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Síntese e caracterização de novos azoestilbenóides como potenciais agentes antineoplásicos

机译:新型偶氮二苯乙烯类化合物作为潜在抗肿瘤药的合成与表征

摘要

Melanoma is a malignant tumor that develops anywhere on the skin is 1 to 3% of all malignant neoplasms, and also affects men and women, especially in light skin. The development of melanoma may be associated with excessive sun exposure, sunburn, fair skin, blond or red hair, lots of freckles on their shoulders and backs, family history and presence of actinic keratosis. The chemotherapeutic strategies have been based on the use of dacarbazine and temozolomide. In addition to these monoclonal antibodies are also being used, such as ipilimumab, approved in 2011 for the palliative treatment of patients with metastatic cancer. Many studies are underway to evaluate the anticancer activity of compounds like resveratrol. Resveratrol, 3,5,4'-trihydroxy-trans-stilbene (RESV) is a natural phenolic stilbene which has, among the most important properties, antioxidant, anticarcinogenic - inhibiting various cellular events associated with three major stages of carcinogenesis: started, promotion and progression - anti-inflammatory, antiplatelet, antifungal and estrogen. Resveratrol analogs were synthesized by modification of substituents on both rings, without altering the double bond between them: one by the fusion of benzene and other two by fusing a heterocyclic ring; these newly synthesized analogues showed anticancer activity, vasodilatory and anti-tyrosinase. In this paper we propose the synthesis of resveratrol analogues in order to evaluate the biological activity of these. The structural change of resveratrol stilbene modified (alternate double bond between the carbons of the double nitrogens) may be a promising strategy to improve the pharmacological parameters. The replacement of hydroxyl groups by methyls and acetyls can increase the molecular stability, so that there is decreasing susceptibility in the reaction phase II conjugation in vivo, significantly potentiate the cytotoxic activity. Assay in cell culture using melanoma line, B16F10, showed that compounds synthesized had IC50 less than resveratrol. In evaluating the IC50 of the compounds synthesized in fibroblasts, 3T3 line, we see that showed higher values than in melanoma strain except Redresv001 compound, suggesting a specificity of the synthesized compounds in these cancer cells. Among the compounds, methylated Redresv003 and acetylated Redresv004 and Redresv005 have greater prominence, because of having antiproliferative activity at lower concentrations, are selective for cancer tested lineage and maintain their activity long period of time (72 hours), suggesting that did not generate resistance in the B16F10 line. For the qualitative analysis of the mechanism of cell death, we find that the Redresv003, Redresv004 and Redresv005 compounds showed differences compared to the control for apoptosis assay and also by autophagy, suggesting no specific target for action based on these assays.
机译:黑色素瘤是一种恶性肿瘤,占所有恶性肿瘤的1%至3%在皮肤上的任何部位发展,并且还影响男性和女性,特别是在浅色皮肤中。黑色素瘤的发展可能与过度的日晒,晒伤,皮肤白皙,金色或红色的头发,肩膀和背上的许多雀斑,家族病史以及光化性角化病有关。化疗策略基于达卡巴嗪和替莫唑胺的使用。除这些单克隆抗体外,2011年批准使用的ipilimumab等单克隆抗体也可用于转移性癌症患者的姑息治疗。许多研究正在进行中,以评估白藜芦醇等化合物的抗癌活性。白藜芦醇3,5,4'-三羟基-反式-二苯乙烯(RESV)是一种天然酚类二苯乙烯,具有最重要的特性,抗氧化剂,抗癌性-抑制与癌变三个主要阶段相关的各种细胞事件:开始,促进和发展-抗炎,抗血小板,抗真菌和雌激素。白藜芦醇类似物是通过修饰两个环上的取代基而合成的,而不改变它们之间的双键:一种是通过苯的融合,另一种是通过杂环的融合;这些新合成的类似物显示出抗癌活性,血管舒张性和抗酪氨酸酶。在本文中,我们提出合成白藜芦醇类似物以评估其生物活性。白藜芦醇二苯乙烯修饰的结构改变(双氮碳原子之间的交替双键)可能是改善药理学参数的有前途的策略。甲基和乙酰基取代羟基可增加分子稳定性,从而使体内反应阶段II共轭反应的敏感性降低,从而显着增强了细胞毒活性。使用黑素瘤系B16F10在细胞培养中进行的分析表明,合成的化合物的IC50低于白藜芦醇。在评估在成纤维细胞3T3系中合成的化合物的IC50时,我们发现除Redresv001化合物外,该值显示出比黑素瘤菌株更高的值,表明合成的化合物在这些癌细胞中具有特异性。在这些化合物中,甲基化的Redresv003和乙酰化的Redresv004和Redresv005具有较高的突出性,因为它们在较低的浓度下具有抗增殖活性,对癌症检测的谱系具有选择性,并能长时间(72小时)保持其活性,这表明在B16F10系列。对于细胞死亡机制的定性分析,我们发现Redresv003,Redresv004和Redresv005化合物与凋亡检测对照以及通过自噬相比显示出差异,表明基于这些检测没有特定的作用靶标。

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