Search

Overexpression of β3-tubulin is a common occurrence in human tumors and is associated with resistance to microtubule-targeting agents. PROTAC strategy has demonstrated significant potential in overcoming drug resistance. Herein, we report the discovery of W13 as the first PROTAC against tubulin, which was created by connecting a CRBN ligand to the widely recognized microtubule-destabilizing agent CA-4. Notably, it retains the inhibitory activity of the parental CA-4 and further exhibits substantial degradation of α/β/β3-tubulin in both A549 and A549/Taxol cell lines. The degradation of tubulin was subsequently verified to be mediated by the ubiquitin-proteasome system. Importantly, tumor xenograft research clearly showed W13 's promising antitumor activity against human lung cancer. Taken together, the discovery of W13 demonstrated the practicality and feasibility of PROTAC targeting tubulin, hence establishing a potential therapeutic approach for treating NSCLC caused by the overexpression of β3-tubulin. [Display omitted] • A series of CRBN-based PROTACs have been firstly synthesized as tubulin degrader. • W13 induces α/β/β3-tubulin in A549S and A549T cells via UPS-dependent manners. • The RI values of W13 on drug-resistant cancer cells was superior to that of Taxol. • The tumor growth inhibition values of W13 were 65.8% on A549T xenograft tumor model. [ABSTRACT FROM AUTHOR]

Phosphorus fertilisation and increasing litter input are widely employed to restore the degraded grasslands. Despite the key roles of nitrogen-cycling microbes in determining the soil nitrogen dynamics and development of grassland degradation, little is known about their responses to these restoration efforts. Here, a microcosm experiment, with soils collected from a degraded Tibetan alpine meadow, was conducted to investigate the responses of nitrogen-cycling microbes to litter and phosphorus amendments, and their links with the changes in soil properties. Copies of the corresponding nitrogen-cycling genes ( nifH , amoA , narG , nirK , and nirS genes) and their mRNAs were determined using real-time PCR. The results showed that the litter amendment significantly stimulated the transcription of nifH and nirS genes, but reduced the copies of amoA gene and bacterial amoA mRNA. It also significantly increased soil dissolved organic carbon, available phosphorus, ammonium nitrogen, and microbial biomass concentrations, but decreased soil inorganic and nitrate nitrogen concentrations. The phosphorus amendment exerted little effects on soil properties and nitrogen-cycling microbes, while the litter-phosphorus interactions significantly offset the individual negative effects of the litter and phosphorus amendments on the denitrifier abundance. The soil nitrate and inorganic nitrogen concentrations were positively correlated with the amoA genes and bacterial amoA mRNA copies, but negatively correlated with nirS mRNA copies. These results indicate that litter addition may decrease soil nitrate and inorganic nitrogen concentrations by suppressing nitrifiers and stimulating nirS gene expression, highlighting the vital roles of nitrogen-cycling microbes in determining the soil nitrogen dynamics during the restoration of degraded grasslands. [ABSTRACT FROM AUTHOR]

In an effort to discover anticancer agents with simultaneous effects on tubulin and angiogenesis, we designed and synthesized two series of piperlongumie (PL) derivatives by replacing of phenyl group with a variety of benzoheterocycle (series II) or cyclizing the C7–C8 olefin into an aromatic heterocycle (series I). Most of the new compounds showed better antiproliferative activities against six cancer cell lines than the parent drug PL. Compound II-14b had the best cytotoxic profile of these two series in cancer cells, whilst being relatively low cytotoxicity against normal human cells and high potency against drug-resistant cells. It disrupted cellular microtubule networks and inhibited tubulin assembly with an IC 50 value of 5.8 μM. Further studies elucidated that II-14b showed antitumor activities through multiple mechanisms, including the pruduction of abundant ROS, the dissipation of mitochondrial membrane potential, the accumulation of DNA double-strand breaks, and the induction of cell cycle in G2/M phase. More importantly, we have observed that it possesses potential anti-angiogenesis capabilities, including suppression of HUVECs cell migration, invasion, and endothelial tube formation in vitro and in vivo. In vivo assessment indicated that II-14b inhibits the growth and metastasis of MGC-803 xenograft tumour in zebrafish. These findings show that II-14b is a high-efficacy and non-toxic antitumor agent. [Display omitted] • A total of fifty novel piperlongumine analogues were prepared as microtubule polymerization inhibitors. • II-14b exhibited higher selectivity than normal human cells, with an IC 50 value of 0.458 ± 0.01 μM against MGC-803 cell line. • II-14b effectively attenuated the migration and invasion of MGC-803 cells by blocking the FAK, MMP9 and ERK/EMT pathway. • II-14b exhibited potent anti-angiogenesis effect through theVEGFR2/PI3K/AKT/MAPK pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Forty-seven novel 2-methoxyestradiol (2ME 2) derivatives were prepared as potent dual Tubulin/HDAC inhibitors. • 4s exhibited higher selectivity than normal human cells with IC 50 value of 1.782 μM against A549 cell line. • 4s effectively attenuated the migration and invasion capacity of A549 cells. • 4s exhibited potent anti-angiogenesis effect in vitro and in vivo. Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME 2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME 2 derivatives were synthesized and evaluated for antiproliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC 50 = 0.06 µM toward HDAC2) activity, as well as the most potent cytotoxicity IC 50 values of 0.37–4.84 µM against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel inhibitors of microtubule protein polymerization targeting the colchicine site were designed and synthesized. • K10 exhibited nanomolar anti-proliferative efficacies with IC 50 values of 0.07–0.80 μM against four cancer cell lines. • K10 caused cycle arrest and apoptosis and inhibit tubulin polymerization by binding to the colchicine site. • K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4‑benzodioxane moiety and 3,4,5‑trimethoxyphenyl group, exhibiting the most potent activity, with IC 50 values of 0.07–0.80 μM against four cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5‑trimethoxyphenyl ring may deserve consideration for cancer therapy. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated that neuroinflammation is the key to perioperative neurocognitive disorders (PND); however, the specific mechanism postsurgery and anesthesia has not yet been fully clarified. The present study is aimed at exploring the effects of P2X4/NLRP3 signaling pathway in neuroinflammation and cognitive impairment after surgery. 12–14-month-old male C57BL/6 mice undergoing open tibial fracture surgery by sevoflurane anesthesia were administered P2X4R inhibitor 5-BDBD or saline was intraperitoneally for 3 consecutive days after surgery. Then, the animals were subjected to Morris water maze test or sacrificed to collect the hippocampus. The level of P2X4R and NLRP3 was estimated by Western blot, the activation of microglia was detected via immunohistochemistry, and the expression of TNF-α, IL-1β, and IL-6 was quantified by enzyme-linked immunosorbent assay. These results indicated that tibial surgery caused cognitive impairment, increased the expression of P2X4R and NLRP3, and aggravated the neuroinflammation and microglia activation. However, intraperitoneal injection of 5-BDBD attenuated these effects. In conclusion, these findings indicated that the P2X4/NLRP3 pathway might be involved in the pathophysiology of PND. [ABSTRACT FROM AUTHOR]

[Display omitted] • 9i acted as a novel colchicine site tubulin polymerization inhibitor with an IC 50 value of 4.87 μM. • 9i showed strong potency to decrease angiogenesis in vitro and in vivo. • 9i suppressed migration and invasion of breast cancer in vitro and in vivo. Here, we report the structural optimization of a hit natural compound, 2-ME 2 (2-methoxyestradiol), which exhibited inhibitory activity but low potency on tubulin polymerization, anti- angiogenesis, MCF-7 proliferation and metastasis in vitro and in vivo. A novel series of 3,17-modified and 17-modified analogs of 2-ME 2 were synthesized and investigated for their antiproliferative activity against MCF-7 and another five different human cancer cell lines leading to the discovery of 9i. 9i bind to tubulin colchicine site tightly , inhibited tubulin polymerization and disrupted cellular microtubule networks. Cellular mechanism studies revealed that 9i could induce G2/M phase arrest by down-regulated expression of p-Cdc2, P21 and cell apoptosis by regulating apoptosis-related proteins (Parp, Caspase families) in a dose-dependent manner. Importantly, 9i significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 9i could effectively inhibit the proliferation and metastasis of MCF-7 cells in vitro and in zebrafish xenograft. The satisfactory physicochemical property and metabolic stability of 9i further indicated that it can act as a promising and potent anti-angiogenesis, inhibiting proliferation and metastasis of breast cancer agent via targeting tubulin colchicine binding site. [ABSTRACT FROM AUTHOR]

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially in aged patients. Neuroinflammation has been closely associated with the development of POCD. While the contribution of pneumoperitoneum to the systemic inflammation has been well documented, the effect of pneumoperitoneal pressure on neuroinflammation and postoperative cognitive function remains unclear. In this study, we showed that high-pressure pneumoperitoneum promoted the postoperative neuroinflammation and microglial activation in the hippocampus and aggravated the postoperative cognitive impairment in aged mice. These results support the requirement to implement interventions with lower intra-abdominal pressure, which allows for adequate exposure of the operative field rather than a routine pressure. [ABSTRACT FROM AUTHOR]

[Display omitted] Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC 50 = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion. [ABSTRACT FROM AUTHOR]

A novel series of cis -diphenylethene and benzophenone derivatives as tubulin/HDAC dual-targeting inhibitors were designed and synthesized. Among them, compound 28g exhibited the most potent antiproliferative activities against six different human cancer cell lines, 28g could not only inhibited tubulin polymerization, disrupted cellular microtubule networks but also selectively inhibited class IIa HDACs, especially HDAC7 activity. Further molecular docking demonstrated 2 8g could occupy the binding pockets of tubulin and HDAC7 meanwhile. Cellular mechanism studies revealed that 28g could induce G2/M phase arrest by down-regulated expression of p-cdc2 and cell apoptosis by regulating mitochondrial membrane potential, reactive oxygen species (ROS) levels and apoptosis-related proteins (PARP, Caspase families) in a dose-dependent manner. Importantly, 28g significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 28g could effectively suppress the proliferation and metastasis of MGC-803 cells in vitro and in zebrafish xenograft. All above results indicated that 28g can act as a promising antitumor and antiangiogenic agent via targeting tubulin and class IIa HDACs. [Display omitted] • 28 g can obviously inhibit the polymerization of tubulin and has a high selectivity to HDAC-7, with an IC50 value of 0.05 μM. • 28 g showed strong potency to decrease angiogenesis in vitro and in vivo. • 28 g suppressed migration and invasion of stomach cancer in vitro and in vivo. [ABSTRACT FROM AUTHOR]

We report the structural optimization of tanshinone IIA, a natural product which possesses anti-tumor properties but low water-solubility, weak antiproliferative activity and poor PK properties. A new series of ring A/C/D modified tanshinone analogues were synthesized and studied for their antiproliferative capacities against six human cancer cell lines. SAR study revealed that ring A cleavage of tanshinone IIA led to improved anti-cancer activity. Introduction of a methoxy group to the phenyl ring could enhance the anti-cancer activity even further. Compound 2f with methoxy group at C-8 position was selected as an early lead with IC 50 values of 0.28–3.16 μM against six tested cell lines. 2f could bind to tubulin colchicine site, inhibit tubulin assembly and disrupt the normal formation of microtubule networks. Cellular mechanistic studies revealed that 2f induced apoptotic cell death of A549 cells in a dose-dependent manner. In vitro investigations showed that 2f impeded the tubule-formation of HUVECs and potently inhibited the proliferation, migration and invasion of A549 cells as well as HUVECs. Furthermore, the in vivo anti-angiogenic effect of 2f was confirmed via a zebrafish model test. The satisfactory physicochemical property and metabolic stability of 2f , as well as improved water-solubility, further suggested that 2f could serve as a promising tubulin inhibitor and anti-angiogenic agent. [Display omitted] • Ring A modification of tanshinone IIA potently improved its anti-cancer activities. • 2f acted as a novel colchicine site tubulin polymerization inhibitor. • 2f showed potent anti-angiogenetic and anti-metastasis activities. [ABSTRACT FROM AUTHOR]