Jiyuan Oridonin A (JOA), a type of ent-kaurene diterpenoid isolated from Jiyuan Isodon rubescens, exhibits well-documented antitumor activity against a broad panel of cancer cell lines. However, the uptake and distribution at the cellular, tissue, and organ levels, as well as the underlying antitumor mechanisms remain poorly reported. We designed and synthesized a novel fluorescent probe B12, which was a derivative of JOA conjugated with naphthalimide dye. B12 exhibited a large Stokes shift and favorable photostability, as well as significantly enhanced antitumor activity against eight cancer cell lines compared with JOA. In particular, the IC50 value against MGC-803 cells was 0.64 ± 0.03 μM. B12 also could inhibit the proliferation and migration of MGC-803 cells, reduce mitochondrial membrane potential and induce apoptosis. Fluorescence imaging showed that it was rapidly internalized and predominantly localized to the endoplasmic reticulum, mitochondria and lysosomes. Further mechanistic studies revealed that B12 induced apoptosis through the mitochondrial pathway and the endoplasmic reticulum stress-mediated PERK/ATF4/eIF-2α/CHOP pathway, along with changes in autophagyrelated protein (LC3/p62) expression. In addition, B12 was mainly distributed in the stomach and upper part of the small intestine in mice. In summary, this study provides a new approach for exploring the imaging properties in tumors and underlying antitumor mechanisms about the fluorescent derivative of JOA.

Antisense oligonucleotides (ASOs) are promising sequence-specific nucleic acid therapeutics for lung cancer, but their clinical translation is hindered by poor serum stability, low cellular internalization, and lack of tumor targeting. Herein, we developed a triple-synergistic strategy integrating 2′-O-methyl (2′-OMe) modification, DOTAP/Chol liposomal (LP) delivery, and dual-end Biotin-PS conjugation to address these bottlenecks. A library of 30 2′-OMe-modified ASOs targeting the HIF1A-AS2/MYC axis was screened, identifying lead candidate B4 (IC₅₀ = 79.24±8.55 nM against H1299 cells) with a 7.6 °C higher Tₘ than unmodified A0, enhancing target binding and serum stability. The DOTAP/Chol LP (≈100 nm, ζ≈60 mV, PDI<0.3) exhibited excellent biocompatibility and in vitro stability. Novel dual-end Biotin-modified B4-4 achieved tumor-selective internalization via caveolin-mediated endocytosis (72.5% uptake in A549 vs. 15.6% in 16HBE cells). In vitro, LP-B4-4 efficiently inhibited H1299 cell proliferation/migration/invasion and silenced HIF1A-AS2/MYC. In H1299 tumor-bearing mice, LP-B4-4 exerted the most potent antitumor efficacy (72.7% inhibition rate) without obvious acute toxicity. This work provides a scalable design paradigm for targeted nucleic acid drug delivery systems in cancer therapy.

Foam cells (FC), recognized as an early biomarker for atherosclerosis, exhibit significant increases in intracellular viscosity and hypochlorous acid (HClO) levels during their formation. Based on the above results, the development of a fluorescent probe responsive to both viscosity and HClO is anticipated to become a crucial tool for the early diagnosis of atherosclerosis. In this study, we chose tetraphenylethylene (TPE) as the chromophore for the fluorescence probe. By leveraging its molecular rotor properties, along with electron-donating and conjugation effects, we successfully developed a near-infrared fluorescence probe. This probe integrates intramolecular twisted charge transfer (TICT) and aggregation-induced emission (AIE) mechanisms to achieve dual responsiveness to viscosity and HClO. Furthermore, we evaluated the probe's efficacy in detecting viscosity and HClO both in vitro and in vivo, including in zebrafish models.

Objective: Based on the observed in vitro antitumor activity, the conformational influence of various substituents at the 2-position of the pyrimidine ring was systematically investigated to develop more effective antitumor pyrimidine analogs. Methods: A series of novel pyrimidine derivatives containing acrylamide and cyano groups were designed and synthesized. Their antiproliferative activities against four human tumor cell lines (MDA-MB-231, MGC-803, PC-3, and A549) were evaluated using the MTT assay. Additionally, colony formation, migration, cell cycle distribution, and apoptosis assays were performed to elucidate the antitumor mechanisms of compound (XVIIIg). Results and Discussion: Compound (XVIIIg) exhibited the strongest inhibitory activity against PC-3 cells, with an IC50 value of 1.50 ± 0.29 μM. Cellular assays confirmed that (XVIIIg) significantly suppressed PC-3 cell proliferation and migration, induced G0/G1 cell cycle arrest, and promoted apoptosis. Structural modifications at the 2-position of the pyrimidine ring had a pronounced effect on in vitro antitumor activity. The 4-fluorophenyl (4-F-C6H4) substituent in compound (XVIIIg) contributed to its superior inhibitory effect, suggesting its potential as a lead compound. Conclusions: Among the 21 synthesized compounds, (XVIIIg) demonstrated the most potent antiproliferative and antimigratory activity, along with dose-dependent apoptosis induction in PC-3 cells. These results highlight its promise as a candidate for further development of novel antitumor agents.

Objective: In order to discover new antitumor small molecules, research has been conducted on quinazoline derivatives to explore potential new compounds. Methods: A series of 2,4,7-trisubstituted quinazoline derivatives containing an aminomethyl piperidine moiety were designed and synthesized. The MTT assay was used to evaluate the inhibitory effect of the compounds on the proliferation of various tumor cell lines (Eca-109, A549, PC-3, MGC-803), and the IC50 values were calculated. Cell cycle analysis, cell migration assays, colony formation assays, and apoptosis assays were performed to investigate the antitumor mechanism of compound (XVIe). Results and Discussion: Compound (XVIe) exhibited the most potent antiproliferative activity against MGC-803 cells, with an IC50 value of 0.74 μM, significantly lower than that of 5-fluorouracil. Additionally, compound (XVIe) effectively inhibited the migration and colony formation of MGC-803 cells, induced G0/G1 phase arrest, and increased ROS accumulation, ultimately leading to apoptosis of MGC-803 cells. Meta-substituents in the benzene ring demonstrated superior antiproliferative activity compared to para- and ortho-substituents. The sequence of antiproliferative activity for the meta-substituted compounds against the four cancer cell lines was: methyl > ethoxy > fluorine ≈ methoxy > chlorine. Conclusions: Compound (XVIe) demonstrated significant antitumor activity and holds potential for further development as an antitumor drug.

The mechanisms underlying the development and progression of clear cell renal cell carcinoma (ccRCC) and its sunitinib resistance are elusive. Fbxo45 is a member of the F-box protein family that has been demonstrated to participate in tumorigenesis. However, the role of Fbxo45 in ccRCC progression has not been characterized. This study aims to investigate the biological functions and molecular mechanism of Fbxo45 in ccRCC progression. We found that Fbxo45 knockdown inhibited the viability and motility of ccRCC cells, while Fbxo45 overexpression resulted in the opposite phenotype. Ectopic expression of Fbxo45 promoted tumor growth in mice. Fbxo45 expression was negatively correlated with Erbin expression, which has been reported to mediate anti-tumor activities in ccRCC. Furthermore, Fbxo45 facilitated ccRCC cell viability and motility by inhibiting Erbin. Notably, Fbxo45 upregulation reduced sunitinib sensitivity in ccRCC cells. Our results suggest that Fbxo45 could be a potential target for ccRCC treatment and sunitinib resistance.

We report the rational design and synthesis of TCR1, a novel dual-responsive fluorescent probe for simultaneous detection of glutathione (GSH) and viscosity. TCR1 uses 2,4-dinitrophenoxy as the GSH reactive moiety and aggregation-induced emission (AIE) core as the viscosity sensing module. It exhibits dual reactions of GSH and viscosity in detection solutions, cell lines, and zebrafish models. It could emit stable high fluorescence in the pH range of 1-10 and is not interfered with by other common biological small molecules, such as amino acids and cations. The probe exhibited negligible cytotoxicity in MCF-10A, A549 and HCT116 cell lines and had good mitochondrial localization ability.

BACKGROUND:Chromosomal rearrangements involving the Mixed lineage leukemia (MLL) gene are observed in acute leukemia (AL) patients, which have poor prognosis, especially in infants. Hence, there is still a challenge to develop other effective agents to treat AL with MLL rearrangements (MLLr). MLL has been shown to rearrange with partner genes, of which the most frequently observed are AF4 and AF9. Moreover, AL is characterized by a differentiation blockage resulting in the accumulation of immature cells. An ent-kaurene diterpenoid compound, Jiyuan Oridonin A (JOA), has been shown to reduce the viability of AML cells by differentiation. METHODS:We aimed to evaluate the effect of JOA on the growth and differentiation of AL cells (SEM, JURKAT and MV4-11) including cells with MLLr-AF4 by cell proliferation assay, colony formation assay, cell cycle analysis, cell apoptosis analysis, measurement of cell surface antigens and cell morphology, mRNA-sequencing analysis, quantitative Real-time PCR and Western blotting analysis. RESULTS:Our findings demonstrated that the proliferation of AL cells including cells with MLLr-AF4 was significantly suppressed by JOA, which induced cell differentiation followed by G0/G1 cell cycle withdrawal. Moreover, JOA-mediated cell differentiation was likely due to activation of G-CSFR in MV4-11 cells. CONCLUSION:Our results suggest that JOA may be considered a promising anti-leukemia compound to develop to surmount the differentiation block in AL patients.

In this study, we designed and synthesized 41 quinazoline derivatives with different base amine termini. Compound 15n showed the best antiproliferation activity against A549 cells with IC50 value of 1.91 μM in four cancer cell lines (MGC-803, PC-3, A549, and Eca-109). In colony, scratch, and apoptosis experiments, compound 15n inhibited proliferation, migration, and apoptosis of A549 cells in a concentration-dependent manner and blocked the cell cycle in the G0/G1 phase. Overall, our study suggests that compound 15n has potential as a lead compound for the development of antitumor drugs.

In this study, a series of novel pyrimidine-phenylsulfonylfuroxan hybrids were designed, synthesized and evaluated for their biological activities. Most of the compounds demonstrated considerable antiproliferative activity against MDA-MB-231 and PC-3 cells. Among them, 21y (IC50 = 0.82 ± 0.08 μM) possessed excellent antiproliferative activity against PC-3 in vitro, significantly superior to the positive control drug 5-FU, which inhibited PC-3 colony formation and migration ability in a dose-dependent manner and blocked the cell cycle at the GO/G1 phase. Furthermore, 21y dramatically induced apoptosis of PC-3 cells via the mitochondrial pathway, the ROS pathway, and the regulation of apoptosis-related proteins. Notably, the high-level NO generated by 21y in PC-3 cells had a synergistic antitumor effect. With these results, compound 21y could act as an antitumor candidate with potential for further studies.

Objective: In order to enrich the library of anti-tumor small molecule compounds, 19 compounds, with highly effective anti-tumor, have been designed and synthesized. Methods: MTT assay was used to detect the anti-proliferation activity of 19 compounds on four human tumor cell lines (PC-3, H1975, A549 and Eca-109). Cell cycle experiment, cell migration experiment, cell clone experiment and cell apoptosis experiment were used to study the anti-tumor mechanism of compound (XIVm). Results: The compound (XIVm) showed the strongest anti-tumor activity against the above four human tumor cells, especially against H1975 cells, with an IC50 value of 1.09 ± 0.04 μM, which was significantly lower than that of 5-fluorouracil (5-FU). The results of a variety of cell experiments showed that the compound (XIVm) significant anti-tumor activity, such as inhibiting the proliferation and migration of H1975 cells, arresting H1975 cells at G2/M phase, and inducing apoptosis in H1975 cells. Discussion: Slight changes in the R group can cause significant changes in the in vitro anti-tumor activity. And when R is a strong electron withdrawing group of cyano and trifluoromethyl, compound (XIVm) exhibits the strongest inhibitory effect, with an IC50 value of 1.09 ± 0.04 μM on H1975 cells. Conclusions: 19 compounds showed significant anti-tumor activity, and the compound (XIVm), with a strong electron withdrawing group of cyano and trifluoromethyl, showed the most significant effect, and the anti-proliferation and anti-migration effects of compound (XIVm) was further investigated.

Sulfur dioxide (SO2) is emerging as a double-edged molecule, while plays vital roles in food and biological system. However, the fast, highly sensitive, and versatile fluorescent probe still remains a tough challenge among current reports. Herein, we developed a novel aggregation-induced emission (AIE) fluorescent probe TPE-PN for specifically sensing SO2 derivatives with high sensitivity (150 nmol/L) and rapid response time (10 s) based on intramolecular charge transfer (ICT) mechanism. And the fluorescence at 575 nm decreased tremendously with 31-fold after the probe was treated with HSO3-. Employing the probe, the accurate analysis of HSO3- was successfully realized in food samples, cells, plant tissues, and zebrafishes. Furthermore, we successfully demonstrate the eruption of SO2 derivatives within plant during drought and salt stress processes. Therefore, probe TPE-PN illustrates significant potential for applications in food analysis and monitoring of SO2 derivatives levels in biological systems under stress conditions.

Jiyuan oridonin A （JOA）,a diterpenoid ingredient purified from Isodon rubescens collected in Jiyuan,Henan Province,exhibited a variety of anti-tumor activities.In order to further develop the medicinal potency of JOA,a series of its14-OH benzoate derivatives were designed and synthesized,and then their anti-proliferative activities in vitro were evaluated.The results turned out that the anti-tumor activities of this series of derivatives had been improved compared with the those of JOA,and were much better than that of oridonin.Among them,7α,20-olide-ent-kaur-16-en-11,15-dione-14β-yl 2-nitro-5-chlorobenzoate （OJW8-9） showed the best activity (IC 50 =（0.478±0.109）μmol/L on SW-1990 cells).Further studies revealed that compound OJW8-9 inhibited the proliferation of SW-1990 cells by blocking cell cycle in the G2/M phase in a time-and concentration-dependent,and might induce apoptosis through reactive oxygen species （ROS） pathway.

A series of novel 5-cyano-2,4,6-substituted pyrimidine derivatives containing acrylamide group were designed, synthesized, and evaluated for their antitumor activity against four human cancer cell lines (MGC-803, PC-3, A549, and H1975) using the MTT assay. Among them, compound 20y exhibited the most potent cytotoxicity against PC-3 cells (IC50 = 2.75 ± 0.08 μM). Notably, compound 20y significantly inhibited the colony formation, migration, and invasion of PC-3 cells. Furthermore, compound 20y induced S-phase cell cycle arrest and apoptosis in PC-3 cells. These findings indicate that compound 20y might serve as a valuable lead compound for developing antitumor agents targeting prostate cancer cells.

The ubiquitination process refers to the classification of intracellular proteins by ubiquitin molecules under the action of a series of special enzymes (ubiquitin-activating enzymes, ligases, conjugating enzymes, etc.), and selecting target protein molecules for specific modification. The process of ubiquitination indicates that ubiquitination plays an important role in protein localization, metabolism, regulation, and degradation. At present, the development of novel, high-efficiency, and specific USP7 small-molecule inhibitors and the research on the mechanism of action of these inhibitors to specifically recognize the USP7 enzyme are low in fuel. In this review, the activation process of deubiquitinase USP7 is elaborated, and the small molecule inhibitors are divided into three sites of action according to the different sites of action in the catalytic domain of USP7 and the mechanism of these small molecule compounds inhibiting the activation process of USP7 are dissected. At the same time, the full-length structure of USP7 and the design strategy of representative USP7 inhibitors are briefly described. In addition, we summarize the characteristics of the spatial structure and mechanism of action of each action site and discuss the limiting factors of USP7 inhibitor development. This review may promote small-molecule compounds to generate novel high-efficiency and specific USP7 inhibitors based on backbone structure modification.

A series of novel 4,6,7-trisubstituted quinazoline derivatives containing benzothiazole moiety were designed, synthesized and evaluated for their antitumor activity against four human cancer cells (PC-3, MGC-803, A549 and Eca-109) using MTT assay. Among them, compound 11k showed the most potent cytotoxicity against PC-3 cells (IC 50 = 5.59 ± 0.78 μM). Compound 11k also significantly inhibited the colony formation and migration of PC-3 cells. Meanwhile, compound 11k induced cell cycle arrest at S-phase and cell apoptosis, as well as increased accumulation of intracellular reactive oxygen species. All the findings suggest that compound 11k might be a valuable lead compound for anti-tumor agents targeting prostate cancer cells.

目的 探索疫情期间药物化学专业研究生教育模式.方法 使用在线教育模式.鉴于不同阶段的研究生在知识储备、实验操作能力、学习能力及培养目标方面都有显著差异,因此同时进行差异性教育.结果 于在线教育模式的基础之上,结合药物化学学科特点,对不同阶段的研究生在教育内容、教育方式及考核方式上采取差异性培养方案,取得了与疫情之前线下教育相当的研究生培养质量,并为未来的研究生在线教育积累宝贵的经验.结论 疫情期间合理使用线上教学模式可以达到与疫情前相当的研究生培养质量.

Chronic myeloid leukemia (CML) results from BCR-ABL oncogene, which blocks CML cells differentiation and protects these cells from apoptosis. T315I mutated BCR-ABL is the main cause of the resistance mediated by imatinib and second generation BCR-ABL inhibitor. CML with the T315I mutation has been considered to have poor prognosis. Here, we determined the effect of Jiyuan oridonin A (JOA), an ent-kaurene diterpenoid compound, on the differentiation blockade in imatinib-sensitive, particularly, imatinib-resistant CML cells with BCR-ABL-T315I mutation by cell proliferation assay, apoptosis analysis, cell differentiation analysis, cell cycle analysis and colony formation assay. We also investigated the possible molecular mechanism by mRNA sequencing, qRT-PCR and Western blotting. We found that JOA at lower concentration significantly inhibited the proliferation of CML cells expressing mutant BCR-ABL (T315I mutation included) and wild-type BCR-ABL, which was due to that JOA induced the cell differentiation and the cell cycle arrest at G0/G1 phase. Interestingly, JOA possessed stronger anti-leukemia activity than its analogues such as OGP46 and Oridonin, which has been investigated extensively. Mechanistically, the cell differentiation mediated by JOA may be originated from the inhibition of BCR-ABL/c-MYC signaling in CML cells expressing wild-type BCR-ABL and BCR-ABL-T315I. JOA displayed the activity of inhibiting the BCR-ABL and promoted differentiation of not only imatinib -sensitive but also imatinib -resistant cells with BCR-ABL mutation, which could become a potent lead compound to overcome the imatinib -resistant induced by inhibitors of BCR-ABL tyrosine kinase in CML therapy.

目的 探讨对映-贝壳杉烯型二萜类化合物J32对胰腺癌细胞SW1990的作用及机制.方法 将SW1990 细胞随机分为对照组、0.5 μmol·L-1 J32 组、1.0 μmol·L-1 J32 组、2.0 μmol·L-1J32 组、4.0 μmol·L-1 J32组,分别用含终浓度0.0、0.5、1.0、2.0、4.0 μmol·L-1 J32的培养基培养.采用细胞划痕试验检测细胞迁移能力,单克隆形成试验检测细胞增殖能力,流式细胞术检测细胞凋亡情况、细胞中活性氧水平及细胞周期,磷酸化H2组蛋白家族成员X(γ-H2AX)免疫荧光法检测细胞DNA损伤程度,Western blot法检测共济失调毛细血管扩张和Rad3相关蛋白(ATR)-细胞周期检查点激酶1(Chk1)-p53-细胞周期素D1(Cyclin D1)通路相关蛋白以及凋亡相关蛋白B细胞淋巴瘤-2相关X蛋白(Bax)、caspase-3、B淋巴细胞瘤-2(Bcl-2)表达.结果 培养24、48 h时,1.0 μmol·L-1 J32组、2.0μmol·L-1 J32组、4.0 μmol·L-1 J32组细胞的迁移能力显著低于对照组(P＜0.05),2.0 μmol·L-1 J32组、4.0 μmol·L-1 J32组细胞的迁移能力均显著低于1.0 μmol·L-1 J32组(P＜0.05),4.0μmol·L-1J32组细胞的迁移能力显著低于2.0 μmol·L-1 J32组(P＜0.05).0.5 μmol·L-1 J32组、1.0 μmol·L-1J32组细胞的增殖能力显著低于对照组(P＜0.05),1.0 μmol·L-1 J32组细胞的增殖能力显著低于0.5 μmol·L-1 J32组(P＜0.05).1.0 μmol·L-1 J32 组、2.0 μmol·L-1 J32 组、4.0 μmol·L-1 J32 组细胞的凋亡率显著高于对照组(P＜0.05),2.0 μmol·L-1 J32 组、4.0 μmol·L-1J32 组细胞的凋亡率显著高于 1.0 μmol·L-1 J32 组(P＜0.05),4.0 μmol·L1 J32 组细胞的凋亡率显著高于 2.0 μmol·L-1 J32 组(P＜0.05).1.0 μmol·L-1J32 组、2.0 μmol·L-1 J32 组、4.0 μmol·L-1 J32组细胞的活性氧水平显著高于对照组(P＜0.05),2.0 μmol·L-1 J32组、4.0 μmol·L-1 J32组细胞的活性氧水平显著高于1.0 μmol·L-1 J32组(P＜0.05),4.0 μmol·L-1 J32组细胞的活性氧水平显著高于2.0 μmol·L-1J32组(P＜0.05).1.0 μmol·L-1 J32组、2.0 μmol·L1J32组细胞的DNA损伤程度显著高于对照组(P＜0.05),2.0 μmol·L-1J32 组细胞的 DNA 损伤程度显著高于 1.0 μmol·L-1 J32 组(P＜0.05).1.0 μmol·L-1 J32组、2.0 μmol·L-1 J32组细胞中G1/S期细胞占比显著高于对照组(P＜0.05),2.0 μmol·L-1 J32组细胞中G1/S期细胞占比显著高于 1.0 μmol·L-1 J32 组(P＜0.05).对照组、1.0 μmol·L-1 J32 组、2.0 μmol·L-1 J32 组、4.0μmol·L-1 J32组细胞中,随着J32浓度的增加,磷酸化ATR/ATR值及磷酸化p53蛋白表达呈升高趋势(F=25.534、3.970,P＜0.05),Chk1、CyclinD1 蛋白表达呈降低趋势(F=19.532、0.485,P＜0.05);促凋亡蛋白 caspase-3、Bax的表达呈升高趋势(F=0.219、4.314,P＜0.05),抗凋亡蛋白Bcl-2表达呈下降趋势(F=0.324,P＜0.05).结论 对映-贝壳杉烯型二萜类化合物J32可呈浓度依赖性地抑制胰腺癌SW1990细胞的迁移和增殖、促进细胞凋亡及提高细胞内活性氧水平,此外,J32可促进细胞发生DNA损伤及细胞周期阻滞,其作用机制可能与ATR-Chk1-p53-Cyclin D1通路相关.