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1.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-39000534

RESUMEN

In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer), and SH-SY5Y (neuroblastoma) as well as on human embryonal lung fibroblast cell line MRC-5, which served as a reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window.


Asunto(s)
Alquinos , Antineoplásicos , Proliferación Celular , Vinblastina , Humanos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Alquinos/química , Alquinos/farmacología , Línea Celular Tumoral , Vinblastina/farmacología , Vinblastina/análogos & derivados , Vinblastina/química , Vinblastina/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Relación Estructura-Actividad
2.
Int J Mol Sci ; 25(14)2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39063170

RESUMEN

A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 µM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 µM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 µM, 10.8 µM, and 6.64 µM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.


Asunto(s)
Antineoplásicos , Proliferación Celular , Cricetulus , Piperazina , Piperazinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Células CHO , Animales , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis química , Proliferación Celular/efectos de los fármacos , Piperazina/química , Piperazina/farmacología , Vinblastina/análogos & derivados , Vinblastina/farmacología , Vinblastina/química , Vinblastina/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacos
3.
J Pharm Sci ; 113(7): 1960-1974, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38527618

RESUMEN

The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading Pgp must be developed. Despite similarities in structure, vinca alkaloids (VAs) show disparate Pgp-mediated efflux ratios. ATPase activity and binding affinity studies show at least two binding sites for the VAs: high- and low-affinity sites that stimulate and inhibit the ATPase activity rate, respectively. The affinity for ATP from the ATPase kinetics curve for vinblastine (VBL) at the high-affinity site was 2- and 9-fold higher than vinorelbine (VRL) and vincristine (VCR), respectively. Conversely, VBL had the highest Km (ATP) for the low-affinity site. The dissociation constants (KDs) determined by protein fluorescence quenching were in the order VBL < VRL< VCR. The order of the KDs was reversed at higher substrate concentrations. Acrylamide quenching of protein fluorescence indicate that the VAs, either at 10 µM or 150 µM, predominantly maintain Pgp in an open-outward conformation. When 3.2 mM AMPPNP was present, 10 µM of either VBL, VRL, or VCR cause Pgp to shift to an open-outward conformation, while 150 µM of the VAs shifted the conformation of Pgp to an intermediate orientation, between opened inward and open-outward. However, the conformational shift induced by saturating AMPPNP and VCR condition was less than either VBL or VRL in the presence of AMPPNP. At 150 µM, atomic force microscopy (AFM) revealed that the VAs shift Pgp population to a predominantly open-inward conformation. Additionally, STDD NMR studies revealed comparable groups in VBL, VRL, and VCR are in contact with the protein during binding. Our results, when coupled with VAs-microtubule structure-activity relationship studies, could lay the foundation for developing next-generation VAs that are effective as anti-tumor agents. A model that illustrates the intricate process of Pgp-mediated transport of the VAs is presented.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Alcaloides de la Vinca , Alcaloides de la Vinca/metabolismo , Alcaloides de la Vinca/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Humanos , Vinblastina/metabolismo , Vinblastina/química , Sitios de Unión , Vincristina/metabolismo , Vincristina/química , Vincristina/farmacología , Transporte Biológico , Adenosina Trifosfatasas/metabolismo , Cinética
4.
Physiol Plant ; 175(5): e13994, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37882277

RESUMEN

Plant lipocalins perform diverse functions. Recently, allene oxide cyclase, a lipocalin family member, has been shown to co-express with vindoline pathway genes in Catharanthus roseus under various biotic/abiotic stresses. This brought focus to another family member, a temperature-induced lipocalin (CrTIL), which was selected for full-length cloning, tissue-specific expression profiling, in silico characterization, and upstream genomic region analysis for cis-regulatory elements. Stress-mediated variations in CrTIL expression were reflected as disturbances in cell membrane integrity, assayed through measurement of electrolyte leakage and lipid peroxidation product, MDA, which implicated the role of CrTIL in maintaining cell membrane integrity. For ascertaining the function of CrTIL in maintaining membrane stability and elucidating the relationship between CrTIL expression and vindoline content, if any, a direct approach was adopted, whereby CrTIL was transiently silenced and overexpressed in C. roseus. CrTIL silencing and overexpression confirmed its role in the maintenance of membrane integrity and indicated an inverse relationship of its expression with vindoline content. GFP fusion-based subcellular localization indicated membrane localization of CrTIL, which was in agreement with its role in maintaining membrane integrity. Altogether, the role of CrTIL in maintaining membrane structure has possible implications for the intracellular sequestration, storage, and viability of vindoline.


Asunto(s)
Catharanthus , Catharanthus/genética , Catharanthus/metabolismo , Temperatura , Vinblastina/química , Vinblastina/metabolismo , Lipocalinas/metabolismo , Hojas de la Planta/genética , Hojas de la Planta/metabolismo
5.
J Mol Recognit ; 35(12): e2989, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36054496

RESUMEN

Structural information about drug-receptor interactions is paramount in drug discovery and subsequent optimization processes. Drugs can bind to multiple potential targets as they contain common chemical entities in their structures. Understanding the details of such interactions offer possibilities for repurposing and developing potent inhibitors of disease pathways. Vinblastine (VLB) is a potent anticancer molecule showing multiple receptor interactions with different affinities and degrees of structural perturbations. We have investigated the multi-target binding profile of VLB with DNA and human serum albumin (HSA) in a dynamic physiological environment using spectroscopic, molecular dynamics simulations, and quantum mechanical calculations to evaluate the structural features, mode, ligand and receptor flexibility, and energetics of complexation. These results confirm that VLB prefers to bind in the major groove of DNA with some inclination toward Thymidine residue and the TR-5 binding site in HSA with its catharanthine half making important contacts with both the receptors. Spectroscopic investigation at multiple temperatures has also proved that VLB binding is entropy driven indicating the major groove and TR-5 binding site of interaction. Finally, the overall binding is facilitated by van der Waals contacts and a few conventional H-bonds. VLB portrays reasonable conformational diversity on binding with multiple receptors.


Asunto(s)
Albúmina Sérica Humana , Vinblastina , Humanos , Vinblastina/química , Vinblastina/farmacología , Simulación del Acoplamiento Molecular , Unión Proteica , Espectrometría de Fluorescencia , Termodinámica , Albúmina Sérica Humana/química , Sitios de Unión , ADN/química , Dicroismo Circular
6.
Nature ; 609(7926): 341-347, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36045295

RESUMEN

Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine1. As MIAs are difficult to chemically synthesize, the world's supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale2,3. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.


Asunto(s)
Antineoplásicos , Reactores Biológicos , Vías Biosintéticas , Ingeniería Metabólica , Saccharomyces cerevisiae , Vinblastina , Alcaloides de la Vinca , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/provisión & distribución , Catharanthus/química , Genes Fúngicos , Genes de Plantas , Ingeniería Metabólica/métodos , Fosfatos de Poliisoprenilo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Triptófano , Vinblastina/biosíntesis , Vinblastina/química , Vinblastina/provisión & distribución , Alcaloides de la Vinca/biosíntesis , Alcaloides de la Vinca/química , Alcaloides de la Vinca/provisión & distribución
7.
J Pharm Biomed Anal ; 215: 114772, 2022 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-35462284

RESUMEN

A highly sensitive method was developed for the quantification of vinblastine, vincristine, vinorelbine, and its active metabolite 4-O-deacetylvinorelbine in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Deuterated isotopes were used as internal standard and liquid-liquid extraction with tert-butyl methyl ether (TBME) was used for sample pre-treatment. The final extract was injected on a C18 column (50 × 2.1 mm ID, 5 µm). Gradient elution was used in combination with Reversed Phase chromatography to elute the analytes and internal standards from the column in 5 min and the API4000 triple quadrupole MS detector was operating in the positive ion mode. The calibration model, accuracy and precision, selectivity and specificity, dilution integrity, carryover, matrix factor and recovery, and stability were evaluated over a concentration range from 0.025 to 10 ng/mL for vinblastine, vinorelbine, and 4-O-deacetylvinorelbine and from 0.1 to 40 ng/mL for vincristine. The intra- and inter-assay bias and precisions were within ± 12.4% and ≤ 10.6%, respectively. This method was successfully applied to study the pharmacokinetics of vincristine in paediatrics and vinorelbine and 4-O-deacetylvinorelbine using in vivo mouse models.


Asunto(s)
Espectrometría de Masas en Tándem , Vinblastina , Animales , Niño , Cromatografía Liquida/métodos , Estabilidad de Medicamentos , Humanos , Ratones , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos , Vinblastina/química , Vincristina , Vinorelbina
8.
Appl Microbiol Biotechnol ; 106(7): 2337-2347, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35333954

RESUMEN

Catharanthus roseus (Madagascar periwinkle), a medicinal plant possessing high pharmacological attributes, is widely recognized for the biosynthesis of anticancer monoterpenoid indole alkaloids (MIAs) - vinblastine and vincristine. The plant is known to biosynthesize more than 130 different bioactive MIAs, highly acclaimed in traditional and modern medicinal therapies. The MIA biosynthesis is strictly regulated at developmental and spatial-temporal stages and requires a well-defined cellular and sub-cellular compartmentation for completion of the entire MIAs biosynthesis. However, due to their cytotoxic nature, the production of vinblastine and vincristine occurs in low concentrations in planta and the absence of chemical synthesis alternatives projects a huge gap in demand and supply, leading to high market price. With research investigations spanning more than four decades, plant tissue culture and metabolic engineering (ME)-based studies were attempted to explore, understand, explain, improve and enhance the MIA biosynthesis using homologous and heterologous systems. Presently, metabolic engineering and synthetic biology are the two powerful tools that are contributing majorly in elucidating MIA biosynthesis. This review concentrates mainly on the efforts made through metabolic engineering of MIAs in heterologous microbial factories. KEY POINTS: • Yeast engineering provides alternative production source of phytomolecules • Yeast engineering also helps to discover missing plant pathway enzymes and genes.


Asunto(s)
Catharanthus , Alcaloides de Triptamina Secologanina , Catharanthus/química , Catharanthus/genética , Regulación de la Expresión Génica de las Plantas , Alcaloides Indólicos/metabolismo , Monoterpenos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Alcaloides de Triptamina Secologanina/química , Alcaloides de Triptamina Secologanina/metabolismo , Vinblastina/química , Vincristina
9.
Chem Biodivers ; 19(1): e202100725, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34874114

RESUMEN

Vinca alkaloids are well-known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti-tumor effect, although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad-spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline-chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI50 values on most of the cell lines.


Asunto(s)
Antineoplásicos/síntesis química , Flavonoides/química , Vinblastina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Relación Estructura-Actividad , Vinblastina/química
10.
Molecules ; 26(21)2021 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-34770804

RESUMEN

Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This "windshield wiper" effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 µM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.


Asunto(s)
Benzoquinonas/química , Modelos Químicos , Vinblastina/química , Cobre/química , Teoría Funcional de la Densidad , Espectroscopía de Resonancia Magnética , Oxidación-Reducción
11.
Molecules ; 26(12)2021 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-34208368

RESUMEN

Plant specialized metabolites are widely used in the pharmaceutical industry, including the monoterpene indole alkaloids (MIAs) vinblastine and vincristine, which both display anticancer activity. Both compounds can be obtained through the chemical condensation of their precursors vindoline and catharanthine extracted from leaves of the Madagascar periwinkle. However, the extensive use of these molecules in chemotherapy increases precursor demand and results in recurrent shortages, explaining why the development of alternative production approaches, such microbial cell factories, is mandatory. In this context, the precursor-directed biosynthesis of vindoline from tabersonine in yeast-expressing heterologous biosynthetic genes is of particular interest but has not reached high production scales to date. To circumvent production bottlenecks, the metabolic flux was channeled towards the MIA of interest by modulating the copy number of the first two genes of the vindoline biosynthetic pathway, namely tabersonine 16-hydroxylase and tabersonine-16-O-methyltransferase. Increasing gene copies resulted in an optimized methoxylation of tabersonine and overcame the competition for tabersonine access with the third enzyme of the pathway, tabersonine 3-oxygenase, which exhibits a high substrate promiscuity. Through this approach, we successfully created a yeast strain that produces the fourth biosynthetic intermediate of vindoline without accumulation of other intermediates or undesired side-products. This optimization will probably pave the way towards the future development of yeast cell factories to produce vindoline at an industrial scale.


Asunto(s)
Alcaloides Indólicos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxigenasas/metabolismo , Quinolinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Vinblastina/análogos & derivados , Vías Biosintéticas , Vinblastina/biosíntesis , Vinblastina/química
12.
Artículo en Inglés | MEDLINE | ID: mdl-34233575

RESUMEN

The study aims to clarify the current controversy related to conflicting reports on whether presence of Cr(VI) in rice is possible or not. For this purpose, a method was employed for the single run speciation analysis of Cr(III) and Cr(VI) in rice samples using species-specific isotope dilution (SS-ID) and high performance liquid chromatography coupled to inductively coupled mass-spectrometry (HPLC-ICP-MS) and selective single run species complexation/derivatisation. The quantification limits (LOQs) were 0.014 µg kg-1 for Cr(III) and 0.047 µg kg-1 for Cr(VI), while the detection limits (LODs) were 0.004 and 0.014 µg kg-1 for Cr(III) and Cr(VI), respectively. A total of 10 rice samples of different origin and colour (depending on the type of industrial processing) were analysed in this study. The content of Cr(VI) was below the limit of quantification in all of the rice samples analysed, while the Cr(III) levels ranged between 0.59 (whole grain rice) up to 104 µg kg-1 (brown rice). All samples were also analysed for their total Cr (Crtotal) content by ICP-MS solely and the results were in all cases comparable with the Cr(III) levels determined in the same samples. To assess the stability of Cr(III) and Cr(VI) in rice, one sample was spiked with Cr(III) and Cr(VI) (individually) at different levels (5.0, 10, 15 and 20 µg kg-1), held for 2 h, and then analysed by SS-ID HPLC-ICP-MS. The results showed a complete reduction of Cr(VI) to Cr(III), while Cr(III) remained stable at all spiking levels. These findings support the general statement from the European Food Safety Authority related to the complete absence of Cr(VI) in foods and confirms that Cr in rice is found solely as Cr(III) species.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/química , Cromatografía Líquida de Alta Presión/métodos , Contaminación de Alimentos , Oryza/química , Clorambucilo/química , Límite de Detección , Espectrometría de Masas , Prednisolona/química , Procarbazina/química , Vinblastina/química
13.
Protein Pept Lett ; 28(7): 735-749, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33302827

RESUMEN

BACKGROUND: Oral cancer is a significant health problem worldwide. Oral squamous cell carcinoma (OSCC) is a malignant neoplasm of epithelial cells that mostly affects different anatomical sites in the head and neck and derives from the squamous epithelium or displays similar morphological characteristics. Generally, OSCC is often the end stage of several changes in the stratified squamous epithelium, which begin as epithelial dysplasia and progress by breaking the basement membrane and invading adjacent tissues. Several plant-based drugs with potent anti-cancer effects are considered inexpensive treatments with limited side effects for cancer and other diseases. OBJECTIVE: The aim of this review is to explore whether some Brazilian plant extracts or constituents exhibit anti-tumorigenic activity or have a cytotoxic effect on human oral carcinoma cells. METHODS: Briefly, OSCC and several metabolites derived from Brazilian plants (i.e., flavonoids, vinblastine, irinotecan, etoposide and paclitaxel) were used as keywords to search the literature on PubMed, GenBank and GeneCards. RESULTS: The results showed that these five chemical compounds found in Cerrado Biome plants exhibit anti-neoplastic effects. Evaluating the compounds revealed that they play a main role in the regulation of cell proliferation. CONCLUSION: Preserving and utilising the biodiversity of our planet, especially in unique ecosystems, such as the Cerrado Biome, may prove essential to preserving and promoting human health in modern contexts.


Asunto(s)
Anticarcinógenos/farmacología , Antineoplásicos Fitogénicos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Proteínas de Neoplasias/genética , Anticarcinógenos/química , Anticarcinógenos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Brasil , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proliferación Celular/efectos de los fármacos , Biología Computacional/métodos , Etopósido/química , Etopósido/aislamiento & purificación , Etopósido/farmacología , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Irinotecán/química , Irinotecán/aislamiento & purificación , Irinotecán/farmacología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Paclitaxel/química , Paclitaxel/aislamiento & purificación , Paclitaxel/farmacología , Extractos Vegetales/química , Plantas Medicinales , Vinblastina/química , Vinblastina/aislamiento & purificación , Vinblastina/farmacología
14.
Molecules ; 25(23)2020 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-33256043

RESUMEN

The Catharanthus roseus plant has been used traditionally to treat diabetes mellitus. Scientific evidence supporting the antidiabetic effects of this plant's active ingredient-vindoline has not been fully evaluated. In this study, extracts of C. roseus and vindoline were tested for antioxidant activities, alpha amylase and alpha glucosidase inhibitory activities and insulin secretory effects in pancreatic RIN-5F cell line cultured in the absence of glucose, at low and high glucose concentrations. The methanolic extract of the plant showed the highest antioxidant activities in addition to the high total polyphenolic content (p < 0.05). The HPLC results exhibited increased concentration of vindoline in the dichloromethane and the ethylacetate extracts. Vindoline showed noticeable antioxidant activity when compared to ascorbic acid at p < 0.05 and significantly improved the in vitro insulin secretion. The intracellular reactive oxygen species formation in glucotoxicity-induced cells was significantly reduced following treatment with vindoline, methanolic and the dichloromethane extracts when compared to the high glucose untreated control (p < 0.05). Plant extracts and vindoline showed weaker inhibitory effects on the activities of carbohydrate metabolizing enzymes when compared to acarbose, which inhibited the activities of the enzymes by 80%. The plant extracts also exhibited weak alpha amylase and alpha glucosidase inhibitory effects.


Asunto(s)
Alcaloides/química , Antioxidantes/química , Antioxidantes/farmacología , Catharanthus/química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Vinblastina/análogos & derivados , Glucemia/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Secreción de Insulina/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polifenoles/química , Especies Reactivas de Oxígeno , Vinblastina/química , alfa-Amilasas/antagonistas & inhibidores
15.
Molecules ; 25(20)2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-33076247

RESUMEN

In the current study, the surface of superparamagnetic iron oxide (SPION) was coated with dextran (DEX), and conjugated with folic acid (FA), to enhance the targeted delivery and uptake of vinblastine (VBL) in PANC-1 pancreatic cancer cells. Numerous analyses were performed to validate the prepared FA-DEX-VBL-SPION, such as field emission scanning transmission electron microscopy, high-resolution transmission electron microscopy, dynamic light scattering (DLS), Zeta Potential, Fourier transform infrared spectroscopy, and vibrating sample magnetometry (VSM). The delivery system capacity was evaluated by loading and release experiments. Moreover, in vitro biological studies, including a cytotoxicity study, cellular uptake assessment, apoptosis analysis, and real-time PCR, were carried out. The results revealed that the obtained nanocarrier was spherical with a suitable dispersion and without visible aggregation. Its average size, polydispersity, and zeta were 74 ± 13 nm, 0.080, and -45 mV, respectively. This dual functional nanocarrier also exhibited low cytotoxicity and a high apoptosis induction potential for successful VBL co-delivery. Real-time quantitative PCR analysis demonstrated the activation of caspase-3, NF-1, PDL-1, and H-ras inhibition, in PANC-1 cells treated with the FA-VBL-DEX-SPION nanostructure. Close inspection of the obtained data proved that the FA-VBL-DEX-SPION nanostructure possesses a noteworthy chemo-preventive effect on pancreatic cancer cells through the inhibition of cell proliferation and induction of apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Nanopartículas de Magnetita/química , Neoplasias Pancreáticas/tratamiento farmacológico , Vinblastina/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Dextranos/química , Dextranos/farmacología , Ácido Fólico/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/patología , Vinblastina/farmacología
16.
Molecules ; 25(16)2020 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-32796768

RESUMEN

Biological activity of antisense oligonucleotides (asON), especially those with a neutral backbone, is often attenuated by poor cellular accumulation. In the present proof-of-concept study, we propose a novel delivery system for asONs which implies the delivery of modified antisense oligonucleotides by so-called transport oligonucleotides (tON), which are oligodeoxyribonucleotides complementary to asON conjugated with hydrophobic dodecyl moieties. Two types of tONs, bearing at the 5'-end up to three dodecyl residues attached through non-nucleotide inserts (TD series) or anchored directly to internucleotidic phosphate (TP series), were synthesized. tONs with three dodecyl residues efficiently delivered asON to cells without any signs of cytotoxicity and provided a transfection efficacy comparable to that achieved using Lipofectamine 2000. We found that, in the case of tON with three dodecyl residues, some tON/asON duplexes were excreted from the cells within extracellular vesicles at late stages of transfection. We confirmed the high efficacy of the novel and demonstrated that MDR1 mRNA targeted asON delivered by tON with three dodecyl residues significantly reduced the level of P-glycoprotein and increased the sensitivity of KB-8-5 human carcinoma cells to vinblastine. The obtained results demonstrate the efficacy of lipophilic oligonucleotide carriers and shows they are potentially capable of intracellular delivery of any kind of antisense oligonucleotides.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Oligonucleótidos Antisentido/genética , ARN Mensajero/antagonistas & inhibidores , Vinblastina/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Humanos , Neoplasias/genética , Neoplasias/patología , ARN Mensajero/genética , Células Tumorales Cultivadas , Vinblastina/administración & dosificación , Vinblastina/química
17.
Appl Microbiol Biotechnol ; 104(11): 4811-4835, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32303816

RESUMEN

Catharanthus roseus (L.) G. Don, also known as Madagascar periwinkle or Sadabahar, is a herbaceous plant belonging to the family Apocynaceae. Being a reservoir for more than 200 alkaloids, it reserves a place for itself in the list of important medicinal plants. Secondary metabolites are present in its leaves (e.g., vindoline, vinblastine, catharanthine, and vincristine) as well as basal stem and roots (e.g., ajmalicine, reserpine, serpentine, horhammericine, tabersonine, leurosine, catharanthine, lochnerine, and vindoline). Two of its alkaloids, vincristine and vinblastine (possessing anticancerous properties), are being used copiously in pharmaceutical industries. Till date, arrays of reports are available on in vitro biotechnological improvements of C. roseus. The present review article concentrates chiefly on various biotechnological advancements based on plant tissue culture techniques of the last three decades, for instance, regeneration via direct and indirect organogenesis, somatic embryogenesis, secondary metabolite production, synthetic seed production, clonal fidelity assessment, polyploidization, genetic transformation, and nanotechnology. It also portrays the importance of various factors influencing the success of in vitro biotechnological interventions in Catharanthus and further addresses several shortcomings that can be further explored to create a platform for upcoming innovative approaches. KEY POINTS: • C. roseus yields anticancerous vincristine and vinblastine used in pharma industry. •In vitro biotechnological interventions prompted major genetic advancements. • This review provides an insight on in vitro-based research achievements till date. • Key bottlenecks and prospective research methodologies have been identified herein.


Asunto(s)
Alcaloides/aislamiento & purificación , Biotecnología/tendencias , Catharanthus/química , Plantas Medicinales/química , Alcaloides/química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Hojas de la Planta/química , Raíces de Plantas/química , Metabolismo Secundario , Vinblastina/química , Vinblastina/aislamiento & purificación , Vincristina/química , Vincristina/aislamiento & purificación
18.
Molecules ; 25(4)2020 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-32102414

RESUMEN

New Vinca alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC50 values in the low micromolar concentration range.


Asunto(s)
Aminoácidos/química , Antineoplásicos Fitogénicos/síntesis química , Citotoxinas/síntesis química , Morfolinas/química , Piperazinas/química , Triazoles/química , Vinblastina/análogos & derivados , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Citotoxinas/farmacología , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Vinblastina/química
19.
J Am Chem Soc ; 141(36): 14349-14355, 2019 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-31442047

RESUMEN

A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1-10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16' stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction and simplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.


Asunto(s)
Aminas/química , Vinblastina/análogos & derivados , Vinblastina/síntesis química , Alcaloides de la Vinca/química , Cationes/química , Radicales Libres/química , Estructura Molecular , Estereoisomerismo , Vinblastina/química
20.
J Chem Inf Model ; 59(7): 3240-3250, 2019 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-31188585

RESUMEN

Drug-induced liver injury (DILI), one of the most common adverse effects, leads to drug development failure or withdrawal from the market in most cases, showing an emerging challenge that is to accurately predict DILI in the early stage. Recently, the vast amount of gene expression data provides us valuable information for distinguishing DILI on a genomic scale. Moreover, the deep learning algorithm is a powerful strategy to automatically learn important features from raw and noisy data and shows great success in the field of medical diagnosis. In this study, a gene expression data based deep learning model was developed to predict DILI in advance by using gene expression data associated with DILI collected from ArrayExpress and then optimized by feature gene selection and parameters optimization. In addition, the previous machine learning algorithm support vector machine (SVM) was also used to construct another prediction model based on the same data sets, comparing the model performance with the optimal DL model. Finally, the evaluation test using 198 randomly selected samples showed that the optimal DL model achieved 97.1% accuracy, 97.4% sensitivity, 96.8% specificity, 0.942 matthews correlation coefficient, and 0.989 area under the ROC curve, while the performance of SVM model only reached 88.9% accuracy, 78.8% sensitivity, 99.0% specificity, 0.794 matthews correlation coefficient, and 0.901 area under the ROC curve. Furthermore, external data sets verification and animal experiments were conducted to assess the optimal DL model performance. Finally, the predicted results of the optimal DL model were almost consistent with experiment results. These results indicated that our gene expression data based deep learning model could systematically and accurately predict DILI in advance. It could be a useful tool to provide safety information for drug discovery and clinical rational drug use in early stage and become an important part of drug safety assessment.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Regulación de la Expresión Génica , Aprendizaje Automático , Vinblastina/efectos adversos , Algoritmos , Animales , Simulación por Computador , Descubrimiento de Drogas , Masculino , Modelos Biológicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Relación Estructura-Actividad , Vinblastina/química
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