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1.
Molecules ; 25(24)2020 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-33352660

RESUMEN

During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams.


Asunto(s)
Factores Biológicos/química , Lactamas/química , Cromatografía Líquida de Alta Presión/métodos , Estructura Molecular , Estereoisomerismo
2.
Phytochem Anal ; 30(4): 377-384, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30687967

RESUMEN

INTRODUCTION: Marrubium vulgare is a herbal remedy presents in several European Pharmacopoeias and commonly marketed as white horehound. The chemotaxonomic marker of Marrubium genus is marrubiin and its content may change in response to biotic and abiotic stress. OBJECTIVE: Development of a microwave-assisted solvent extraction (MASE) methodology suitable for exhaustively extracting marrubiin from M. vulgare leaves, easily applicable to large sets of samples. Evaluation of the influence of copper(II) on marrubiin production. MATERIAL AND METHODS: M. vulgare leaves were dried, extracted exploiting MASE and analysed via high-performance liquid chromatography ultraviolet photodiode array detection (HPLC-UV/PAD) system. A design of experiments approach was adopted to select the best extraction conditions. Extraction parameters (solvent composition, extraction time and temperature), were studied applying two full factorial experimental designs in a sequential approach. To analyse samples, a rapid HPLC-UV/PAD method was set up. RESULTS: The best results in terms of marrubiin extraction yield were obtained extracting samples at 120°C with 100% ethanol, for 15 min (3 × 5 min microwave cycles). The developed methodology was successfully applied to matrices grown in Greenhouse conditions and under stress induced by copper(II), selected as model agent for abiotic stress. Progressively decreasing production of marrubiin was evidenced in connection with treatment with 80, 200 and 300 mg/L copper sulphate. CONCLUSION: An efficient methodology for the extraction and determination of the amount of marrubiin in large sets of samples of M. vulgare plants was developed. Results demonstrated that marrubiin is an easily detectable marker useful for evaluating M. vulgare reaction to stress.


Asunto(s)
Diterpenos/análisis , Marrubium/química , Fitoquímicos/análisis , Extractos Vegetales/aislamiento & purificación , Biomarcadores/análisis , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión , Marrubium/fisiología , Microondas , Extractos Vegetales/química , Hojas de la Planta/química , Proyectos de Investigación , Estrés Fisiológico
3.
Bioorg Med Chem Lett ; 27(4): 701-707, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28073672

RESUMEN

20-(S)-Camptothecin (CPT) is a natural alkaloid extracted from the bark of Camptotheca acuminata (Chinese happy tree). It acts as a DNA topoisomerase 1 poison with an interesting antitumor activity and its use is limited by low stability and solubility and unpredictable drug-drug interactions. Since the late 20th century, it has been widely used in cancer therapy and, since extraction yields from plant tissues are very low, various synthetic routes have been developed to satisfy the increase in demand for CPT. Moreover, SAR studies have allowed for the development of more potent CPT analogues topotecan and irinotecan. Unfortunately, resistance has already occurred in several tumour lines. Additional studies are needed to better understand the relationship between substituents and resistance, its clinical relevance and the impact of related gene polymorphism. One of the latest research approaches focuses on modifying the delivery mode to improve tumour cell uptake and reduce toxicity.


Asunto(s)
Antineoplásicos Fitogénicos/química , Camptotecina/análogos & derivados , Medicina Tradicional , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/toxicidad , Apoptosis/efectos de los fármacos , Camptotheca/química , Camptotheca/metabolismo , Camptotecina/uso terapéutico , Camptotecina/toxicidad , ADN-Topoisomerasas de Tipo I/química , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad
4.
Molecules ; 22(4)2017 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-28338625

RESUMEN

Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the (R) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that (R)-ASME inhibits Leishmania infantum promastigotes viability (IC50 73 µg/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections.


Asunto(s)
Antraquinonas/aislamiento & purificación , Antraquinonas/uso terapéutico , Leishmaniasis/tratamiento farmacológico , Éteres Metílicos/aislamiento & purificación , Éteres Metílicos/uso terapéutico , Animales , Antraquinonas/química , Antraquinonas/farmacología , Recuento de Células , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Citometría de Flujo , Leishmania infantum/efectos de los fármacos , Leishmania infantum/crecimiento & desarrollo , Leishmaniasis/parasitología , Estadios del Ciclo de Vida/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Éteres Metílicos/química , Éteres Metílicos/farmacología , Ratones , Células RAW 264.7 , Espectrometría de Masa por Ionización de Electrospray , Asphodelaceae
5.
J Clin Med ; 13(12)2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38930041

RESUMEN

Background: The assessment of cardiac risk is challenging for elderly patients undergoing major orthopedic surgery with preoperative functional limitations. Currently, no specific cardiac risk scores are available for these critical patients. Echocardiography may be a reliable and safe instrument for assessing cardiac risks in this population. This study aims to evaluate the potential benefits of echocardiography in elderly orthopedic patients, its impact on anesthesiologic management, and postoperative Major Adverse Cardiac Events (MACEs). Methods: This is a retrospective, one-arm, monocentric study conducted at ''Federico II'' Hospital-University of Naples-from January to December 2023, where 59 patients undergoing hip or knee revision surgery under neuraxial anesthesia were selected. The demographic data, the clinical history, and the results of preoperative Echocardiography screening (pEco-s) were collected. After extensive descriptive statistics, the χ2 test was used to compare the valvopathies and impaired Left Ventricular Function (iLVEF) prevalence before and after echocardiography screening and the incidence of postoperative MACE; a p-value < 0.05 was considered statistically significant. Results: The mean age was 72.5 ± 6.9, and the prevalence of cardiac risk factors was about 90%. The cumulative prevalence of iLVEF and valvopathy was higher after the screening (p < 0.001). The pEco-s diagnosed 25 new valvopathies: three of them were moderate-severe. No patients had MACE. Conclusions: pEco-s evaluation could discover unknown heart valve pathology; more studies are needed to understand if pEco-s could affect the anesthetic management of patients with functional limitations, preventing the incidence of MACE, and assessing its cost-effectiveness.

6.
ACS Med Chem Lett ; 14(11): 1509-1516, 2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-37970588

RESUMEN

The RNA binding protein HuR regulates the post-transcriptional process of different oncogenes and tumor suppressor genes, and its dysregulation is linked with cancer. Thus, modulating the complex HuR-RNA represents a promising anticancer strategy. To search for novel HuR ligands able to interfere with the HuR-RNA complex, the protein-templated dynamic combinatorial chemistry (pt-DCC) method was utilized. The recombinant RRM1+2 protein construct, which contains essential domains for ligand-HuR binding and exhibits enhanced solubility and stability compared to the native protein, was used for pt-DCC. Seven acylhydrazones with over 80% amplification were identified. The binding of the fragments to HuR extracted from DCC was validated using STD-NMR, and molecular modeling studies revealed the ability of the compounds to bind HuR at the mRNA binding pocket. Notably, three compounds effectively interfered with HuR-RNA binding in fluorescence polarization studies, suggesting their potential as foundational compounds for developing anticancer HuR-RNA interfering agents.

7.
Ann Ital Chir ; 93: 178-182, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35476703

RESUMEN

BACKGROUND: In this study, the authors evaluated the role of narrow band imaging endoscopy in the early detection of infiltration of the colon wall by flat and depressed lesions, highlighted during colonoscopy, to confirm the possibility of removal with Endoscopic Mucosal Resection (EMR). METHODS: 67 patients (37 males and 30 females) with non-polypoid colorectal lesions were included in this study. The location of the lesions, the size and possible infiltration of the colon wall were performed with a colonoscopy with NBI. Lesions without massive invasion were treated with an EMR. RESULTS: NBI was found to be a sensitive, specific, and accurate technique in assessing any infiltration of the colon wall. Endoscopic resection of the mucous membrane was successfully performed in 62 patients, it was not possible to perform it in 5 patients, due to the lack of dissection, and they underwent surgery. CONCLUSIONS: Non-polypoid colorectal lesions and early tumors can be treated with EMR. Certainly, early detection with Narrow Band Imaging endoscopy and subsequent endoscopic resection can reduce colorectal cancer mortality. Many studies have confirmed that these two methods have achieved important results comparable with surgical procedures. KEY WORDS: Endoscopic Mucosal Resection, Narrow Band Imaging, Therapy.


Asunto(s)
Neoplasias Colorrectales , Resección Endoscópica de la Mucosa , Colonoscopía/métodos , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Masculino , Imagen de Banda Estrecha/métodos
8.
Ann Ital Chir ; 93: 633-636, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35297781

RESUMEN

BACKGROUND: In our study we evaluated from an oncological and psychological point of view, a group of patients who had previously undergone total laryngectomy and candidates for the placement of a vocal prosthesis, which allows to recover the voice using the air that passes from the trachea to the esophagus, thus vibrating a segment of the cervical esophagus. For the placement of the prosthesis and the oncological follow-up, we used the support of videoendoscopy, to exclude any recurrence or secondary tumors. At the same time, we subjected patients to a psychological evaluation before and after the implantation of the prostheses, to understand the behavioral changes in the two phases, and the possible achievement of the result of total autonomy, social reintegration, and recovery of oral communication, in the post-surgical phase. METHODS: We performed a complete esophagogastroduodenoscopy and psychological evaluation on 42 patients who had previously undergone a total laryngectomy, before proceeding to the creation of a tracheoesophageal fistula and the placement of a phonatory prosthesis. After six months, we re-evaluated the same patients, both from an oncological and psychological point of view. RESULTS: At the preimplantation control of the prosthesis, in endoscopy we detected three neoplastic relapses that did not allow the placement of a prosthesis, and four patients who had grade B esophagitis according to the Los Angeles classification, in the remaining 35 patients there were no complications. At the psychological evaluation, most of the patients had psychosocial disorders, with phenomena of anxiety and depression. At the check-up six months after implantation, none of the patients had relapses, and the voice prosthesis was not fully functional in a single patient. From a psychological point of view, voice recovery has significantly improved relationships both in the family and in the social sphere. CONCLUSIONS: Our experience has confirmed the interesting and advantageous use of videoendoscopy in patients undergoing total laryngectomy and candidates for the placement of a tracheoesophageal vocal prosthesis, in the evaluation of neoplastic relapses and secondary lesions of the esophagus. The role of the psychologist both in the pre and post prosthetic phase is fundamental in assessing the discomfort of these patients by helping them solve some problems such as isolation and anxiety. KEY WORDS: Anxiety, Depression, Total laryngectomy, Voice prosthesis.


Asunto(s)
Laringe Artificial , Humanos , Laringe Artificial/efectos adversos , Recurrencia Local de Neoplasia/cirugía , Implantación de Prótesis , Esófago/cirugía , Laringectomía , Tráquea/cirugía
9.
Ann Ital Chir ; 93: 435-438, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35674003

RESUMEN

BACKGROUND: The therapeutic arsenal for colorectal cancer is largely made up of surgery. In digestive tumors, ostomy devices induce loss of function and control. This medical device generates changes that affect all aspects of patients' lives. This study evaluates the postoperative follow-up from the oncological point of view and the psychological impact of colostomy on the quality of life of patients with colorectal cancer, analyzing any complications or relapses, and the high risk of self-concept disorder and social isolation. METHODS: The aim of the work was to identify all the surgeries for colorectal cancer performed in the Federico II University Hospital of Naples, from 2018 to 2021, and among them how many had been packaged a colostomy. We then analyzed how many patients had been evaluated 12 months after surgery, with a transanal endoscopy or transtomy, and the percentage of any complications or relapses. The same patients who underwent endoscopic control were also evaluated psychologically, to analyze how they lived the packaging of the ostomy and how it had affected the quality of life. RESULTS: At endoscopic control, diversion colitis phenomena and few cases of stoma stenosis and stomatitis were detected. No case of neoplastic recurrence. From the psychological point of view, the problems detected were in particular the alteration of body image, the loss of sphincter control, embarrassment and shame for the bad smell, impairment of sexuality and difficulties in the couple relationship and social contacts, anxiety, depression and loneliness. CONCLUSIONS: The post-operative evaluation of the ostomy patient following colorectal cancer requires endoscopic control to suddenly detect recurrences and complications and psychological support that improves their quality of life. KEY WORDS: Permanent Colostomy, Psychological Adjustment, Quality of Life, Temporary Colostomy.


Asunto(s)
Neoplasias Colorrectales , Colostomía , Imagen Corporal , Neoplasias Colorrectales/cirugía , Colostomía/efectos adversos , Humanos , Calidad de Vida/psicología , Recurrencia
10.
ACS Med Chem Lett ; 11(5): 883-888, 2020 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-32435400

RESUMEN

The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Intrigued by this concept, our research efforts aim at identifying small molecules able to modulate HuR-RNA interactions, with a focus on subtype HuR, upregulated and dysregulated in several cancers. By applying structure-based design, we had already identified racemic trans-BOPC1 as promising HuR binder. In this Letter, we accomplished the enantio-resolution, the assignment of the absolute configuration, and the recognition study with HuR of enantiomerically pure trans-BOPC1. For the first time, we apply DEEP (differential epitope mapping)-STD NMR to study the interaction of BOPC1 with HuR and compare its enantiomers, gaining information on ligand orientation and amino acids involved in the interaction, and thus increasing focus on the in silico binding site model.

11.
ACS Med Chem Lett ; 10(4): 615-620, 2019 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-30996806

RESUMEN

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies (i.e., cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex.

12.
Sci Rep ; 8(1): 13780, 2018 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-30214075

RESUMEN

Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds (i.e., flavonoids and coumarins), naturally decorated with different functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV-RNA complexes.


Asunto(s)
Cumarinas/metabolismo , Proteína 1 Similar a ELAV/metabolismo , Flavonoides/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Procesamiento Postranscripcional del ARN/efectos de los fármacos , Proteína 1 Similar a ELAV/genética , Humanos , Ligandos , Imagen por Resonancia Magnética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , ARN Mensajero/genética
13.
Pharmaceuticals (Basel) ; 10(2)2017 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-28524095

RESUMEN

Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic strategies to overcome these issues. On the basis of these considerations, the comprehension of the molecular cascades behind these pathological conditions could allow the identification of molecules against chronic wounds. In this context, the regulation of the Protein Kinase C (PKC) cascade has gained relevance in the prevention and/or reparation of tissue damages. This class of phosphorylating enzymes has already been considered for different physiological and pathological pathways and modulation of such enzymes may be useful in reparative processes. Herein, the recent developments in this field will be disclosed, highlighting the pivotal role of PKC α and δ in regenerative medicine. Moreover, an overview of well-established PKC ligands, acting via the modulation of these isoenzymes, will be deeply investigated. This study is aimed at re-evaluating widely known PKC modulators, currently utilized for treating other diseases, as fruitful molecules in wound-healing.

14.
Eur J Med Chem ; 102: 425-44, 2015 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-26301559

RESUMEN

X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4ß2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-ß2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids.


Asunto(s)
Azepinas/farmacología , Carbamatos/farmacología , Piridinas/farmacología , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Azepinas/síntesis química , Azepinas/química , Sitios de Unión/efectos de los fármacos , Carbamatos/síntesis química , Carbamatos/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad
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