SK119, a Novel Shikonin Derivative,Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC₅₀ values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy.     

N-苄基吲哚类熊果酸衍生物的合成及抗肝癌活性

为开发高效低毒的抗肝癌天然产物衍生物,依据药物拼合原理设计并合成了一系列未见文献报道的熊果酸衍生物.将熊果酸与不同取代的N-苄基吲哚片段通过Claisen-Schmidt缩合反应得到目标化合物,其化学结构均经过核磁氢谱、核磁碳谱以及质谱的联合确证.采用噻唑蓝(MTT)法考察其体外抗肝癌活性,结果表明,2-{[1-(2-...     

新疆紫草的超声波强化提取

对新疆紫草色素进行了超声提取的研究,探讨了超声波功率、液固比、提取温度、原料粒度和超声作用时间对色素提取效果的影响,得到超声提取新疆紫草色素的优化工艺参数为：80目(180 mm)的新疆紫草根粉末,液固比为12 mg/L,在50℃水浴中超声处理25 min,超声波功率1800 W,提取率可达到87%.     

罗丹明衍生物合成新方法

以N ,N -二乙基间氨基苯酚 ,对羧基苯甲醛为原料 ,合成了两种新的罗丹明衍生物 ,这种合成方法获得的产物单一 ,避免了在罗丹明染料通常的合成工艺中产生 5 ,和 6 ,位异构体混合产物 ,减少了繁琐的分离纯化工序 ,降低了制备成本 ,该合成方法操作简便 ,产率优良 (总收率≥ 90 % )。     

新型邻甲酰胺基苯甲酰胺衍生物的合成与生物活性研究

合成了9个新型邻甲酰胺基苯甲酰胺衍生物,其结构经1H NMR进行确证。初步杀虫、杀螨活性测试表明所合成的化合物在1 000 mg/L浓度下对磷翅目的粘虫(Mythimna separata)有100%的致死率。在500 mg/L浓度下,大多化合物对同翅目的蚕豆蚜(Aphis fabae)以及稻黑尾叶蝉(Nephotettix cincticeps)具有明显活性,如化合物3-溴-1-(3-氯-2-吡啶基)-N-[4-氯-2-甲基-6-[((3,3-二氯烯丙氧基)氨基)羰基]苯基]-1H-吡唑-5-甲酰胺(14c)对蚕豆蚜的致死率达到89.29%;化合物14b对叶蝉的致死率达到81.82%。在500 mg/L浓度下,所合成化合物对蜱螨目棉红蜘蛛(Tetranchus urticae)没有表现出明显活性。     

5-硝基靛红衍生物的合成

以靛红为原料,经过硝化和亲核取代,合成了3个N取代5-硝基靛红衍生物,其结构经1H NMR、13C NMR、MS分析确认。     

Mannich反应合成新型氮杂环取代岩白菜素衍生物

岩白菜素分别与四氢吡咯和哌啶经Mannich反应,合成得到2个新的氮杂环取代岩白菜素衍生物(2a,2b)。考察了溶剂、温度和时间等因素对反应的影响。在优化反应条件下,2a和2b的合成收率分别为48%和44%。     

Mitsunobu反应合成新型岩白菜素含氮衍生物

岩白菜素分别与四氢吡咯和二乙胺经Mitsunobu反应,得到2个新的岩白菜素含氮衍生物(2a,2b),并对反应条件进行了优化。优化条件为:偶氮二甲酸二异丙酯为偶氮试剂,n(岩白菜素)∶n(偶氮二甲酸二异丙酯)∶n(仲胺)=1∶1.5∶2,反应温度45℃,优化反应条件下合成收率分别为54%和48%。     

Effect of Antibiotic Amphotericin B Combinations with Selected 1,3,4-Thiadiazole Derivatives on RPTECs in an In Vitro Model

4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (C1) and 4-[5-(naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-yl] benzene1,3-diol (NTBD) are representative derivatives of the thiadiazole group, with a high antimycotic potential and minimal toxicity against normal human fibroblast cells. The present study has proved its ability to synergize with the antifungal activity of AmB. The aim of this work was to evaluate the cytotoxic effects of C1 or NTBD, alone or in combination with AmB, on human renal proximal tubule epithelial cells (RPTECs) in vitro. Cell viability was assessed with the MTT assay. Flow cytometry and spectrofluorimetric techniques were used to assess the type of cell death and production of reactive oxygen species (ROS), respectively. The ELISA assay was performed to measure the caspase-2, -3, and -9 activity. ATR-FTIR spectroscopy was used to evaluate biomolecular changes in RPTECs induced by the tested formulas. The combinations of C1/NTBD and AmB did not exert a strong inhibitory effect on the viability/growth of kidney cells, as evidenced by the negligible changes in the apoptotic/necrotic rate and caspase activity, compared to the control cells. Both NTBD and C1 displayed stronger anti-oxidant activity when combined with AmB. The relatively low nephrotoxicity of the thiadiazole derivative combinations and the protective activity against AmB-induced oxidative stress may indicate their potential use in the therapy of fungal infections.     

N-取代苯基酞酰亚胺新化合物的合成与生物活性研究

选择原卟啉原氧化酶抑制剂N-苯基酞酰亚胺类衍生物作为主要研究方向,以对氟(氯)苯酚、四氢邻苯二甲酸酐、不同取代的卤代化合物等为原料,通过氯化、保护、硝化、去保护、还原、醚化、缩合等一系列化学反应合成了18个N-取代苯基酞酰亚胺类新化合物。按照国家南方农药创制中心江苏基地生测SOP,以苘麻、反枝苋、藜、稗草、马唐、狗尾等6种不同单双子叶杂草为生物靶标,对这些化合物进行除草活性筛选,发现其中14个化合物对阔叶杂草具有A级生物活性。     

Design,Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach

To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core‐scaffold‐modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R‐, S‐, and 2‐ and 6‐isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor‐inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells.     

Synthesis,In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

A novel class of potential protein kinase inhibitors 7–16 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC₅₀ values for compounds 7 and 10 were 2.27 and 2.53 μM for K562 cells, 1.42 and 1.52 μM for HL-60 cells, and 4.56 and 24.77 μM for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase, preventing the cell division of OKP-GS cells. Compounds 7, 9, and 10 showed 36–45% inhibitory activity against PDGFRα and PDGFRβ at the concentration of 1 μM. Molecular modeling experiments showed that obtained compounds could bind to PDGFRα as either type 1 (compound 7, ATP-competitive) or type 2 (compound 10, allosteric) inhibitors, depending on the substituent in the amide part of the molecule.     

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4-(4-morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′-tetrachloro-1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.     

香豆素及其衍生物研究进展

香豆素类衍生物因具有重要的生物活性而受到人们的普遍关注,综述了香豆素、4-羟基香豆素类衍生物、香豆素类荧光染料等香豆素类衍生物的合成方法,展望了香豆素类衍生物良好的发展前景。     

Synthesis and Biological Evaluation of New Geiparvarin Derivatives

New geiparvarin derivatives modified at the alkenyloxy bridge, where the 3′‐methyl group was replaced by a hydrogen atom, were synthesized and evaluated against a panel of human tumor cell lines in vitro. Compounds (R)‐ 4 and (R)‐ 5 show greater inhibitory activity toward cell growth than the parent geiparvarin.

     

二茂铁衍生物的合成及溶致变色效应

报道了一组具有非线性光学活性的二茂铁衍生物的合成以及这些化合物关不同极性溶剂中的溶致变色效应。     

2-氯烟酸及其衍生物的合成

探索了从烟酸出发合成 2 氯烟酸及其衍生物的方法 ,实验表明 ,这些方法原料易得 ,产物的收率高 ,易于实现工业化生产 ,具有重要实用价值     

4-取代氨基喹唑啉类化合物的研究进展

综述了4-取代氨基喹唑啉类化合物的几种主要的合成方法,主要包括以2-氨基苯甲酸、2-氨基苯甲腈、2-氨基苯甲酰胺、2-氨基苯甲酸脂、苯甲醛等为原料的合成方法,并对这些方法进行简单的评价。