单羰基姜黄素类似物的结构改造及药理作用研究进展

姜黄素是中药姜黄的主要活性成分,具有抗肿瘤、抗炎、抗氧化等多种药理活性。临床前研究发现,姜黄素具有体内代谢速度快、溶解度不高、生物利用度低等缺陷,因此,其临床应用受到了限制。近年来国内外科学家以姜黄素为先导化合物,设计合成了大量的单羰基姜黄素类似物,并对其药理活性进行了评价,以解决姜黄素存在的缺陷。本文从单羰基姜黄素类似物连接链的角度进行分类,分别对1,4-戊二烯-3-酮类、环酮类和查尔酮类姜黄素类似物的设计合成、活性测试和构效关系等方面进行综述,并对未来姜黄素类似物的设计合成进行展望,为开发更为高效的姜黄素类新药提供参考。     

N-异丙基哌啶酮类单羰基姜黄素类似物的设计、合成及抗乳腺癌活性评价

摘要：目的:寻找抗乳腺癌活性较好的新型小分子化合物。方法:以姜黄素为起点,通过合理的设计,将姜黄素结构中不稳定的β-二酮部分替换成更加稳定的N-异丙基哌啶酮母核,并在两侧苯环上引入不同的取代基团,设计、合成了5个新型的N-异丙基哌啶酮类单羰基姜黄素类似物CN1～CN5,通过MTS法和Western Blot法评价新化合物的抗肿瘤活性,分子对接模拟预测活性化合物与信号转导与转录激活因子3（STAT3）的结合模式,并采用OSIRIS Property Explorer软件预测类似物CN1～CN5的理化特性。结果:体外MTS实验结果表明,类似物CN1～CN5对5种不同乳腺癌细胞（MCF-7、MDA-MB-231、MDA-MB-468、T47D和Bcap37）具有比姜黄素更佳的抑制活性。其中类似物CN1活性最佳,在Bcap37细胞系中表现出比临床常用抗乳腺癌化疗药物表柔比星更佳的抑制活性,且对乳腺癌细胞系T47D和MCF-7抑制效果最好,IC50值均低于10μmol·L-1。Western Blot实验结果表明,类似物CN1在2.5～10μmol·L-1浓度范围内可以剂量依赖性抑制乳腺癌细胞MCF-7中转录因子STAT3的磷酸化,且效果优于10μmol·L-1姜黄素。分子对接模拟也显示,类似物CN1可能通过与STAT3蛋白的SH2结构域结合而影响STAT3的磷酸化。类似物CN1的理化特性符合类药五规则和Veber规则。结论:新型N-异丙基哌啶酮类单羰基姜黄素类似物是一类有前景的抗乳腺癌小分子先导物。     

姜黄素衍生物的合成方法研究进展

姜黄素是姜科和天南星科植物中广泛存在的一种色素,具有抗肿瘤、抗炎、抗氧化等活性,毒性低,但其临床应用因稳定性差、生物利用度低而受到限制。近年来,对姜黄素衍生物的合成方法主要分为两类,一是改变姜黄素的哥二酮结构或苯环结构,设计合成其类似物;二是在姜黄素结构中引入其他活性小分子。通过以上结构改造,能够有效改善姜黄素的稳定性、溶解度及生物活性,为其临床应用创造了良好的前景。     

萘环类姜黄素类似物的合成及其对HepG2细胞株的增殖抑制活性

目的：合成萘环类姜黄素类似物并研究其对人肝癌（ HepG2）细胞的增殖抑制作用。方法以萘酚为原料,合成了4种萘环类姜黄素类似物,并采用噻唑蓝（ MTT）法测定对人肝癌细胞的增值抑制作用。结果6-羟基取代的萘环姜黄素类似物对人肝癌细胞的增殖抑制活性最强,其半抑制浓度（ IC50）达到了20μmol · L-1,与姜黄素相比提高了近2倍。结论6-羟基取代的萘环姜黄素类似物对人肝癌细胞具有良好的增殖抑制活性。     

白藜芦醇衍生物及类似物的研究进展

分类综述白藜芦醇衍生物和类似物的生理药理活性及其构效关系，其中包括羟基类似物及甲基化和酯类衍生物等。白藜芦醇衍生物和类似物与白藜芦醇一样具有多种生理药理活性，其中有些化合物的活性、选择性及稳定性均要强于白藜芦醇，故备受关注，成为近些年的研究热点。     

含氮姜黄素衍生物的合成及抗肿瘤活性研究

目的 合成具有新结构骨架的含氮姜黄素类抗肿瘤化合物并考察目标化合物的体外抗肿瘤活性.方法 以姜黄素和查耳酮为先导物,利用药效团和骨架迁越原理,设计并合成一系列含碱基的姜黄素类似物.选取人肺癌细胞(A-549)和人胃癌细胞(SGC-7901)对所合成的新化合物进行体外抗肿瘤活性筛选.并且用Discovery Studio...     

1-烷基-6-氟-1,4-二氢-7-(4-酰基-1-哌嗪基)-4-氧代喹啉-3-羧酸类似物的合成及其抗菌活性

目的 设计合成具有广谱抗菌活性的含氟喹诺酮类化合物。方法 利用吡酮酸7位哌嗪基4位氮上存在的活性氢为反应修饰基点，与磺酰氯，酰氯，氯甲酸酯进行Schotten-Baumann酰基化反应设计合成一系列含有磺酰基、酰基和烷氧羰基类氟喹诺酮类似物。结果 合成了20个含有磺酰基、酰基和氧羰基的氟喹诺酮类似物，利用元素分析、核磁共振进行了结构确认。结论 合成了16个未见报道的新化合物，初步体外活性测试结果表明，其中的4个化合物有较高的生物活性。     

五味子丙素类似物合成的研究—— Ⅱ.4,4′-二甲氧基-5,6,5′,6′-二次甲二氧基-2,2′-二甲氧羰基联苯及其异构体的合成

在合成五味子丙素及共类似物的过程中,合成一些联苯中间体。其中4,4′-二甲氧基-5,6,5′,6′-二次甲二氧基-,2′-二甲氧羰基联苯经药理筛选具有降高血清谷丙转氨酶效果。本文报道上述联苯及其异构体的合成分离和有关光谱数据。     

抗病毒药拉米夫定及其类似物合成研究概况

目的综述抗病毒药拉米夫定 ( 3TC)及其类似物 ( - ) FTC的化学合成、药理活性研究进展。方法依据国内外有代表性的文献 ,对拉米夫定及其类似物 ( - ) FTC的化学合成、药理活性进行整理和归纳。结果明确了拉米夫定的合成工艺路线、作用机制等方面的情况。结论近年在抗爱滋病手性化合物的研发方面取得了很大进展 ,手性药物拉米夫定可利用作者所示的路线C进行定向合成     

姜黄素金属配合物的合成、表征和抗肿瘤活性研究

目的:合成和表征了4个姜黄素的金属配合物,并对其抗肿瘤活性进行初步的研究.方法:以姜黄素为配体合成其乙酰丙酮氧钒、锌、铜、锡的配合物,用红外光谱、紫外光谱、元素分析对配合物进行了表征,并进行体外抗肿瘤活性初步筛选.结果:合成了4个姜黄素的金属配合物,并确定其结构.结论:药理活性筛选结果表明,多个配合物对肿瘤K562,HL-60细胞有效,部分配合物显示了较强的抗癌活性.     

姜黄素衍生物的药理活性及构效关系研究进展

姜黄素具有抗肿瘤、抗炎、抗氧化、抗抑郁和抑制组织因子等多种药理作用.本文综述了近几年姜黄素衍生物药理活性的研究现状,论述了姜黄素及其衍生物的结构与其抗氧化、抗炎和抗肿瘤的药理作用的关系,为姜黄素的开发利用提供基础.     

姜黄素的水溶性药物递送系统的研究进展

天然活性产物姜黄素具备良好的药理学、药效学活性及用药安全性,近年来其抗肿瘤活性成为研究热点,但是姜黄素水溶性差、易降解、生物利用度低的特点限制了其应用。因此姜黄素水溶性剂型的研制与开发成为解决其临床应用的一种有效途径,本文对近年来姜黄素新剂型的研究进展进行概述。     

Asymmetrical mono-carbonyl ferrocenylidene curcumin and their dihydropyrazole derivatives: Which possesses the highest activity to protect DNA or scavenge radical?

A series of asymmetrical mono-carbonyl ferrocenylidene curcumin and their dihydropyrazole derivatives were synthesized. Their antioxidant abilities in protecting DNA against 2,2′-azobis(2-amidinopropane hydrochloride)-induced oxidation and scavenging 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS) radical were evaluated. In synthesis, the Michael addition reactions between phenylhydrazine and asymmetrical ferrocenylidene curcumin derivatives exhibit evident regioselectivity. The direction of addition depends on whether the benzene ring is substituted or not. The antioxidant abilities of compounds will increase when the ferrocenyl group is introduced. Moreover, such improvement derived from ferrocenyl group is also related to other substituent groups in molecule, not independent. Interestingly, p-dimethylamino group which is never considered as an active group, however, exhibits the best activity in protecting DNA and scavenging ABTS radical.     

Arylnitro monocarbonyl curcumin analogues: Synthesis and in vitro antitubercular evaluation

Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting Mycobacterium tuberculosis (M.tb) and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is, however, unstable, and several analogues, noticeably monocarbonyl analogues, have been synthesized to overcome this challenge. Curcumin and its monocarbonyl analogues reported so far exhibit moderate antitubercular activity in the range of 7 to 16 μM. Herein, we report a straightforward synthesis of novel monocarbonyl curcumin analogues, their antitubercular activity, and the structure–activity relationship. The hit compound from this study, 3a , exhibits potent MIC₉₀ values in the range of 0.2 to 0.9 μM in both ADC and CAS media.     

姜黄素纳米凝胶的制备及其应用研究进展

姜黄素是从姜黄根茎中提取分离得到的黄色多酚类化合物,具有抗肿瘤、抗炎、抗菌、抗氧化等广泛的药理活性。但由于其稳定性、水溶性差,生物利用度低等缺点严重地限制了姜黄素的治疗应用。纳米凝胶在改善姜黄素的溶解度、生物相容性、稳定性、靶向性和治疗效果方面均表现出良好的潜力。本文对姜黄素纳米凝胶的制备方法及其在肿瘤防治、创面治愈、炎症治疗和眼部给药等领域的应用进行综述,为姜黄素的进一步临床研究和应用开发提供文献参考。     

Effects of Novel Diarylpentanoid Analogues of Curcumin on Secretory Phospholipase A2, Cyclooxygenases,Lipo‐oxygenase,and Microsomal Prostaglandin E Synthase‐1

Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti‐inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A₂, cyclooxygenases, soybean lipo‐oxygenase as well as microsomal prostaglandin E synthase‐1. Among the curcumin analogues, compounds 3 , 6 , 9 , 12, and 17 exhibited strong inhibition of secretory phospholipase A₂ activity, with IC₅₀ values ranging from 5.89 to 11.02 μm . Seven curcumin analogues 1 , 3 , 6 , 7 , 9 , 11, and 12 showed inhibition of cyclooxygenases‐2 with IC₅₀ values in the range of 46.11 to 94.86 μm , which were lower than that of curcumin. Compounds 3 , 6 , 7 , 12, and 17 showed strong inhibition of lipo‐oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase‐1 activity revealed that four diarylpentanoid curcumin analogues 5 , 6 , 7 , and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase‐1 activity with IC₅₀ ranging from 2.41 to 4.48 μm , which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti‐inflammatory agents.     

Immunomodulatory effects of diarylpentanoid analogues of curcumin

Diarylpentanoid analogues of curcumin are known for their various pharmacological activities which include the inhibition of inflammatory mediators and are good candidates as immunomodulators that could be useful in the treatment of inflammation. In the work described here, seventeen diarylpentanoid curcumin analogues were assessed for their inhibitory effects on the reactive oxygen species (ROS) production, chemotaxis and phagocytosis of human neutrophils. ROS production was evaluated using luminol and lucigenin-based chemiluminesence assay, while inhibition of isolated polymorphonuclear neutrophils chemotaxis and phagocytosis abilities were investigated using the Boyden chamber technique and the Phagotest kit, respectively. Two of the analogues, compounds 1e and 2e, which contain the 2-methyl-4(N-ethyl-N-ethylacetonitrile)aniline functional group, were active in all the assays performed. Moreover, analogues containing heteroatoms (1a, 1e, 2c, 2d, 2e, 3a and 3c) were active in suppressing the neutrophil phagocytic activity. The information obtained gave new insight into curcumin analogues with the potential to be developed as new immunomodulators.     

Structure-activity relationships for the inhibition of lipid peroxidation and the scavenging of free radicals by synthetic symmetrical curcumin analogues

A number of ring substituted analogues of curcumin were synthesized. Their antioxidant properties were studied using three models, inhibition of lipid peroxidation, scavenging of 1,1'-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethyl-benzthiazoline-6-sulphonate radical (ABTS+.). In all the models, the phenolic analogues were more active than the non-phenolic analogues, some of which were inactive. The highest antioxidant activity was obtained when the phenolic group was sterically hindered by the introduction of two methyl groups at the ortho position. This and several other compounds were more active than the standard antioxidants alpha-tocopherol and trolox. This study has demonstrated that the phenolic group is important for the antioxidant activity of curcumin and that the structural features that enhance the antioxidant properties of phenols are optimized in curcumin to a significant extent.     

姜黄素及其类似物辅助奥沙利铂治疗的研究进展

奥沙利铂（oxaliplatin,OXA）为第三代铂类抗肿瘤药物,因其高效的抗肿瘤特性,目前已被广泛用于治疗以结直肠癌为主的各种人类恶性肿瘤。但OXA的应用仍存在一定的不良反应：如神经毒性、骨髓抑制、胃肠道反应、肝损伤等,同时由于部分肿瘤会产生对OXA的耐药性,使其治疗效果受到影响。姜黄素是一种来源于植物姜黄并具有抗肿瘤、抗氧化等多种药理活性的单体物质。近年来的系列研究表明,姜黄素及其合成类似物与奥沙利铂联用,可增强OXA细胞毒性并提升抗肿瘤效果,同时姜黄素还可发挥抑制血管生成和侵袭转移、减弱肿瘤细胞耐药性和减轻OXA氧化损伤等作用。本文综述了姜黄素和OXA联合使用的体内外抗肿瘤研究结果,并阐明可能的相关机制,为姜黄素类物质增益OXA治疗提供了有效证据。