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The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood-brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.

The stems and leaves of the tomatillo (Physalis ixocarpa or Physalis philadelphica) were considered agricultural waste during the processing of tomatillo fruits. However, their potential value for utilization has not yet been explored. The investigation resulted in the isolation of a total of 29 withanolides, out of which 15 never reported. These newly discovered withanolides were then tested for their cytotoxicity against eight different human tumor cell lines. Compounds 2-3, 6-7, 17, 19, and 25-27 displayed encouraging cytotoxic effects. Given the potent inhibitory activity of physagulin C (25) on the proliferation of HepG2 cells in vitro, further investigation was conducted to determine its molecular mechanism. Physagulin C inhibited epithelial-mesenchymal transition (EMT) process through the down-regulation of the JAK2/STAT3 and PI3K/AKT/mTOR pathways. Withanolides presenting in the stems and leaves of tomatillo make the plant possess potential commercial importance. Therefore, tomatillos could be commercialized worldwide in the food and pharmaceutical industries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Four new sesquiterpenoids, dstramonins A-D ( 1-4 ), and one new natural product ( 5 ), together with three known compounds ( 6-8 ), were isolated from the leaves of Datura stramonium L. The structures of new compounds were elucidated by extensive spectroscopic analysis and comparison with the literature. The cytotoxicity of isolates against LN229 cells was assessed and compounds 2 - 4 , and 7 displayed cytotoxic activity with IC 50 values ranging from 8.03 to 13.83  μ M.

Introduction: Phosphatase of regenerating liver (PRL) family proteins, also known as protein tyrosine phosphatase 4A (PTP4A), have been implicated in many types of cancers. The PRL family of phosphatases consists of three members, PRL1, PRL2, and PRL3. PRLs have been shown to harbor oncogenic potentials and are highly expressed in a variety of cancers. Given their roles in cancer progression and metastasis, PRLs are potential targets for anticancer therapies. However, additional studies are needed to be performed to fully understand the roles of PRLs in blood cancers., Areas Covered: In this review, we will summarize recent studies of PRLs in normal and malignant hematopoiesis, the role of PRLs in regulating various signaling pathways, and the therapeutic potentials of targeting PRLs in hematological malignancies. We will also discuss how to improve current PRL inhibitors for cancer treatment., Expert Opinion: Although PRL inhibitors show promising therapeutic effects in preclinical studies of different types of cancers, moving PRL inhibitors from bench to bedside is still challenging. More potent and selective PRL inhibitors are needed to target PRLs in hematological malignancies and improve treatment outcomes.

Our previous studies have demonstrated that BML284 is a colchicine-site tubulin degradation agent. To improve its antiproliferative properties, 45 derivatives or analogs of BML284 were designed and synthesized based on the cocrystal structure of BML284 and tubulin. Among them, 5i was the most potent derivative, with IC 50 values ranging from 0.02 to 0.05 μM against the five tested tumor cell lines. Structure-activity relationship studies verified that the N1 atom of the pyrimidine ring was the key functional group for its tubulin degradation ability. The 5i-tubulin cocrystal complex revealed that the binding pattern of 5i to tubulin is similar to that of BML284. However, replacing the benzodioxole ring with an indole ring strengthened the hydrogen bond formed by the 2-amino group with E198, which improved the antiproliferative activity of 5i. Compound 5i effectively suppressed tumor growth at an intravenous dose of 40 mg/kg (every 2 days) in paclitaxel sensitive A2780S and paclitaxel resistant A2780T ovarian xenograft models, with tumor growth inhibition values of 79.4% and 82.0%, respectively, without apparent side effects, showing its potential to overcome multidrug resistance. This study provided a successful example of crystal structure-guided discovery of 5i as a colchicine-targeted tubulin degradation agent, expanding the scope of targeted protein degradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Six novel withanolides, along with nine known related compounds were isolated from the leaves of Datura stramonium L. The structures and absolute configurations of the new withanolides were elucidated by employing various spectral techniques and comparing them with those previously reported in the literature. In addition, four withanlides demonstrated interesting cytotoxic activity on LN229 cells with IC 50 <20 μM., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Hypericum perforatum L. (HPL) is a potential traditional Chinese medicine. It could promotes menopausal 'kidney-yin deficiency syndrome' that characterized by renal function decline. However, its potential pharmacological effect and mechanism remains unknown., Objective: The aim of this study was to investigate whether HPL can improve menopausal renal function decline and to explore its mechanism of action., Methods: The mainly ingredients of HPL were identified using UPLC-Q-TOF-MS/MS approach, and the potential therapeutic targets of HPL for renal function decline were chose via network pharmacology technique. The key therapeutic metabolites were selected through non-targeted metabolomic and chemometric methods. Then, the network were constructed and the key targets and metabolites were screened. At last, the validation experiments and mechanism exploring were adopted by using Immunofluorescence, enzyme-linked immunosorbent assay (ELISA), real-time PCR (RT-PCR), and western blotting assays., Results: mainly ingredients of HPL were identified and determined 17 compounds and 29 targets were chose as mainly active compounds and potential therapeutic targets. Based on OVX induced renal decline rat model, after chemometric analysis, 59 endo-metabolites were selected as key therapeutic metabolites, and AGE-RAGE signal pathway in diabetes complications was enriched as the key pathway. By constructing a "disease-component-target" network, Hyperoside, Quercetrin, and quinic were selected as the key therapeutic compounds, and the AKT1 and NOS3 were selected as the key therapeutic targets. The results of ELISA, RT-PCR and western blot experiments indicated that HPL could rescue the abnormal expressions both of AKT1 and NOS3, as well as their related metabolites distortion., Conclusion: Our findings indicated that HPL regulated expression of AKT1 and NOS3 through modulating AGE-RAGE signaling pathway in OVX stimulated rats` renal dysfunction, implicating the potential values of HPL in menopause syndromes therapy., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work; there is noprofessional or other personal interest of any nature or kind in any product, serviceand/or company that could be construed as influencing the position presented in,or the review of the manuscript entitled Hypericum perforatum L. protects against renal function decline in OVX rats by regulating expressions of NOS3 and AKT1 in AGE-RAGE pathway., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Nine polyacetylenes, including five new compounds named sadivaethynes E -I (1 – 5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1 – 5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1 – 2 , 4 – 5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC 50 value of 11.66 μM against HEPG2. [Display omitted] • Five undescribed compounds were isolated from the roots of Saposhnikovia divaricata. • The structures were characterized chemically by NMR, quantum chemical calculations and CD data analysis. • Compound 9 showed moderate inhibitory effect with an IC 50 value of 11.66 μM against HEPG2. [ABSTRACT FROM AUTHOR]

Five new sesquiterpenoids, dictamtrinorguaianols E and F (1–2), and dictameudesmnosides F, G, and H (3–5), along with seven known sesquiterpenoids (6–12) were isolated from Dictamnus dasycarpus Turcz. The structures of all new compounds were characterized by spectroscopic methods, including UV, IR, HR-ESI-MS, and 1D and 2D NMR. The In-vitro anti-proliferative activities of all the compounds against two human cancer cell lines (SW982 and A549) were evaluated by CCK-8 assay. Compounds 1 and 4 showed medium anti-proliferative activity against SW982 cells, with IC 50 values of 3.49 ± 0.10 and 6.42 ± 1.23 μM, respectively. Additionally, compounds 2 , 7 , and 8 exhibited medium anti-proliferative activity against A549 cells, with IC50 values ranging from 0.80 ± 0.05 to 6.60 ± 0.46 μM. [Display omitted] [ABSTRACT FROM AUTHOR]

The article titled "Retraction Note: A New Porous Metal–Organic Framework Constructed from 2, 5-Thiophenedicarboxylate and Melamine Ligands: Catalysis Dye Degradation and Anti-tumor Activity in Myocardioma" has been retracted by the Editor-in-Chief and the Publisher of the Journal of Cluster Science. The retraction was prompted by evidence of systematic manipulation of the publication process, including issues with citations, phrasing, figures, and ethics approval statements. The authors have not responded to correspondence regarding the retraction. Springer Nature, the publisher, remains neutral in regards to jurisdictional claims and institutional affiliations. [Extracted from the article]

• A new derivative of podophyllotoxin (GHGT-17) was synthesized by incorporation of cyclopropyl, formyl, piperazinyl groups. • GHGT-17 exhibits significant cytotoxicity against a variety of cancer cells. • The IC 50 of GHGT-17 was less than 100 nM against A549 and H460 cells and greater than 100 µM against 16HBE cells. • In silico ADMET analysis suggests GHGT-17 is unlikely to toxic to normal organs. • Molecular docking study indicates that GHGT-17 could directly bind to the colchicine binding pocket of tubulin. Podophyllotoxin (PPT) is a naturally occurring lignan extracted from the rhizomes of the Podophyllum plant. It exhibits toxicity towards a broad spectrum of cancer cells and can induce cell death by inhibiting the polymerization of microtubule proteins. In our pursuit of more potent anticancer drug candidates, 4α-(cyclopropyl formylpiperazinyl)-4-deoxypodophyllotoxin (GHGT-17) was successfully synthesized by introducing a piperazine group, formyl group, and cyclopropyl group at the C-4 position of PPT. The activity of GHGT-17 against various types of cancer cells was evaluated using the MTT assay. It exhibited significant potency against lung cancer cells, with IC 50 values of 0.080 ± 0.020 μM (A549) and 0.086 ± 0.004 μM (H460), without obvious toxicity towards lung epithelial cells 16HBE (IC 50 > 100 μM). Further investigations demonstrated that GHGT-17 induced morphological changes in A549 and H460 cells, inhibited proliferation in a time- and dose-dependent manner. Furthermore, GHGT-17 inhibited the formation of cell colonies in a dose-dependent manner. It was found to inhibit cell migration, arrest the cell cycle in the G2/M phase, induce nuclear wrinkling, decrease mitochondrial membrane potential, and inhibit microtubule protein polymerization. These effects ultimately contribute to the induction of endogenous apoptosis. In silico studies, ADMET analysis revealed that GHGT-17 exhibited a satisfactory bioavailability with good water solubility, easy absorption, and well-proportioned distribution in the body. Molecular docking was performed to predict the binding mode and interactions of GHGT-17 with tubulin protein (1SA0). Additionally, GHGT-17 was submitted to molecular dynamics simulation and RMSD, RMSF, Rg, hydrogen bonding was analyzed. The complex showed a rather low binding free energy (−36.37 kJ mol−1) and thus exhibited a superior binding affinity towards to tubulin protein. In summary, the combined results indicated that GHGT-17 exhibits promise as a prospective potential novel drug candidate worthy of further investigation for its potential application in lung cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Implementing the concept of turning waste into treasure, the conversion of biomass waste into high-value carbon materials, especially carbon dots (CDs), has pointed out a new direction for disease diagnosis, tumor treatment, and other aspects. In this work, we have reported the GL-CDs(Fe) via a simple synthesis route exploiting Ganoderma lucidum waste as the precursor. Thanks to their excellent optical property and peroxidase mimetic activity, a novel GL-CDs(Fe)-based ratio fluorescence/colorimetric/smartphone triple mode sensing platform is cleverly fabricated for glucose determination with the LOD of 0.28, 0.37, and 0.52 μΜ separately. Especially, this triple mode biosensor is successfully utilized for glucose detection in serum samples with the relative error of less than ±8 % compared with clinical reports. Surprisingly, the GL-CDs(Fe) also presents immense application prospects in high-level anti-counterfeiting aspects due to their excellent luminescent properties, high water-solubility, and easy availability. Furthermore, GL-CDs(Fe) can catalyze excessive H 2 O 2 inside tumor cells to produce massive hydroxyl radicals (· OH) which break down the redox levels of cancer cells and thereby eliminate tumor cells. Thus, this integrated "Three-in-One" multifunctional platform based on GL-CDs(Fe) unveils enormous research and application prospects for bio-sensing, anti-counterfeiting, cancer treatment. [Display omitted] • GL-CDs(Fe) with ideal optical and peroxidase-like property was derived from biomass waste. • A novel GL-CDs(Fe)-based triple mode sensing platform was fabricated for glucose analysis. • GL-CDs(Fe) was also used for anti-counterfeiting ink and anticancer cell effect. [ABSTRACT FROM AUTHOR]

The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo. [Display omitted] • Eleven diterpenoids were obtained from the SFE extract of C. crassifolius roots. • Chettaphanin II showed the strongest antitumor activity against A549 cells. • Chettaphanin II inhibited A549 cell proliferation and arrested cells in G2/M-phase. • Chettaphanin II induced A549 cell apoptosis by inhibiting PI3K/AKT/mTOR pathway. • Chettaphanin II significantly inhibited the growth of tumor tissue in nude mice. [ABSTRACT FROM AUTHOR]

• A new anthrahydrazone ligand (9-THA) and its three metal complexes were synthesized. • The tested cancer cell lines were most sensitive to the Cu(II) complex, 9-THA-Cu. • 9-THA-Cu could bind with DNA in an intercalative mode by its planar structure. • The Cu(II) center play a key role to exert anticancer activity and induce apoptosis. In the present study, we synthesized and extensively characterized a novel ligand, 9-THA, based on 9-benzothiazolanthrahydrazone, along with its three corresponding transition metal complexes: 9-THA-Co (1), 9-THA-Ni (2), and 9-THA-Cu (3). The crystallographic analysis revealed distinct coordination geometries - six-coordinate for 9-THA-Co and 9-THA-Ni, binding three and two 9-THA ligands, respectively, and four-coordinate for 9-THA-Cu, binding one 9-THA ligand. In vitro anticancer screening demonstrated that 9-THA-Cu exhibited significant growth inhibition in HeLa-229, NCI-H460, and SK-OV-3 cancer cells with IC 50 values of 12.10 ± 0.54, 12.12 ± 0.58, and 17.65 ± 0.66 μM, respectively. Moreover, it displayed comparable cytotoxicity to cisplatin on HL-7702 normal liver cells. In contrast, 9-THA and 9-THA-Co/9-THA-Ni did not exhibit significant growth inhibition in the tested cancer cells, suggesting that Cu(II) played a pivotal role in its anticancer mechanism. Further investigation revealed the intercalative DNA binding mode of 9-THA-Cu by UV–Vis and fluorescent spectral analyses. It also exhibited competitive binding with two typical DNA intercalators, Gel-red (GR) and ethidium bromide (EB). Cell cycle and cell apoptosis experiments indicated that 9-THA-Cu at a concentration of 22 μM could induce cell cycle arrest in the S phase in 40 % of HeLa-229 cancer cells. Simultaneously, it induced 33.2 % apoptosis in HeLa-229 cells, suggesting that 9-THA-Cu may employ multiple mechanisms to exert its anticancer effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. Our study showed that ZZC4 is an anticancer drug candidate. • ZZC4 is a novel purine-containing EGFR tyrosine kinase inhibitor. • ZZC4 potently inhibited the proliferation and tumor growth of lung and breast cancer cells. • Network pharmacology can be used the determine the possible target of small molecules drugs. [ABSTRACT FROM AUTHOR]