Despite significant advances in cancer treatment in recent years, existing therapies still exhibit notable limitations. Consequently, the continuous development of novel anticancer agents remains paramount. Natural products remain the major source for discovering highly effective and low-toxicity anticancer drug leads. Isoalantolactone, a natural product, demonstrates diverse pharmacological activities, including anti-inflammatory and anticancer effects, but suffers from drawbacks such as poor water solubility, necessitating structural modifications. The enzyme Poly (ADP-ribose) polymerase 1 (PARP1) is a key therapeutic target in breast cancer and its inhibition represents a vital advancement in cancer treatment. In this study, in silico molecular docking was employed to identify binding sites between isoalantolactone and the PARP1 protein. Subsequently, thirty-four of isoalantolactone-benzylamine derivatives were synthesized. Among them, compound ‌ 3-(((3,4,5-trimethoxybenzyl)amino) methyl)-3-demethylene isoalantolactone (3f) exhibited potent inhibitory activity against MCF-7 cells (IC50 = 3.67 μM), which represented a ∼ 7-fold improvement over isoalantolactone itself and demonstrated markedly enhanced solubility. And, MCF-7 cancer cells take up 3 f from the culture environment much more efficiently than L-02 normal cells. The molecular docking results showed that 3 f binds to PARP1 through multiple interactions, exhibiting significantly more interaction bonds than isoalantolactone, and ELISA assays confirmed that 3 f potently inhibits intracellular PARP1 of MCF-7 cancer cells. Moreover, 3 f suppresses the enzymatic function of PARP1 and inhibits the PARP1-mediated DNA damage repair pathway by elevating γH2AX expression levels. In vitro, compound 3 f exhibited significant dose-dependent anti-cancer activity, inhibiting MCF-7 cancer cell migration, invasion, COL1 protein expression and colony formation. It also significantly elevated intracellular reactive oxygen species (ROS) levels in MCF-7 cancer cells. Additionally, 3 f markedly decreased the mitochondrial membrane potential of MCF-7 cells, which may have led to their apoptosis and death. These findings suggest that 3 f acts as a novel PARP1 inhibitor and holds considerable promise for future breast cancer therapy.

Interleukin-2 (IL-2) is a potent mediator of T-cell activation with significant potential for cancer immunotherapy, yet its clinical utility is severely constrained by its narrow therapeutic window. Here we report a chemically masked IL-2 prodrug (Cm-proIL2) that enables tumor-microenvironment-responsive cytokine activation through tumor-associated protease cleavage. Site-specific conjugation of a poly-(ethylene glycol) (PEG) moiety selectively masks peripheral receptor engagement, while PEG removal within the tumor microenvironment restores IL-2 receptor binding and reduces molecular size, thereby enhancing intratumoral lymphocyte penetration and effector T cell functionality. Building on this modular platform, we further engineered a PD-1-targeted nanobody fusion, PD1-Cm-proIL2, to enable the cis delivery of IL-2 activity to PD-1+ tumor-infiltrating T cells. PD1-Cm-proIL2 induces robust antitumor immunity, resulting in complete tumor regression and durable protection upon tumor rechallenge in a murine colorectal cancer model. Together, these findings demonstrate the feasibility of chemically masked, tumor-responsive cytokine activation as a strategy for improving the therapeutic index of IL-2-based immunotherapies.

Objective: This study aimed at synthesizing 13 series of novel derivatives with 2-phenylacrylonitrile, evaluating antitumor activity both in vivo and in vitro, and obtaining novel tubulin inhibitors. Method: The 13 series of 2-phenylacrylonitrile derivatives were synthesized by Knoevenagel condensation and the anti-proliferative activities were determined by MTT assay. The cell cycle and apoptosis were analyzed by flow cytometer. Quantitative cell migration was performed using 24-well Boyden chambers. The proteins were detected by western blotting. in vitro kinetics of microtubule assembly was measured using ELISA kit for Human β-tubulin (TUBB). Molecular docking was done by Discovery Studio (DS) 2017 Client online tool. Results: Among the derivatives, compound 1g2a possessed strong inhibitory activity against HCT116 (IC50 = 5.9 nM) and BEL-7402 (IC50 = 7.8 nM) cells. Compound 1g2a exhibited better selective antiproliferative activities and specificities than all the positive control drugs, including taxol. Compound 1g2a inhibited proliferation of HCT116 and BEL-7402 cells by arresting them in the G2/M phase of the cell cycle, inhibited the migration of HCT116 and BEL-7402 cells and the formation of cell colonies. Compound 1g2a showed excellent tubulin polymerization inhibitory activity on HCT116 and BEL-7402 cells. The results of molecular docking analyses showed that 1g2a may inhibit tubulin to exert anticancer effects. Conclusion: Compound 1g2a shows outstanding antitumor activity both in vivo and in vitro and has the potential to be further developed into a highly effective antitumor agent with little toxicity to normal tissues.

Protein recognition using host-guest recognition approach is of great interest but has been limited mainly to the protein N-terminal residues. Here, we site-specific incorporated two novel non-canonical amino acids containing supramolecular guest motifs into protein via an expanded genetic code. Through Staudinger reduction reactions, the encoded unnatural residues on protein becoming activated and can be specifically recognized by cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]). We demonstrated that enzyme containing guest amino acid incorporated near the active site can be reversibly regulated by CB[7] recognition, and CB[8] recognition induces protein dimerization. These amino acids will make useful addition to the supramolecular toolbox for protein targeting using molecular recognition approaches.

Combretastatin A-4 (CA-4) is a potent tubulin polymerisation inhibitor. However, the clinical application of CA-4 is limited owing to its low aqueous solubility and the easy conversion of the olefin double bond from the more active cis- to the less active trans-configuration. Several structural modifications were investigated to improve the solubility of CA-4 derivatives. Among the compounds we synthesized, the kinetic solubility assay revealed that the solubility of compounds containing a piperazine ring increased the most, and the solubility of compounds 12a1, 12a2, 15 and 18 was increased 230–2494 times compared with that of the control compound (Z)-3-(4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (9a). In addition, these synthesised stilbene nitriles had high anticancer cell (AGS, BEL-7402, MCF-7, and HCT-116) selectivity over L-02 and MCF-10A normal cells while maintaining micromolar activity against cancer cells. The most cytotoxic compound is 9a, and the IC50 value is 20 nM against HCT-116 cancer cells. Preliminary studies indicated that compound 12a1 had excellent plasma stability and moderate binding to rat plasma proteins, suggesting it is a promising lead compound for the development of an anticancer agent.

OBJECTIVE To design and synthesize a novel set of 20 stilbenenitrile sulfonamide derivatives based on combretastatin A-4（CA-4） and ABT-751 possessing high potency and low toxicity. METHODS The anti-proliferation activity and toxicity of these compounds were evaluated by MTT assay with five kinds of cancer cell lines and two normal cell lines, and the candidates were selected out. Then the cell cycle and apoptosis assays were carried out and the effect of the candidate on the expressions of VEGF and MMP-9 were evalusted. RESULTS A majority of compounds demonstrated potent anti-proliferation activity in five kinds of tumor cell lines. Particularly, the compound 8h exhibited the most potent anticancer activity in MCF-7 cancer cell line(IC 50 =8.7 μmol·L -1 ), but low toxicity on normal human breast cell MCF-10A(IC 50 ＞100 μmol·L -1 ), which showed a selectivity. Simultaneously, compound 8h inhibited the proliferation of MCF-7 by arresting at the G 2 /M phase. In addition, the inhibition of VEGF expression of compound 8h was concentration-dependent under hypoxia and normoxia and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. Synchronously, the inhibition of MMP-9 expression of compound 8h was concentration-dependent and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. CONCLUSION Compound 8h are worthy of further study as an efficient and low-toxicity anti-breast cancer drug.

OBJECTIVE To obtain novel candidate compounds with safety and good anticancer activity. METHODS Using substituted acetophenone and substituted aromatic aldehydes as the starting materials, chalcone was synthesized by Claisen-Schmidt condensation reaction, and then 17 compounds were synthesized by reacting with hydrazine hydrate and chloroacetyl chloride successively. The structures of these compounds were confirmed and their anticancer and antibacterial activities were detected in vitro. RESULTS The results of biological activity test showed that the compounds 4a-4h had good anticancer activity in vitro, and exhibited different inhibitory activity against cancer cells of different origin. The IC50 values of compound 4a against human colorectal cancer cell HCT116 was 1. 1μmol·L–1. The IC50 values of compound 4c against human hepatoma cell BEL-7402 was 4. 8 μmol·L–1.The IC50 values of compound 4b against human cervical cancer cell HeLa was 13. 2 μmol·L–1, and the inhibitory effect was stronger. CONCLUSION Some of the synthesized target compounds showed good anticancer activity and cell selectivity,which has the potential to develop new anticancer drugs.

中药川芎中主要含有苯酞类、酚酸类、生物碱类及多糖类等化学成分.药理学研究表明,川芎具有镇痛、对血管内皮细胞增殖的促进作用和再灌注损伤的保护作用、抗炎、对心脑血管系统的保护作用等多种生物活性.川芎的提取方法主要包括超声波提取法、微波辅助萃取法和超临界流体萃取法等.本文综述川芎的化学成分、药理作用及提取工艺的研究进展,为川芎的药效物质基础和作用机制等研究提供参考.

为了寻找安全且具有良好抗菌效果的防腐剂,本文设计合成了8个厚朴酚衍生物,并评价其抗菌活性及对四种正常细胞的毒性,同时测定其水溶性.结果表明,化合物3a对耐甲氧西林金黄色葡萄球菌3167与白色念珠球菌7535等6种菌的抗菌活性明显优于厚朴酚,三种化合物2a、5a及8a的抗菌效果优于或相当于厚朴酚.7个化合物对正常细胞的毒性很低,化合物5a等5个化合物的水溶性高于厚朴酚.作为天然防腐剂,化合物3a具有值得进一步研究的价值.

The amide intermediates 5a similar to 5j were prepared by acylation, which used 2-thiopheneethylamine and several self-synthetic chalcone acids as starting materials. Then ten dihydrothiophenopyridine-chalcone derivatives 6a similar to 6j which haven't been reported before were synthesized by Bischer-Napieralski cyclization reaction from the intermediates. In addition, two new thiophenopyridine-chalconone derivatives 7a and 7b were obtained by further dehydrogenation. The anti-cancer activity and safety in vitro of 11 kinds of cells were evaluated by methyl thiazolyl tetrazolium (MTT) assay. The results indicated that the compounds 6a (p-F), 6d (o-Br) and 6h (m-OCH3) exerted better anticancer activity against HeLa and SGC-7901 cells than taxol. When treating cells for a short time (<4 h), 6j (3,4,5-(OCH3)(3)) showed strong anticancer activity against MCF-7 cancer cell but displayed little toxicity on normal breast cell MCF-10A. Hence, 6j deserves further research and exploitation.

刘雅雪 陈志豪 秦 巍 田玉顺 * (延边大学药学院 长白山天然药物研究教育部重点实验室 吉林延吉 133002) 摘要 以 2-噻吩乙胺与自制的查尔酮酸进行酰化反应得到酰胺类中间体 5a～5j, 经 Bischer-Napieralski 环合反应合成了 10 个未见报道的二氢噻吩并吡啶-查尔酮衍生物 6a～6j, 再经去氢反应获得 2 个噻吩并吡啶-查尔酮衍生物 7a 和 7b.通 过噻唑蓝(MTT)法对 11 种细胞进行体外抗癌活性及安全性测试.

白藜芦醇(RSV)是存在于浆果、葡萄、虎杖等多种植物中的一种二苯乙烯结构,是A环的C3及C5位和B环的C4'位分别有酚羟基的2个苯环通过一个乙烯基相连的结构(图1中的RSV).因2个苯环间有乙烯基,所以白藜芦醇具有2种几何异构体,即cis-与trans-.天然的白藜芦醇一般是trans-构型(图1中的RSV所示构型),当trans-构型被紫外线或可见光照射时可发生光异构化现象而生成cis-构型,但cis-构型不稳定且无市售的产品[1-2].白藜芦醇在抗炎、抗癌和抗氧化等诸多方面具有广泛的功效[3].因天然白藜芦醇具有较差的水溶性、生物利用度、化学稳定性及活性,且它的代谢速度较快,所以很多学者就着手研究它的衍生物以寻找理想的化合物并已发现诸多类似物,如反式-3,4,5,4'-四甲氧基二苯乙烯等[4-5].虽然白藜芦醇及其类似物在实验室阶段具有良好的功效,但尚未开发出有特定功效的药物,目前市售的还是以白藜芦醇保健品类为主.随着科技的发展,不断涌现出新的靶点基因和蛋白质,而且测定技术也越来越先进,这对发现药物的新作用机制方面有重要意义.本文对白藜芦醇及其衍生物的药物开发可能性的研究进展进行了综述.

[目的]获得安全并具有良好抗肝癌细胞活性的新型候选化合物.[方法]合成一系列含芳基酰胺考布他汀衍生物并验证其结构,采用MTT法检测所合成的化合物对人肝癌细胞株BEL-7402和HepG-2及人正常肝细胞L-02的抗增殖活性.[结果]所合成的一系列含芳基酰胺考布他汀衍生物中多数化合物对人肝癌细胞株BEL-7402表现出良好的抑制活性,其中(Z)-N-(4-(2-氰基-2-(3,4,5-三甲氧基苯基)乙烯基)苯基)-3,4,5-三甲氧基苯甲酰胺(8g)显示出最佳的抗肝癌细胞活性,且对人正常肝细胞的毒性较小.[结论]所合成的化合物8g具有良好的抗肝癌细胞活性.

Ketocalix[3]carbazole, a facilely synthesized rigid “basket” capable of sensing baicalin.

为了寻找高效的潜在抗肿瘤药物,设计合成Idelalisib类似物并测定其抗肿瘤活性.以2-氟-6-硝基苯甲酸为起始原料,经缩合、还原、脱保护和胺化反应等5步反应合成目标化合物,并采用MTT法对所合成的化合物进行抗肿瘤活性的测定.所有的目标化合物结构均经氢谱和高分辨质谱进行确证.其中,(S)-2-(2-((9H-嘌呤-6-基)氨基)-3-苯基丙酰胺基)-6-氟-N-苯基苯甲酰胺的抗肿瘤活性最强,它对4种肿瘤细胞的抗肿瘤活性均优于阳性对照药物Idelalisib,具有后续研究的价值.

以4-三氟甲基苯甲酸和3,4,5-三甲氧基苯甲酸为原料合成出2-(4-(三氟甲基)苯基)乙腈和2-(3,4,5-三甲氧基苯基)乙腈,将其作为中间体和几种醛类合成一系列含4-三氟甲基及3,4,5-三甲氧基二苯乙烯腈衍生物.所合成的化合物通过氢谱、碳谱与高分辨质谱进行表征后用MTT法在12种细胞上测得其细胞增殖抑制率,其中(Z)-3-(4-丙氧基苯基)-2-(3,4,5-三甲氧基苯基)丙烯腈显示最好的抗癌活性及选择性抑制活性,经进一步研究发现通过抑制细胞迁移与抑制集落形成达到抗癌效果,具有进一步开发研究的价值.

A series of novel oridonin derivatives bearing various substituents on the 14-OH position were designed and synthesised. Their antitumour activity was evaluated in vitro against three human cancer cell lines (HCT116, BEL7402, and MCF7). Most tested derivatives showed improved anti-proliferative activity compared to the lead compound oridonin and the positive control drug 5-fluorouracil (5-Fu). Among them, compound C7 (IC50 = 0.16 μM) exhibited the most potent anti-proliferative activity against HCT116 cells; it was about 43- and 155-fold more efficacious than that of oridonin (IC50 = 6.84 μM) and 5-Fu (IC50 = 24.80 μM) in HCT116 cancer cells. Interestingly, the IC50 value of compound C7 in L02 normal cells was 23.6-fold higher than that in HCT116 cells; it exhibited better selective anti-proliferative activity and specificity than oridonin and 5-Fu. Furthermore, compound C7 possibly induced cell cycle arrest and apoptosis by regulating the p53-MDM2 signalling pathway. Notably, C7 displayed more significant suppression of tumour growth than oridonin in colon tumour xenograft models where the tumour growth inhibition rate was 85.82%. Therefore, compound C7 could be a potential lead compound for the development of a novel antitumour agent.

Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. Most of the derivatives tested here exhibited improved antiproliferative activity with high selectivity when compared with the parent compound isosteviol and the positive control drug 5-fluorouracil. Among these derivatives; compound 5d exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells. In addition; compound 5d inhibited the colony formation of HCT-116 cells in a concentration-dependent manner. Further studies revealed that compound 5d arrested the HCT-116 cell cycle in the S phase; and western blot analysis demonstrated the mechanism may be correlated with a change in the expression of cyclin A; cyclin B1; and cyclin E1. Furthermore; the results of a docking study that involved placing compound 5d into the CDK2/cyclin A binding site revealed that its mode of action was possibly as a CDK2/cyclin A inhibitor.

Eighteen novel 2,3‐diphenyl acrylonitrile derivatives bearing halogens were designed, synthesized, and evaluated for biological activity. Preliminary in vitro results indicated that the majority of the compounds with apara‐substituted halogen had considerable antiproliferative activity against five human cancer cell lines, includingMGC‐803,AGS, andBEL‐7402, withIC50values in the range of 0.46–100 μm. No significant toxic effects on the non‐cancerous human liver cell line L‐02 were observed. The selective inhibitory activities against cancer cells were significantly better than that of the control lead compoundCA‐4 andCA‐4P. Particularly, potent activities were found for the derivatives of 3‐(4‐halogen phenyl)‐2‐(3,4,5‐trimethoxyphenyl)acrylonitrile, such as5c(4‐fluoro),5f(4‐bromo),5h(4‐chloro), and5k(4‐trifluoro‐ methyl), forAGSwithIC50values of 0.75 ± 0.24, 0.68 ± 0.21, 0.41 ± 0.05, and 1.49 ± 0.92 μm, respectively. The antiproliferative effects of5fwere attributed to cell‐cycle arrest in the G2/M phase, induction of cellular apoptosis, suppression of cell migration, and inhibition of cell colony formation inAGScells.

The aim of the present study was to determine the cytotoxic effects of a series of novel dehydroepiandrosterone derivatives containing triazole at the C16 position on human cancer cells. The cancer cells used in the present study were A549, Hela, HepG-2, BEL7402, MCF-7, and HCT116. Several of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound was (E)-3-hydroxy-16-((1-(4-iodophenyl)-1H-1,2,3-triazole-4-yl)methylene)-10,13-dimet-hyl-1,3,4,7,8,9,10,11,12,13,15,16-dodecahydro-2H-cyclopenta[a]phenanthren-17(14)-one (compound 2n), which showed considerably high antiproliferative activity in the HepG-2 cell line, with an IC50 value of 9.10 µM, and considerably high activity against the MCF-7 cell line, with an IC50 value of 9.18 µM. Flow cytometry assays demonstrated that compound 2n exerted antiproliferative effects by arresting cells in the G2 phase of the cell cycle and inducing apoptosis.