Advances in antitumor research of bifunctional small molecule inhibitors targeting heat shock protein 90 / 药学学报

The heat shock protein 90 (Hsp90) protein family is a cluster of highly conserved molecules that play an important role in maintaining cellular homeostasis. Hsp90 and its co-chaperones regulate a variety of pathways and cellular functions, such as cell growth, cell cycle control and apoptosis. Hsp90 is closely associated with the occurrence and development of tumors and other diseases, making it an attractive target for cancer therapeutics. Inhibition of Hsp90 expression can affect multiple oncogenic pathways simultaneously. Most Hsp90 small molecule inhibitors are in clinical trials due to their low efficacy, toxicity or drug resistance, but they have obvious synergistic anti-tumor effect when used with histone deacetylase (HDAC) inhibitors, tubulin inhibitors or topoisomerase II (Topo II) inhibitors. To address this issue, the design of Hsp90 dual-target inhibitors can improve efficacy and reduce drug resistance, making it an effective tumor treatment strategy. In this paper, the domain and biological function of Hsp90 are briefly introduced, and the design, discovery and structure-activity relationship of Hsp90 dual inhibitors are discussed, in order to provide reference for the discovery of novel Hsp90 dual inhibitors and clinical drug research from the perspective of medicinal chemistry.

Research Progress on the Anti-tumor Activity and Mechanism of Narciclasine / 昆明医科大学学报

Narciclasine(NCS),a hymenocallis littoralis alkaloid extracted from the bulbs of the genus Narcissus in the Lycoriaceae family,has been proven to have significant anti-tumor activity against a variety of tumor cells.The antitumor mechanisms of NCS are diverse and NCS exhibits antitumor effects through different pathways,which adapts to the current trend of developing multi-target anti-tumor drugs.This review introduces the research progress of the anti-tumor activity and mechanism of NCS in recent years based on the inhibitory effect of NCS on gastric cancer cells,oral cancer cells,polymorphous glioblastoma cells,colon cancer cells,breast cancer cells,melanoma cells and primary exudative lymphoma cells,aiming to provide ideas and references for the research and development,and design of NCS type anti-tumor drugs in the future.

A new strategy for evaluating antitumor activity in vitro with time-dimensional characteristics of RTCA technology / 中国药理学通报

Aim To analyze the anti-A549 and HI299 lung ade-nocarcinoma activities via using examples of baicalin, astragalo-side, hesperidin and cisplatin based on real time cellular analysis (RTCA) technology, and to build a new strategy for EC50 e-valuation reflecting the time-dimensional characteristic. Methods Using RTCA Software Pro for data analysis and GraphPad Prism and Origin Pro plotting, the in vitro anti-A549 and H1299 lung adenocarcinoma activities of baicalin, astragaloside, hesperidin, and cisplatin were characterized using the endpoint method and time dimension, respectively. Results (X) There were significant differences in EC50 values of A549 and H1299 cells at 24 h and 48 h endpoint methods. (2) The correlation coefficient of the curve fitted with the four-parameter equation was > 0. 9, and the dynamic change of EC50 remained relatively stable (the linear fitting of EC50 at adjacent 4 points I slope 1

Elemene Antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook / 中国结合医学杂志

Elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian, introduced the innovative concept of "molecular compatibility theory" by combining Chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of Chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

Synthesis and antitumor activity evaluation of glycoconjugates derived from natural product harmine / 中国药科大学学报

@#Based on our previous work, the study herein designed and synthesized eight glycoconjugates of natural product harmine (14a-14h)by introducing a cyclohexylmethyloxyl group at its C7 position and coupling a methyl-2-amino-β-D-glucopyranoside to the N9 position through different lengths of alkyl chains.In vitro anti-tumor activity screening and structure-activity relationship studies showed that the antitumor activity of the conjugates increased with the lengthening of the alkyl chain in the linker.Compound 14h exhibited significantly better proliferative inhibitory activity against MDA-MB-231 breast cancer cells than harmine.As compared to harmine, the introduction of the carbohydrate moiety improved the water solubility of compound 14h and enhanced its tumor cell selectivity through the Warburg effect.Mechanism of action studies revealed that compound 14h induced apoptosis and G0/G1 cell cycle arrest in MDA-MB-231 cells, and inhibited tumor cell migration by interfering with epithelial-mesenchymal transition process.This study provides a new approach for the development of antitumor drugs based on harmine.

Diterpenoid constituents in Pseudolarix amabilis and their antitumor activities in vitro / 中国中药杂志

By various chromatographic techniques and extensive spectroscopic methods, 17 abietane diterpenoids were isolated from the dichloromethane fraction of the 95% ethanol cold-soak extracts of the seeds of Pseudolarix amabilis, namely pseudoamaol A(1), 12α-hydroxyabietic acid(2), 12-methoxy-7,13-abietadien-18-oic acid(3), 13-hydroxy-8,11,13-podocarpatrien-18-oic acid(4), 15-hydroxy-7,13-abietadien-12-on-18-oic acid(5), 8(14)-podocarpen-13-on-18-oic acid(6), holophyllin K(7), metaglyptin B(8), 7α-hydroxydehydroabietinsaure-methylester(9), 7-oxodehydroabietic acid(10), 15-hydroxy-7-oxodehydroabietinsaure-methy-lester(11), 15-methoxydidehydroabietic acid(12), 7-oxo-15-hydroxy-dehydroabietic acid(13), 15-hydroxydehydroabietic acid(14), 8,11,13-abietatriene-15,18-diol(15), 8,11,13-abietatriene-15-hydroxy-18-succinic acid(16), and 7β-hydroxydehydroabie-tic acid(17). Compound 1 was a new compound. The isolated compounds were evaluated for their antitumor activities(HepG2, SH-SY5Y, K562), and compounds 8 and 17 showed potential cytotoxic activity against K562 cells, with IC_(50) values of 26.77 and 37.35 μmol·L~(-1), respectively.

Effect of Morus alba extract sanggenon C on growth and proliferation of glioblastoma cells / 中国中药杂志

Glioblastoma is the most common primary cranial malignancy, and chemotherapy remains an important tool for its treatment. Sanggenon C(San C), a class of natural flavonoids extracted from Morus plants, is a potential antitumor herbal monomer. In this study, the effect of San C on the growth and proliferation of glioblastoma cells was examined by methyl thiazolyl tetrazolium(MTT) assay and 5-bromodeoxyuridinc(BrdU) labeling assay. The effect of San C on the tumor cell cycle was examined by flow cytometry, and the effect of San C on clone formation and self-renewal ability of tumor cells was examined by soft agar assay. Western blot and bioinformatics analysis were used to investigate the mechanism of the antitumor activity of San C. In the presence of San C, the MTT assay showed that San C significantly inhibited the growth and proliferation of tumor cells in a dose and time-dependent manner. BrdU labeling assay showed that San C significantly attenuated the DNA replication activity in the nucleus of tumor cells. Flow cytometry confirmed that San C blocked the cell cycle of tumor cells in G_0/G_1 phase. The soft agar clone formation assay revealed that San C significantly attenuated the clone formation and self-renewal ability of tumor cells. The gene set enrichment analysis(GSEA) implied that San C inhibited the tumor cell division cycle by affecting the myelocytomatosis viral oncogene(MYC) signaling pathway. Western blot assay revealed that San C inhibited the expression of cyclin through the regulation of the MYC signaling pathway by lysine demethylase 4B(KDM4B), which ultimately inhibited the growth and proliferation of glioblastoma cells and self-renewal. In conclusion, San C exhibits the potential antitumor activity by targeting the KDM4B-MYC axis to inhibit glioblastoma cell growth, proliferation, and self-renewal.

Structural characteristics and antitumor activity of polysaccharides from Cordyceps species / 药学学报

Polysaccharides is one of the main bioactive components of Cordyceps species, because of the potential clinical value with stronger anti-tumor, such as anti-neuroblastoma, anti-melanoma, anti-lung cancer, anti-colon cancer and so on, its have received widespread attention in biomedical field and increasing research in last decades. According to structural elucidation, this review gives a systematic literature overview on antitumor mechanism of Cordyceps species-derived polysaccharides from three aspects, including inhibition of tumor cell growth, enhancement of immunomodulatory activity and reduction of tumor metastasis. Finally, it also puts forward some scientific problems for follow up research.

Research progress on natural guaiane-type sesquiterpenoids and their biological activities / 中国中药杂志

Guaiane-type sesquiterpenoids are a class of terpenoids with [5,7] ring-fused system as the basic skeletal structure composed of three isoprene units, which are substituted by 4,10-dimethyl-7-isopropyl. According to the difference in functional groups and degree of polymerization, they can be divided into simple guaiane-type sesquiterpenoids, sesquiterpene lactones, sesquiterpene dimers, and sesquiterpene trimers. Natural guaiane-type sesquiterpenoids are widely distributed in plants, fungi, and marine organisms, especially in families such as Compositae, Zingiberaceae, Thymelaeaceae, Lamiaceae, and Alismataceae. Guaiane-type sesquiterpenoids have good antibacterial, anti-inflammatory, anticancer, and neuroprotective effects. In this paper, the novel guaiane-type sesquiterpenoids isolated and identified in recent 10 years(2013-2022) and their biological activities were reviewed in order to provide refe-rences for the research and development of guaiane-type sesquiterpenoids.

Design, synthesis, antibacterial and antitumor activities of novel pyrazolo3,4-bpyridine-4-one-5-carboxylic acid derivatives / 药学学报

To discover new structural hits, based on the important role of pyrazole ring and fragment of pyridinone carboxylic acid in drug design, novel title pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives (10a-10p) were designed and synthesized, the structures were confirmed by spectral data and elemental analyses. The antibacterial and antitumor activities were evaluated by the measured minimum inhibitory concentration (MIC) values against the tested four strains and half inhibitory concentration (IC50) values against the tested four cancer cells, respectively. The results displayed markedly poor antibacterial activity and observably potent antitumor activity. In particularly, the title difluorophenyl (10d, 10e, 10f), pyridyl (10j), ethyl (10k) and cycloproyl (10l) compounds exhibited comparable activity against Capan-1 and A549 cells to that of the comparison doxorubicin. Thus, pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives as promising antitumor hits need to be developed.

Discovery and bioassay of disubstituted β-elemene-NO donor conjugates: synergistic enhancement in the treatment of leukemia / 中国天然药物

Natural products are essential sources of antitumor drugs. One such molecule, β-elemene, is a potent antitumor compound extracted from Curcuma wenyujin. In the present investigation, a series of novel 13,14-disubstituted nitric oxide (NO)-donor β-elemene derivatives were designed, with β-elemene as the foundational compound, and subsequently synthesized to evaluate their therapeutic potential against leukemia. Notably, the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. In vivo studies indicated that compound 13d could effectively inhibit tumor growth, exhibiting no discernible toxic manifestations. Specifically, a significant tumor growth inhibition rate of 62.9% was observed in the K562 xenograft tumor mouse model. The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Suppressive effect of lignans from Euphorbia neriifolia L.on esophageal squamous cancer cell / 中国药科大学学报

@#Eubhorbia neriifolia L. is a plant of Euphorbia family.Five known lignans were isolated from the aerial parts of E. neriifolia L. by silica gel for column chromatography and preparative high-performance liquid chromatography (HPLC).Their potential antitumor activities were evaluated in vitro.Compound 2 exhibited proliferation inhibition and cytotoxicity against esophageal squamous cancer cells, especially KYSE-410 and KYSE-450 cells.Further analyses showed that compound 2 could significantly induce apoptosis through the activation of caspase 3/9 and down-regulation of the Bcl-2/Bax protein ratio.These results suggested that compound 2 had a significant inhibitory effect on the esophageal squamous cancer cells, especially KYSE-410, which deserves further research as a potential antitumor agent.

A new diphenyl butanedione from Astragalus membranaceus of northern Shanxi / 药学学报

Seven compounds were isolated from Astragalus membranaceus of northern shaanxi by silica gel and Sephadex LH-20 column chromatographies. Their chemical structures were identified on the basis of their physical and chemical properties. These compounds were elucidated as astragaloside IV (1), formononetin (2), calycosin (3), 1-(4-hydroxyphenyl)-4-(2,4-hydroxyphenyl)-2-hydroxy-1,4-but anedione (4), (E)-4-methylcinnamic acid (5), quercetin (6), and uridine (7). Compound 4 is a new compound and compound 5 was isolated from the plants of Astragalus Linn. for the first time. The results of in vitro antitumor activity assay showed that compound 4 could inhibit the proliferation of A549 with IC50 values of 11.41 μmol·L-1.

Bibliometric analysis for research hotspot and frontier of ursolic acid / 中国药房

OBJECTIVE To e xplore the research hots pots and development frontiers of ursolic acid in recent 20 years，and to provide reference for researchers in this field. METHODS Research literatures related to ursolic acid in Web of Science from Jan. ， 1，2002 to Dec. 31，2021 were collected ，and visualization analysis was performed on countries or regions ，research institutions ， authors，journals and keywords involved in the literatures using CiteSpace software ，to obtain the spatial and temporal distribution of ursolic acid and research frontiers. The research status and development frontier of ursolic acid were further analyzed by analyzing keywords co-occurrence ，keyword emergence ，keyword clustering ，etc. RESULTS & CONCLUSIONS Totally 3 528 valid papers were included in this study ，and the top three countries were China ，India and the United States. Analysis of publishing institutions showed that Chinese Academy of Sciences ，Univisity of Karachi and China Medical University were the top 3 research institutions in the list of publication amount. Analysis of published journals showed that Molecules （127 articles），Journal of Ethnopharmacology（90 articles），Journal of Agricultural and Food Chemistry （75 articles）had high number of literatures on ursolic acid. The analysis of keyword analysis showed that pharmacological effects ，such as antitumor activity of ursolic acid ， antioxidant activity ，antibacterial activity and anti-inflammatory activity ，are always the focus of the research ；the mechanism ursolic acid induced apoptosis ，oxidative stress and autophagy ，the research on ursolic acid signaling pathway ，drug delivery of ursolic acid nanoparticles were the research direction in the future.

Chemical constituents of Scrophulariae Radix and their antitumor activities in vitro / 中国中药杂志

The present study investigated the chemical constituents of Scrophulariae Radix and their antitumor activities in vitro. The compounds in the ethyl acetate extract were separated and purified by conventional column chromatographies(such as silica gel, Sephadex LH-20, and ODS column) and semi-preparative high-performance liquid chromatography(HPLC), and their structures were identified by various spectral techniques such as nuclear magnetic resonance(NMR) and mass spectrometry(MS). Twenty-three compounds were isolated and identified as benzyl-β-D-(3',6'-di-O-acetyl) glucoside(1), 5-O-p-methoxybenzoyl kojic acid(2), 5-O-methoxybenzoyl kojic acid(3), 7-O-methylbenzoyl kojic acid(4), 5-O-benzoyl kojic acid(5), methyl ferulate ethyl ether(6), trans-ferulic acid(7), trans-isoferulic acid(8), trans-caffeic acid(9), trans-caffeic acid methyl ester(10), caffeic acid ethyl ester(11), trans-cinnamic acid(12), trans-p-methoxycinnamic acid(13), trans-p-hydroxycinnamic acid(14), trans-p-hydroxycinnamic acid methyl ester(15), 2-(3,4-dihydroxyphenethyl) alcohol(16),(p-hydroxyphenyl) propanoic acid(17), coniferaldehyde(18), sinapaldehyde(19), benzyl β-primeveroside(20), 5-(hydroxymethyl) furfural(21), furan-2-carboxylic acid(22), and decanedioic acid(23). Among them, compound 1 is a new benzyl glucoside, compounds 2-4 are new pyranone compounds, compound 5 is a new natural product of pyranone. The NMR data of compounds 5 and 6 are reported for the first time. Compounds 6 and 20 were isolated from the Scrophularia plant for the first time. Compounds 8, 11, 14, 16, 18, 19, 22, and 23 were isolated from this plant for the first time. The in vitro cytotoxic activities of these compounds against three tumor cell lines(HepG2, A549, and 4 T1) were evaluated. The results showed that compounds 10 and 15 showed cytotoxic activities against HepG2 cells with IC_(50) values of(19.46±0.48) μmol·L~(-1) and(46.10±1.21) μmol·L~(-1).

Recent progress on betulinic acid and its derivatives as antitumor agents: a mini review / 中国天然药物

Natural products are one of the important sources for the discovery of new drugs. Betulinic acid (BA), a pentacyclic triterpenoid widely distributed in the plant kingdom, exhibits powerful biological effects, including antitumor activity against various types of cancer cells. A considerable number of BA derivatives have been designed and prepared to remove their disadvantages, such as poor water solubility and low bioavailability. This review summarizes the current studies of the structural diversity of antitumor BA derivatives within the last five years, which provides prospects for further research on the structural modification of betulinic acid.

Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC

Design, synthesis and antitumor activity of 3-arenobufagin esters / 药学实践杂志

Objective To search for novel potent 3-ester derivatives of arenobufagin and test their antitumor activities in vitro. Methods Target compounds were synthesized by esterification of arenobufagin with acids. CellTiter method was used to assay the in vitro antitumor activities. Results 3-Ester derivatives exhibited excellent antitumor activities against all the cancer cells. Conclusion Among the 3-ester derivatives, compound 2a had the best activities with the IC50 of 4.0−91.7 nmol/L and appeared to be a valuable candidate for further study.

Chemical constituents of Psidium guajava and their antitumor and antifungal activities / 中国中药杂志

Twenty-six compounds, including sixteen meroterpenoids(1-16), a triterpenoid(17), four terpenoid derivatives(18-21), and five aromatic compounds(22-26), were isolated from the leaves of Psidium guajava. Their structures were identified by spectroscopic analyses including NMR and MS. Compounds 21-26 were obtained from plants of Psidium for the first time. Based on the structure,(R)-2-ethylhexyl 2H-1,2,3-triazole-4-carboxylate(24 a), an α-glucosidase inhibitor recently isolated from Paramignya trimera, should be revised as compound 24. Meroterpenoids 1-16 were evaluated for their antitumor and antifungal activities. Meroterpenoids psiguajadial D(4), guapsidial A(5), 4,5-diepipsidial A(7), guadial A(14), and guadial B(15) showed cytotoxicities against five human tumor cell lines(HL-60, A-549, SMMC-7721, MCF-7, and SW-480), among which 5 was the most effective with an IC_(50) of 3.21-9.94 μmol·L~(-1).