RESUMO
Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50â years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70â years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.
Assuntos
Linhagem , Humanos , Masculino , Feminino , Criança , Adulto , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Animais , Extremidade Inferior/fisiopatologia , Caenorhabditis elegans , Espasticidade Muscular/genética , Espasticidade Muscular/fisiopatologia , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/fisiopatologia , MutaçãoRESUMO
Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.
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Epilepsia Generalizada , Epilepsia , Criança , Humanos , Egito/epidemiologia , Estudos Retrospectivos , Epilepsia/diagnóstico , Convulsões/genética , Convulsões/complicações , FenótipoRESUMO
This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation.
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Fatores de Troca do Nucleotídeo Guanina , Humanos , Egito/epidemiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Análise Mutacional de DNA , MutaçãoRESUMO
Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are four MPS III subtypes (A, B, C, and D) that are clinically indistinguishable with variable rates of progression. A retrospective analysis was carried out on 34 patients with MPS III types at Cairo University Children's Hospital. We described the clinical, biochemical, and molecular spectrum of MPS III patients. Of 34 patients, 22 patients had MPS IIIB, 7/34 had MPS IIIC, 4/34 had MPS IIIA, and only 1 had MPS IIID. All patients presented with developmental delay/intellectual disability, and speech delay. Ataxia was reported in a patient with MPS IIIC, and cerebellar atrophy in a patient with MPS IIIA. We reported 25 variants in the 4 MPS III genes, 11 of which were not previously reported. This is the first study to analyze the clinical and genetic spectrum of MPS III patients in Egypt. This study explores the genetic map of MPS III in the Egyptian population. It will pave the way for a national registry for rare diseases in Egypt, a country with a high rate of consanguineous marriage and consequently a high rate of autosomal recessive disorders.
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Doenças por Armazenamento dos Lisossomos , Mucopolissacaridose III , Criança , Humanos , Egito/epidemiologia , Estudos Retrospectivos , AtaxiaRESUMO
Alzheimer's disease (AD) is one of the most prevalent geriatric diseases and a significant cause of high mortality. This crippling disorder is becoming more prevalent at an unprecedented rate, which has led to an increase in the financial cost of caring. It is a pathologically complicated, multifactorial disease characterized by ß-amyloid precipitation, ß-amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD-related processes, including cholinesterase activity, anti-Aß aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple-target DNP-hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.
Assuntos
Doença de Alzheimer , Humanos , Idoso , Donepezila/farmacologia , Donepezila/química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Peptídeos beta-AmiloidesRESUMO
A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All the newly synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and the most active compounds were tested for their butyrylcholinesterase (BuChE) inhibitory activity. Moreover, all the synthesized compounds were evaluated for their inhibitory effects against Aß aggregation and antioxidant activity using the oxygen radical absorbance capacity method. Compounds 4b, 6b, and 8b displayed the most prominent AChE inhibitory action comparable to donepezil. Compound 6b showed the greatest AChE inhibitory action (IC50 = 0.07 ± 0.003 µM) and the most potent BuChE inhibitory action (IC50 = 0.059 ± 0.004 µM). Furthermore, the three compounds exhibited significant antioxidant activity. Compounds 6b and 8b exerted more inhibitory action on Aß aggregation than donepezil. The cytotoxic activity of compounds 4b, 6b, and 8b against the WI-38 cell line in comparison with donepezil was examined using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results revealed that compounds 6b and 8b were less cytotixic than donepezil, while compound 4b showed nonsignificant cytotoxicity compared to donepezil. For more insights about the binding patterns of the most promising compounds (4b, 6b, and 8b) with the AChE at molecular levels; molecular docking and molecular dynamics simulations were performed. The density functional theory calculations and absorption, distribution, metabolism, excretion and toxicity properties were described as well. The results highlighted compound 6b, which incorporates a phenylpiperazine moiety coupled to a thienopyrimidone scaffold via two-atom spacer, to be a promising multifunctional therapeutic agent for the treatment of Alzheimer's disease. It is a potent dual AChE and BuChE inhibitor. Furthermore, it had stronger Aß aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Donepezila/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Simulação de Acoplamento Molecular , Antioxidantes/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Desenho de FármacosRESUMO
A series of tetrahydrobenzothienopyrimidines and tetrahydrobenzothienotriazines incorporating a pharmacophore from donepezil molecule were designed and synthesized. The 12 newly synthesized compounds were screened for their inhibition activity against acetylcholinesterase enzyme (AChE). Compounds that exerted the most potent AChE inhibitory action were further evaluated for their BChE inhibitory activity. In addition, the inhibitory effects of all newly synthesized compounds on Aß and reactive oxygen species were assessed. Compounds 4d, 10b, and 10c showed potent inhibitory activity on AChE comparable to donepezil. Compound 10b (IC50 = 0.124 ± 0.006 nM) showed the greatest AChE inhibitory action and the most potent BChE inhibitory action (IC50 = 0.379 ± 0.02 nM). These three compounds showed more inhibitory action on Aß accumulation than donepezil. Moreover, they showed potent antioxidant activity. The binding pattern of compounds 4d and 10b into AChE active site rationalized their remarkable AChE inhibitory activity. Taken together, these results indicated that these derivatives could be promising multifunctional agents for Alzheimer's disease management.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/química , Donepezila/farmacologia , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas , Relação Estrutura-AtividadeRESUMO
Newly designed levofloxacin analogues were synthesized to act as topoisomerase II beta inhibitors (Topo2ß). Their cytotoxic activity was screened against breast, liver, and leukemia cancer cell lines. The best activity against liver cancer cell line (Hep3B) was exhibited by the target compounds 3c, 3e, 4a, and 6d (IC50 = 2.33, 1.38, 0.60 and 0.43, respectively). (L-SR) leukemia cancer cell line was pronouncedly affected by compounds 3b, 3g and 4a (IC50 = 1.62, 1.41 and 1.61, sequentially). 3c possessed the best activity against breast cancer cell line (MCF-7) with IC50 = 0.66. Compounds 3c, 3e, 3g, 4a and 4c exhibited Topo2ß inhibition activities exceeding etoposide and levofloxacin as reference drugs and variant cell lines. In DNA-Flow cytometry cell cycle analysis, compound 3c arrested the cell cycle at G2/M phase like etoposide and levofloxacin, while compounds 3e and 4a exhibit its arrest at S phase. In addition, 3c, 3e and 4a showed a significant elevation in active caspase-3 levels (10.01, 8.98 and 10.71 folds, respectively). The effect of the new compounds on normal cells was also investigated including breast (MCF10a), liver (THLE2), and lymphocytic (PCS-800-011) normal cell lines.
Assuntos
Antineoplásicos/síntese química , DNA Topoisomerases Tipo II/química , Desenho de Fármacos , Levofloxacino/análogos & derivados , Inibidores da Topoisomerase II/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Levofloxacino/metabolismo , Levofloxacino/farmacologia , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
A new series of 4-benzyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidines was synthesized motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines and triazolothienopyrimidines. The in vitro cytotoxic activity of some selected compounds was evaluated against two human cell lines: prostate cancer (PC-3) and colon cancer (HCT-116). A preliminary study of the structure-activity relationship of the target compounds was discussed. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 16c had the highest potency against the PC-3 cell line with an IC50 of 5.48 µM compared to Doxorubicin (IC50 = 7.7 µM), the reference standard used in this study. On the other hand, 6c and 18c were the most active against HCT-116 (IC50 = 6.12 and 6.56 µM, respectively) relative to IC50 = 15.82 µM of the standard. Thus, some of the synthesized thienopyrimidine derivatives, specially 6c, 16c and 18c, have the potential to be developed into potent anticancer agents.
Assuntos
Pirimidinas/química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Pirimidinas/síntese química , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).
Assuntos
Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Bases de Mannich/síntese química , Bases de Mannich/farmacologia , Estrutura MolecularRESUMO
3-Methyl-1H-pyrazol-5(4H)-one (1) was used as a template to develop new anticancer compounds and investigate their SAR. The ring modification of compound 1 occurred through its reaction with aromatic aldehydes and different reagents to afford the corresponding 6-oxopyrano[2,3-c]pyrazoles4a-c and their amino analogues 6-aminopyrano[2,3-c]pyrazoles6a-c, 8; the pyrazolopyrano[2,3-b]pyridines 10a-c and the chromenopyrano[2,3-c]pyrzolones13, 14. The reaction of compound 1 with thiourea and appropriate aromatic aldehydes afforded the pyrazolo[3,4-d]pyrimidine derivatives 17a-c. On the other hand, the pyrazolo[3,4-d]thiazole derivatives 22a-d were obtained via the reaction of 1 with sulpher and aryl isothiocyanates in presence of triethylamine. The reaction of compound 1 with phenylisothiocyanate followed by treatment with the a-halocarbonyl compounds 24a-c afforded the thiazole derivatives 25a-c. The synthesized products were evaluated for their cytotoxicity against cancer and normal cell lines. Most compounds showed significant anticancer activity without affecting the normal fibroblast cells. The toxicity of the mostpontent cytotoxic compounds was measured using Brine-Shrimp Lethality Assay.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirazóis/química , Pirazóis/toxicidade , Antineoplásicos/química , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Pirazóis/síntese química , Relação Estrutura-Atividade , Células Tumorais CultivadasAssuntos
Biomarcadores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/genética , Fenótipo , Egito , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Proteína C1 de Niemann-Pick , Sequenciamento do ExomaRESUMO
Repositioning of already approved medications through repurposing or re-profiling for new medical uses after certain structural modifications is a novel approach in drug discovery. Fluoroquinolone antibiotics are one of the cardinal agents investigated for potential anticancer activities. In this work, levofloxacin was repositioned for anticancer activities. A series of levofloxacin-based compounds were designed and synthesized through the derivatization of levofloxacin's carboxylic acid functionality. The newly synthesized compounds were screened for cytotoxic activities against breast, liver, and leukemia cancer cell lines. Their effect on normal cells was also investigated. The target compounds were evaluated for their proliferative inhibitory activity toward topoisomerase II beta polymerization. Compound 5 showed higher inhibitory activity against a breast cancer cell line (MCF-7) with IC50 = 1.4 µM and lesser side effects on a normal breast cell line (MCF-10a) with IC50 = 30.40 µM than reference drugs. The best activity against a liver cancer cell line (Hep3B) was exhibited by compounds 3c, 4b, 5, 7, 8, 13a and 13c with IC50 values ranging from 0.43 to 8.79 µM. Regarding the effect of compounds 5 and 13a on a leukemia cancer cell line (L-SR), their IC50 values were 0.96 and 3.12 µM, respectively. Compounds 3c and 5 showed Topo2ß inhibitory effects on Hep3B cells (81.33% and 83.73%, respectively), which was better than levofloxacin and etoposide as reference drugs. Cytometry cell cycle analysis revealed that compounds 3c and 5 arrested the cell cycle at the S phase (37.56% and 39.09%, respectively). Compounds 3c and 5 exhibited an elevation in active caspase-3 levels by 4.9 and 4.5 folds, respectively. Molecular modeling simulation of compounds 3c and 5 demonstrated energy scores (-29.77 and -20.46 kcal mol-1, respectively) more than those of the reference drugs as they interact with the most essential amino acids required for good affinity towards human topoisomerase II beta enzyme (PDB ID: 3QX3). Physicochemical characteristics of the most promising cytotoxic compounds 3c and 5 were investigated and compared to etoposide and levofloxacin as reference drugs. However, they showed high gastrointestinal absorption and could not penetrate the blood-brain barrier.
RESUMO
The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.
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INTRODUCTION: Fragile-X syndrome(FXS) is a neurological disease caused by abnormal repeats in the 5'untranslated region of the FMR1 gene leading to a defective fragile-X-messenger-ribonucleoprotein-1 (FMRP). Although relatively common in children, it is usually under-diagnosed especially in developing countries where genetic screening is not routinely practiced. So far, FXS lacks a laboratory biomarker that can be used for screening, severity scoring or therapeutic monitoring of potential new treatments. METHODS: 110 subjects were recruited; 80 male children with suspected FXS and 30 matched healthy children. We evaluated the clinical utility of serum matrix metalloproteinase-9(MMP9) and amyloid-beta protein precursor(APP) as potential biomarkers for FXS. RESULTS: Out of 80 suspected children, 14 had full mutation, 8 had the premutation and 58 children had normal genotypes. No statistically-significant difference was detected between children with different genotypes concerning age of onset(P = 0.658), main clinical presentation(P = 0.388), clinical severity-score(P = 0.799), patient's disease-course(P = 0.719) and intellectual disability(P = 0.351). Both MMP9 and APP showed a statistically significant difference when comparing different genotype subgroups(P = 0.019 and < 0.001, respectively). Clinically, MMP9 levels were highest in children presenting with language defects, while APP was highest in children with neurodevelopmental delay. In receiver operating curve analysis, comparing full and premutation with the normal genotype group, MMP9 has an area-under-the-curve of 0.701(95 % CI 0.557-0.845), while APP was marginally better at 0.763(95 % CI 0.620-0.906). When combined together, elevated MMP9 or APP had excellent sensitivity > 95 % for picking-up FXS cases in the clinical setting. CONCLUSIONS: Screening for circulating biomarkers in the absence of FXS genetic diagnosis is justified. Our study is the first to evaluate both MMP9 and APP in FXS suspected children in a clinical setting and to assess their correlation with disease presentation and severity.
Assuntos
Precursor de Proteína beta-Amiloide , Síndrome do Cromossomo X Frágil , Criança , Humanos , Masculino , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Biomarcadores , Estudos Transversais , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Metaloproteinase 9 da Matriz/genéticaRESUMO
A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.
Assuntos
Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Acetilcolinesterase/química , Inibidores da Colinesterase/química , Modelos Moleculares , Ligação Proteica , Tiofenos/químicaRESUMO
New series of indole derivatives analogous to donepezil, a well known anti-Alzheimer and acetylcholinesterase inhibitor drug, was synthesized. A full chemical characterization of the new compounds is provided. Biological evaluation of the new compounds as acetylcholinesterase inhibitors was performed. Most of the compounds were found to have potent acetylcholinesterase inhibitor activity compared to donepezil as standard. The compound 1-(2-(4-(2-fluorobenzyl) piperazin-1-yl)acetyl)indoline-2,3-dione (IIId) was found to be the most potent.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Indóis/síntese química , Nootrópicos/síntese química , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Inibidores da Colinesterase/farmacologia , Donepezila , Indanos/farmacologia , Indóis/farmacologia , Cinética , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Nootrópicos/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: Mitral Valve Prolapse (MVP) is a common valvular abnormality accounting for 2% of the population. There is a reported association between pes planus (PP) and MVP in some syndromes such as Marfan. However, this association has not been tested in non-syndromic cases. The primary outcome of this study is to measure the prevalence of MVP in a population of patients with PP. The secondary outcome parameter is to determine if the Meary angle (MA), a measure of the severity of flat foot, can be effectively used in the prediction of the presence of MVP. Forty-one patients with PP were screened using a lateral x-ray foot to determine MA while echocardiography was utilized to identify the presence and grade of MVP. RESULTS: 88% of screened patients were diagnosed with MVP. MA was correlated with the grade of MVP and showed high diagnostic accuracy (sensitivity 100% and specificity 90%) in predicting MVP risk when higher than 5. Children with PP are at a higher risk for MVP than the general population. Accordingly, the utilization of MA in such a specific population for the determination of patients at a higher need for echocardiography seems to be a worthwhile strategy in diagnosing MVP.
Assuntos
Pé Chato , Prolapso da Valva Mitral , Criança , Estudos Transversais , Ecocardiografia , Pé Chato/complicações , Humanos , Valva Mitral/diagnóstico por imagem , Prolapso da Valva Mitral/complicações , Prolapso da Valva Mitral/diagnóstico por imagem , Prolapso da Valva Mitral/epidemiologiaRESUMO
To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.
Assuntos
Variações do Número de Cópias de DNA , Doenças Metabólicas , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Paquistão , Sequenciamento do ExomaRESUMO
BACKGROUND: The oceans cover more than 70% of the earth's surface, which represents over 95% of the biosphere. Therefore, oceans provide a wealth of marine invertebrates, especially sponges, ascidians, bryozoans and molluscs that produce structurally unique bioactive metabolites such as alkaloids. The bioactive scaffolds of marine alkaloids exhibit cytotoxic activities against human cancer cell lines. OBJECTIVE: To prepare analogues of the marine alkaloid nortopsentin [having 2,4-bis(3'- indolyl)imidazole scaffold] as cytotoxic agents via structural modification of the core imidazole ring and one of the side indole rings. METHODS: Four series of nortopsentin analogues were synthesized in which the imidazole ring was replaced by pyrazole, pyrido[2,3-d]pyrimidinone and pyridine rings. Furthermore, one of the side indole rings was replaced by substituted phenyl moiety. The target compounds were tested for their in vitro cytotoxic activity against HCT-116 cell-line and the most potent compound was subjected to further investigation on its effect on HCT-116 cell cycle progression. RESULTS: The cytotoxic screening of the synthesized compounds revealed that bis-indolylpyridinedicarbonitriles 8a-d exhibited the most potent cytotoxic activity with IC50=2.6-8.8 µM. Compound 8c was further tested by flow cytometry analysis to explore its effect on HCT-116 cell cycle progression that, in turn, indicated its anti-proliferative effect. CONCLUSION: Marine-derived bis-indole alkaloids (nortopsentins) have emerged as a new class of indole-based antitumor agents. The design of new analogues involved several modifications in order to obtain more selective and potent cytotoxic agents. Indole derivatives bearing a pyridine core displayed more potent cytotoxic activity than those containing pyrido[2,3-d]pyrimidin-4(1H)-one moiety.