescue erastin-induced low expression of GXP4 and system Xc-. Further experiments indicated that propofol attenuated p-ALOX5 expression at Ser663 independent of ERK. In addition, we built two transient transfection cell lines, ALOX5 OE and Ser663Ala-ALOX5 OE, to confirm the target of propofol. We found that the Ser663 point is the critical role of propofol in rescuing erastin-induced cell injury/lipid peroxidation. In conclusion, propofol may help attenuate ferroptosis, which may provide a new therapeutic method to treat neuronal injury or the brain inflammatory response.


Assuntos
Ferroptose , Propofol , Piperazinas/farmacologia , Propofol/farmacologia , Espécies Reativas de Oxigênio/metabolismo
8.
Eur J Med Chem ; 238: 114442, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35551036

RESUMO

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia
9.
Anticancer Res ; 42(6): 2875-2882, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35641284

RESUMO

BACKGROUND/AIM: Murine double minute 2 (MDM2) is well known to inhibit p53 function and its over-expression is associated with poor prognosis in several human malignancies. Nutlin-3, a small-molecule inhibitor of MDM2, exerts antitumor effects on various solid tumors harboring wild-type p53. We aimed to clarify its effects on esophageal cancer. MATERIALS AND METHODS: We first examined the potential antitumor effects of nutlin-3 according to MDM2 status using esophageal carcinoma cell lines (KYSE 170/180). We then immunolocalized MDM2 immunoreactivity in 62 surgical cases of esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy and correlated the findings with clinicopathological variables. RESULTS: MDM2 mRNA expression in KYSE 170 was significantly higher than that in KYSE 180 cells. No significant changes were detected in both cell lines when nutlin-3 was added. However, cell proliferation was significantly decreased in KYSE 170 cells treated with nutlin-3 and cisplatin compared to cisplatin alone but not in KYSE 180. MDM2 immunoreactivity was also significantly associated with poor sensitivity to neoadjuvant chemotherapy in the cases examined. CONCLUSION: The combination of nutlin-3 with chemotherapeutic agents may become a novel therapeutic strategy in esophageal cancer over-expressing MDM2.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Imidazóis , Piperazinas , Cisplatino/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Humanos , Imidazóis/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
J Biochem Mol Toxicol ; 36(8): e23100, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35608386

RESUMO

Hepatocellular carcinoma (HCC) has emerged as one of the most common and lethal cancers worldwide and is caused due to contamination of diets with aflatoxin B1 and chronic viral hepatitis. Recent reports suggest that phosphodiesterase-5 inhibitor (PDE5i) exhibits anticancer properties against several forms of cancer but till now has not been evaluated against HCC. We aimed to evaluate the anticancer property of phosphodiesterase-5 inhibitors (PDE5i) tadalafil and sildenafil against aflatoxin B1 HCC. Rats of HCC group were fed with 5% alcohol via drinking water for 3 weeks, followed by administration of AFB1 (1 mg/kg/bw, i.p.) at an interval of two subsequent days. PDE5i (tadalafil and sildenafil, 10 mg/kg bw) was administered along with drinking water after 6 weeks of treatment with AFB1 for 2 weeks. In the present investigation, in HCC elevation in the level of SGOT, SGPT, ALP, and urea vis-à-vis activity of key glycolytic enzyme LDH and mRNA expression of c-myc, Akt, LDH-A, and PFKFB3 was noted. Similarly, the level of multidrug resistance protein (MDR) and breast cancer resistance protein (BCRP/ABCG2) was elevated along with increased expression of angiogenesis marker (HIF-1α, VEGF, and TGF-ß1) in HCC. Post-treatment with PDE5 inhibitor (tadalafil and sildenafil) downregulated and brought back the above parameters towards normal and out of two PDE5i (tadalafil and sildenafil), sildenafil effect was more potent as compared to tadalafil. Our findings demonstrate for the first time that PDE5 inhibitors tadalafil and sildenafil are able to prohibit the development and progression of aflatoxin B1 induced HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Citrato de Sildenafila , Tadalafila , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Aflatoxina B1 , Animais , Antineoplásicos/farmacologia , Carbolinas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Reposicionamento de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glucose , Imidazóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Neoplasias , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Purinas/farmacologia , Ratos , Citrato de Sildenafila/farmacologia , Sulfonas/farmacologia , Tadalafila/farmacologia , Triazinas/uso terapêutico , Dicloridrato de Vardenafila
11.
Comput Math Methods Med ; 2022: 2402567, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35535229

RESUMO

Objective: To study the expression and prognostic value of CDK6 in stomach cancer and the function of CDK4/6 inhibitor PD-0332991 on the proliferation of stomach cancer cells. Methods: Immunohistochemistry was used to detect the expression of CDK6 in stomach cancer tissues and adjacent normal tissues and to analyze the effect of CDK6 on clinicopathological parameters of stomach cancer patients. Kaplan-Meier plotter was employed to study the relationship between CDK6 and overall survival in stomach cancer. Western blot and RT-PCR were used to detect protein and gene expression of CDK6 in different cells. The effects of CDK4/6 inhibitor PD-0332991 on apoptosis and aging of stomach cancer cells were detected by flow cytometry and ß-galactosidase aging staining assay. The effects of CDK4/6 inhibitor PD-0332991 on the invasion and migration of stomach cancer cells were explored by the wound healing experiment and the Transwell experiment. The supernatant of stomach cancer cells was collected, and the effect of CDK4/6 inhibitor PD-0332991 on tumor markers of stomach cancer cells was detected by biochemical immunoassay. Results: (1) CDK6 was highly expressed in stomach cancer tissues and cells. (2) Abnormally elevated CDK6 expression results in shorter survival in stomach cancer patients. (3) CDK4/6 inhibitor PD-0332991 could block the proliferation of stomach cancer cells, but not stomach epithelial proliferation. PD-0332991 could inhibit the secretion of pro-GRP by MGC 823. (4) PD-0332991 could advance the development of the apoptosis and senescence of stomach cancer cells and suppressed the invasion and migration of stomach cancer cells. Conclusion: CDK6 expression is elevated in gastric cancer, and the CDK4/6 inhibitor PD-0332991 can remarkably promote apoptosis and senescence of stomach cancer cells and effectively inhibit the migration and invasion of stomach cancer cells.


Assuntos
Quinase 6 Dependente de Ciclina , Neoplasias Gástricas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Piperazinas/farmacologia , Piridinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
12.
Eur J Med Chem ; 238: 114421, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35594652

RESUMO

Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacements of the metabolically labile piperazine ring and use of plate-based arrays for quick diversity scoping. We discuss the success of these strategies within the context of this series and highlight the challenges faced in phenotypic programs when attempting to improve the pharmacokinetic profile of compounds whilst maintaining potency against the desired target.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Piperazinas/farmacologia
13.
Eur J Med Chem ; 235: 114319, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35367707

RESUMO

The 5-HT1A receptors are an important biological target in the treatment of CNS diseases. Recently, their importance in the context of non-CNS disease entities has also been postulated. In the light of these reports, we designed a new group of urea derivatives of N-aryl-N'-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines as 5-HT1AR ligands, focusing on increasing receptor selectivity. We made structural modifications in three areas of the molecule. In the course of our research, we obtained a ligand with reduced basicity (6f), which, despite the loss of the protonable nitrogen atom, did not lose its affinity for the 5-HT1AR (Ki = 35 nM) with a simultaneous increase in selectivity. In particular, a decrease in affinity for D2R (Ki = 1940 nM) was observed, which was analyzed using molecular modeling methods, including FMO and molecular dynamics. Basic ADME-Tox parameters were characterized for 6f, confirming its potential applicability in pharmacotherapy.


Assuntos
Piperazinas , Receptores de Serotonina , Ligantes , Piperazinas/química , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina , Serotonina , Relação Estrutura-Atividade
14.
Biomed Pharmacother ; 150: 113007, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35483190

RESUMO

The heterogeneity of triple negative breast cancer (TNBC) results in the worst prognosis among breast cancer types, making its treatment strategy very challenging. A recent study showed that oleanolic acid (OA) has a radiosensitizing effect on tumor cells, but it does not show a good clinical effect when used alone in radiotherapy. The cytotoxicity of radiotherapy can be enhanced by modulating DNA repair, so new treatment options are being investigated to inhibit DNA repair pathways and sensitize tumors to radiation. Radiation induces DNA double-strand breaks (DSBs), and inhibition of Poly (ADP-Ribose) polymerase (PARP) can prevent the repair of these lesions. Hence, we evaluated the radiosensitization and the underlying mechanism of combination treatment with OA and olaparib in TNBC. Meanwhile, tumor hypoxia was monitored with 18F-Fluoroerythronitroimidazole (FETNIM) positron emission tomography/computed tomography (PET/CT) during radiosensitization therapy. Here, we found that OA and olaparib in combination with radiotherapy significantly inhibited cell proliferation compared with other groups. The results were observed using colony formation assays [sensitization enhancement ratios (SER) 1.16-1.65]. In vivo, tumor growth was significantly delayed in transplanted tumors receiving irradiation (IR) with OA and olaparib. 18F-FETNIM PET/CT can be utilized for tumor hypoxia monitoring and radiosensitization response evaluation. In conclusion, these results suggest that the combination of OA and olaparib with IR enhances the inhibition of MDA-MB-231 in cell culture and in mice, providing a potentially novel combination for the effective treatment of TNBC patients.


Assuntos
Ácido Oleanólico , Ftalazinas , Piperazinas , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , DNA , Humanos , Hipóxia , Camundongos , Nitroimidazóis , Ácido Oleanólico/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tolerância a Radiação , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia
15.
Sci Rep ; 12(1): 5706, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35383224

RESUMO

Although an increasing number of patients benefit from immunotherapy and targeted therapies, melanoma remains incurable with increasing incidence. Drug repositioning and repurposing is an alternative strategy to discover and develop novel anticancer drugs or combined therapeutic regimens. In this study, we demonstrated that albendazole (ABZ), an Food and Drug Administration (FDA)-approved broad-spectrum antiparasitic agent, significantly inhibits the proliferation of melanoma cells in vitro and in vivo. RNA sequencing and flow cytometry analysis revealed that ABZ arrests melanoma cells at the G2/M phase of the cell cycle and induces cell apoptosis. More importantly, the CDK4/6 inhibitor palbociclib, as a member of the first and only class of highly specific CDK inhibitors approved for cancer treatment to date, showed significant synergistic effects with ABZ treatment in melanoma cells and mouse models. Taken together, we revealed a previously unappreciated function of ABZ in antimelanoma proliferation by inducing cell cycle arrest and apoptosis and provided a novel combined therapeutic regimen of ABZ plus CDK4/6 inhibitor treatment in melanoma.


Assuntos
Albendazol , Melanoma , Piperazinas , Piridinas , Albendazol/farmacologia , Albendazol/uso terapêutico , Animais , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Humanos , Melanoma/genética , Camundongos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico
16.
N Engl J Med ; 386(15): 1432-1442, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35417638

RESUMO

BACKGROUND: Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency. METHODS: In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures. RESULTS: Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo. CONCLUSIONS: In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.).


Assuntos
Piperazinas , Piruvato Quinase , Quinolinas , Adulto , Anemia Hemolítica Congênita não Esferocítica/tratamento farmacológico , Método Duplo-Cego , Hemoglobinas/análise , Hemoglobinas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/tratamento farmacológico , Quinolinas/farmacologia , Quinolinas/uso terapêutico
17.
ChemMedChem ; 17(12): e202200137, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35466565

RESUMO

Soluble epoxide hydrolase (sEH) is implicated as a potential therapeutic target for inflammation-related pathologies in the context of cardiovascular, central nervous system and metabolic diseases. In our search for novel sEH inhibitors, we designed and synthesized novel analogs of the piperazine urea derivative 4, a previously discovered dual microsomal prostaglandin E2 synthase-1 (mPGES-1)/soluble epoxide hydrolase (sEH) inhibitor, to evaluate their potential as sEH inhibitors. We identified two 1,3,4-oxadiazol-5-one and -thione congeners (compounds 19 and 20), which demonstrated selective sEH inhibition with IC50 values in the two-digit nanomolar range (42 and 56 nM, respectively). These results suggest that the installation of terminal 1,3,4-oxadiazol-5-one/thione functions to the benzyl end can be regarded as a promising secondary pharmacophore in addition to the urea group for sEH inhibition, and compound 19 can be regarded as novel lead structure for further optimization of improved sEH inhibitors.


Assuntos
Epóxido Hidrolases , Compostos Heterocíclicos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Piperazinas/farmacologia , Relação Estrutura-Atividade , Tionas , Ureia
18.
EMBO Rep ; 23(6): e53932, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35403787

RESUMO

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.


Assuntos
Doenças Autoimunes , Neoplasias , Animais , Doenças Autoimunes/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico
19.
J Am Acad Child Adolesc Psychiatry ; 61(9): 1081-1083, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35364250

RESUMO

In this issue, readers can review a multisite, double-blind, randomized, controlled trial (DBRCT) of vortioxetine for adolescent major depression (AMD) by Findling et al.1 The investigators deserve credit for this industry-sponsored study's several innovations: initial treatment following current guidelines, efforts to reduce placebo response rates (PRRs), and creation of both placebo- and active-control arms. The Journal deserves our respect for its commitment to highlighting these innovations, despite the trial's negative result. It is essential to perform treatment studies in adolescents, and this study underscores the fallacy of presuming that drugs showing efficacy in adults will be as effective in our patients.


Assuntos
Transtorno Depressivo Maior , Adolescente , Adulto , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Humanos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Sulfetos/farmacologia , Sulfetos/uso terapêutico , Vortioxetina/farmacologia , Vortioxetina/uso terapêutico
20.
Inflammopharmacology ; 30(2): 549-563, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35243557

RESUMO

Chronic pain is among the most burdensome and devastating disorders affecting millions of people worldwide. Recent studies suggest the role of kinesin nanomotors in development and maintenance of chronic pain. KIF17 is a member of kinesin superfamily that binds to NR2B cargo system via mLin10 scaffolding protein and makes the NMDARs functional at cell surface. NMDA receptor activation is known to induce the central sensitization and excitotoxicity which can be recognized by the glial cells followed by the release of cytokine storm at spinal and supraspinal level leading to chronic pain. In this study, we have investigated the role of aurora kinase in the regulation of KIF17 and NR2B trafficking in the animal model of chronic inflammatory pain. Tozasertib (10, 20, and 40 mg/kg i.p.), a pan aurora kinase inhibitor, significantly attenuates acute inflammatory pain and suppresses enhanced pain hypersensitivity to heat, cold, and mechanical stimuli in CFA-injected rats. Molecular investigations suggest enhanced expression of KIF17/mLin10/NR2B in L4-L5 dorsal root ganglion (DRG) and spinal cord of CFA-injected rats which was significantly attenuated on treatment with tozasertib. Moreover, tozasertib treatment significantly attenuated CFA-induced oxido-nitrosative stress and macrophage activation in DRG and microglia activation in spinal cord of rats. Findings from the current study suggest that tozasertib mediates anti-nociceptive activity by inhibiting aurora kinase-mediated KIF17/mLin10/NR2B signaling.


Assuntos
Dor Crônica , Piperazinas , Receptores de N-Metil-D-Aspartato , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Humanos , Hiperalgesia/tratamento farmacológico , Piperazinas/farmacologia , Ratos , Receptor Cross-Talk , Receptores de N-Metil-D-Aspartato/metabolismo
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