摘要

植物来源的天然聚合物及其合成类似物及其抗炎和抗癌功效

作者(年代):Vakhtang Barbakadze博士

一种新的具有抗炎和抗肿瘤活性的多糖是一种高分子(>1000 kDa)水溶性制剂的主要化学成分。意大利鳀鱼，洋甘草和黄菖蒲(野菖蒲科)。根据的数据IR，液相1H, 13C NMR, APT, 1D NOE，异核2D 1H/13CHSQC, 2D DOSY和固态13C NMR谱发现了该生物聚合物为咖啡酸衍生聚醚，即聚[氧-1-羧基-2-(3,4-二羟基苯基)乙烯]或聚[3-(3,4-二羟基苯基)甘油酸](PDPGA)。聚氧乙烯链是这种聚合物分子的骨架，3,4-二羟基苯基和羧基是链上两个碳原子的规则取代基。该化合物是一类以3-(3,4-二羟基苯基)甘油酸残基为重复单位的新型重要天然聚醚的第一个代表化合物[1-4]。醚键存在于各种各样的天然产物中，主要是次级代谢产物，包括脂类、氧烷、萜类、类黄酮、聚酮和碳水化合物衍生物。这些化合物中有许多具有不同的药理活性。在药理活性生物聚合物领域中，稳定聚醚领域似乎是相当新的和有吸引力的[5]。据推测，PDPGA是南欧国家广泛使用的民间药物中所含的重要成分。另一方面，PDPGA作为一种聚(甘油酸)也属于一类酸性多糖(糖酸)。它的基本单体部分甘油酸是一种天然的三碳糖酸，是所有常见醛醛中最简单的氧化形式。在这种情况下，聚(甘油酸)链是聚合物分子的骨架，3,4-二羟基苯基是链上碳原子的规则取代基。 We have no information on the biosynthesis of such a polymer in plants, but, from the chemical viewpoint, this process can be conceived as the epoxidation of the double bond in caffeic acid followed by the polymerization of the resulting oxirane. PDPGA is the derivative of polyethylene glycol (PEG), which is the most common among polyethers and prepared by ring-opening polymerization of an oxirane (ethylene oxide). PDPGA was designed on the basis of poly[2-hydroxycarbonyl-3-(3,4-dimethoxyphenyl)oxirane] and 2-hydroxycarbonyl-3-(3,4-dihydroxyphenyl)oxirane is proposed to be an unsymmetrically 2,3-disubstituted oxirane monomer of PDPGA. Consequently, we can consider PDPGA as poly(oxiranes). Thus, PDPGA belongs to the several important classes of biopolymers and is endowed with intriguing pharmacological activities as anticomplementary, antioxidant, anti-inflammatory and anticancer properties [6-8]. Then the racemic monomer 2,3-dihydroxy-3-(3,4-dihydroxyphenyl)propionic acid (DDPPA) and its enantiomers (+)-(2R,3S)-DDPPA and (–)-(2S,3R)-DDPPA were synthesized via Sharpless asymmetric dihydroxylation利用渗透酸钾催化剂和对映互补催化剂制备反式咖啡酸衍生物金鸡纳树生物碱衍生品(DHQ) 2-PHAL而且(DHQD) 2-PHAL作为手性助剂，分别是[9]。以阳离子引发剂BF3•OEt2为引发剂，以2-甲氧基羰基-3-(3,4-二甲氧基苯基)氧齐烷开环聚合合成了甲基化PDPGA衍生物[10,11]。透明质酸(HA) (Mr 107 Da)是细胞外基质的主要成分，主要存在于皮肤、眼睛玻璃体、滑液和牙周结缔组织中。HA具有多种生物活性。它参与细胞增殖、迁移和细胞分化等过程。HA的生物学和病理生理作用很大程度上取决于它的链大小。高分子质量HA，分子量约> - 20 kDa，具有抗炎、免疫抑制、抗血管生成和填充空间等作用。相反，低分子质量的HA (<20 kDa)通过促进内皮细胞迁移来刺激炎症、侵袭和血管生成。人透明质酸酶(Hyal-1)是HA代谢的主要酶之一。Hyal-1将高分子质量的HA降解为更小的片段，特别是四糖。 It has been shown that Hyal-1 expression is elevated in a variety of cancer cells, for example in prostate, bladder and head tumour cells. Furthermore a correlation between Hyal-1 overexpression and the malignancy of human cancer cell lines MCF-7 has been reported. Because of its role in these (patho)physiological processes, Hyal-1 is an interesting target for drug development and inhibitor testing. The inhibition of Hyal-1 using hyaluronidase inhibitors might be a new additive way in more targeted cancer treatment or in treatment of non-cancer diseases such as arthritis and gingivitis [12]. In this work, Hyal-1 was expressed on the surface of E. coli, by applying Autodisplay, to overcome formation of inactive “inclusion bodies”. With the cells displaying Hyal-1 an activity assay was performed using “stains-all” dye. Subsequently, the inhibitory effects of PDPGA on the activity of surface displayed Hyal-1 were evaluated. A stains-all assay was used to measure the inhibition of Hyal-1 by PDPGA. In order to exclude PAINS-like behavior of the polymer, inhibition of Esterase was tested as a control. As there was no inhibition at any concentration, PDPGA appeared to be selective for Hyal-1. The Live-Cell Analysis system was used to assess the effect of polymer on cell proliferation. Cytotoxicity was measured in real time. The IncuCyte® Live-Cell Analysis demonstrated the non-toxic character of PDPGA. MTT assay as performed in addition demonstrated the non-toxic character of PDPGA. Our results indicate that PDPGA possesses the ability to inhibit the enzymatic activity of Hyal-1completely. Consequently, PDPGA exhibited anti-inflammatory effect [13]. Besides its inhibitory effect on Hyal-1, PDPGA and its synthetic monomer suppressed the growth and induced death in androgen-dependent (LNCaP) and -independent (22Rv1) human prostate cancer (PCA) cells, with comparatively lesser cytotoxicity towards non-neoplastic human prostate epithelial cells PWR-1E. PDPGA and its synthetic monomer caused G1 phase arrest of cell cycle progression in PCA cells through modulating the expression of cell cycle regulators, especially an increase in cyclin-dependent kinase inhibitors (p21, p27). PDPGA induced apoptotic death by activating caspases, and also strongly decreased androgen receptor and prostate specific antigen (PSA) expression. In 22Rv1 xenograft model male athymic nude mice with 22Rv1 xenografts was administered orally of PDPGA. The tumor volume was decreased by 88%. Plasma analyses revealed that PDPGA administration caused a strong dose-dependent decrease in PSA levels by 87%. Anticancer efficacy of PDPGA against human PCA cells is more compared to its synthetic monomer DDPPA [8]. Methylated synthetic analogue of PDPGA did not show any activity against PCA. Overall, this study identifies PDPGA as a potent agent against PCA without any toxicity and supports its clinical application.

关键词:咖啡酸衍生聚醚、聚[氧-1-羧基-2-(3,4-二羟基苯基)乙烯]、聚[3-(3,4-二羟基苯基)甘油酸]、3-(3,4-二羟基苯基)甘油酸、聚(甘油酸)、糖酸、聚(氧基烷)。