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.

Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® assays. Studies in glioblastoma cell lines showed that the most active compound induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.

Design, synthesis and evaluation of a novel MEK protein inhibitors / 药学学报

This study was conducted to design and synthetize highly efficient, specific, non-resistant small MEK inhibitors. Based on active small molecules which have been reported, we studied the action mode with MEK protein using Autodock 4.2, generated innovative and feasible design method, designed novel small MEK protein inhibitors with a reference to molecular modeling and docking. The anti-tumor activities of four kinds of cells including MCF-7, PANC-1, SY5Y, A549 were tested with MTT method in vitro. The structure of 10 new small molecules has been determined with 1H NMR and 13C NMR. The compounds 4, 6, 7, 8, 10 had high antitumor activities, the compounds 1, 3, 5 also showed good activity, and the compounds 2, 9 showed cell selectivity in killing tumor.

Preparation and in vitro evaluation of pDNA-CaPi-PLGA nanoparticles with a core-shell structure / 药学学报

To develop a core-shell structure pDNA-CaPi-PLGA nanoparticles (CS-pDNA-CaPi-PLGA-NPs), calcium phosphate-pDNA nano complexes (CaPi-pDNA) were encapsulated inside of PLGA shells. The characteristics of the nanoparticles, including morphology, average particle size, zeta potential, entrapment efficiency, loading efficiency, stability in medium, pDNA protection ability from nuclease degradation, in vitro release, cytotoxicity and cell transfection were investigated and compared with the embedded structured CaPi modified PLGA nanoparticles (embedded-pDNA-CaPi-PLGA-NPs). The results showed that the obtained CS-pDNA-CaPi-PLGA-NPs were spherical in shape with an average particle size of (155 +/- 4.5) nm, zeta potentials of (-0.38 +/- 0.1) mV, entrapment efficiency of (80.56 +/- 2.5)% and loading efficiency of (1.16 +/- 0.04)%. The CS-pDNA-CaPi-PLGA-NPs were stable in the release media and could protect pDNA against nuclease degradation. And they also exhibited sustained release of pDNA in vitro. The highest gene transfection efficiency of the CS-pDNA-CaPi-PLGA-NPs in vitro reached (24.66 +/- 0.46)% (after 72 h transfection), which was significantly higher than that of free pDNA [(0.33 +/- 0.04)%, P < 0.01] and the pDNA-PLGA-NPs [(1.5 +/- 0.07)%, P < 0.01]. Besides, the transfection lasted for longer time than that of embedded-pDNA-CaPi-PLGA-NPs and the cytotoxicity of it was significantly lower than that of PEI (P < 0.01). These results indicate that CS-pDNA-CaPi-PLGA-NPs are a promising non-viral gene vector. Key words: gene delivery system; polylactic-co-glycolic acid; calcium phosphate; nanoparticle

Preparation and in vitro evaluation of pDNA-CaPi-PLGA nanoparticles with a core-shell structure / 药学学报

To develop a core-shell structure pDNA-CaPi-PLGA nanoparticles (CS-pDNA-CaPi-PLGA-NPs), calcium phosphate-pDNA nano complexes (CaPi-pDNA) were encapsulated inside of PLGA shells. The characteristics of the nanoparticles, including morphology, average particle size, zeta potential, entrapment efficiency, loading efficiency, stability in medium, pDNA protection ability from nuclease degradation, in vitro release, cytotoxicity and cell transfection were investigated and compared with the embedded structured CaPi modified PLGA nanoparticles (embedded-pDNA-CaPi-PLGA-NPs). The results showed that the obtained CS-pDNA-CaPi-PLGA-NPs were spherical in shape with an average particle size of (155 +/- 4.5) nm, zeta potentials of (-0.38 +/- 0.1) mV, entrapment efficiency of (80.56 +/- 2.5)% and loading efficiency of (1.16 +/- 0.04)%. The CS-pDNA-CaPi-PLGA-NPs were stable in the release media and could protect pDNA against nuclease degradation. And they also exhibited sustained release of pDNA in vitro. The highest gene transfection efficiency of the CS-pDNA-CaPi-PLGA-NPs in vitro reached (24.66 +/- 0.46)% (after 72 h transfection), which was significantly higher than that of free pDNA [(0.33 +/- 0.04)%, P < 0.01] and the pDNA-PLGA-NPs [(1.5 +/- 0.07)%, P < 0.01]. Besides, the transfection lasted for longer time than that of embedded-pDNA-CaPi-PLGA-NPs and the cytotoxicity of it was significantly lower than that of PEI (P < 0.01). These results indicate that CS-pDNA-CaPi-PLGA-NPs are a promising non-viral gene vector. Key words: gene delivery system; polylactic-co-glycolic acid; calcium phosphate; nanoparticle

Novel derivatives of diosgenin: design, synthesis and anti-tumor activity / 药学学报

Diosgenin can inhibit the growth of A375 and K562 cell lines and induce their apoptosis with an effect on pro-apoptotic members of Bcl-2 family. To study the SAR of diosgenin derivatives, and to improve the anti-tumor activity of diosgenin, a series of novel diosgenin derivatives were designed and synthesized. Their anti-tumor activities in vitro were evaluated. The results revealed that most of the new derivatives had potent effects against K562, A375 and A549 (three tumor cell lines) in vitro, and had no or less effect against H293 and L02 (two normal cell lines). Particularly, some compounds (e.g. 1, 6-8) showed excellent activities on K562 with IC50 values ranging from 1.96 to 4.35 micromol x L(-1).

Systematic studies on quality of main species of Herba epimedii / 中国中药杂志

<p><b>OBJECTIVE</b>To achieve the quality control of Herba Epimedii, and to evaluate the quality of medical materials of the 8 official species including the 5 species recorded in 'Chinese Pharmacopoeia' including Epimedium brevicornum, E. sagittatum, E. pubescens, E. koreanum and E. wushanense, and the 3 other species (E. acuminatum, E. myrianthum, E. leptorrhizum) recorded in 'Guizhou Quality Criteria for Traditional Chinese Medical Material and Nationality Medical Material', and E. pseudowushanuse (new species) which is used as E. wushanense for a long time.</p><p><b>METHOD</b>The contents of icariin and total flavonoids of 102 samples of 9 officinal species of Herba Epimedii were determined by HPLC and UV, respectively.</p><p><b>RESULT AND CONCLUSION</b>The contents of icariin in about 30% of the samples of the 5 species recorded in 'Chinese Pharmacopoeia' were lower than 0.5%, which is acceptable quality recorded in 'Chinese Pharmacopoeia'. Refering the literatures, we suggested the total contents of epimedin A, B, C and icariin (epi-medium multi-glycosides, ABCI) should be established as a new standard instead of the content of icariin. The content of total flavonoids, not less than 5.0%, and ABCI, not less than 1.3%, could be used to evaluate the quality of the above medical materials efficiently.</p>