A review of structural modification and biological activities of oleanolic acid.

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since its initial isolation and identification, numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives. Despite this, there has been a dearth of comprehensive reviews in the past two decades, leading to challenges in subsequent research on OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships (SARs) of OA and its derivatives to provide valuable reference for future investigations into OA.

Hybrid chalcogen bonds in prodrug nanoassemblies provides dual redox-responsivity in the tumor microenvironment.

Sulfur bonds, especially trisulfide bond, have been found to ameliorate the self-assembly stability of homodimeric prodrug nanoassemblies and could trigger the sensitive reduction-responsive release of active drugs. However, the antitumor efficacy of homodimeric prodrug nanoassemblies with single reduction-responsivity may be restricted due to the heterogeneous tumor redox microenvironment. Herein, we replace the middle sulfur atom of trisulfide bond with an oxidizing tellurium atom or selenium atom to construct redox dual-responsive sulfur-tellurium-sulfur and sulfur-selenium-sulfur hybrid chalcogen bonds. The hybrid chalcogen bonds, especially the sulfur-tellurium-sulfur bond, exhibit ultrahigh dual-responsivity to both oxidation and reduction conditions, which could effectively address the heterogeneous tumor microenvironment. Moreover, the hybrid sulfur-tellurium-sulfur bond promotes the self-assembly of homodimeric prodrugs by providing strong intermolecular forces and sufficient steric hindrance. The above advantages of sulfur-tellurium-sulfur bridged homodimeric prodrug nanoassemblies result in the improved antitumor efficacy of docetaxel with satisfactory safety. The exploration of hybrid chalcogen bonds in drug delivery deepened insight into the development of prodrug-based chemotherapy to address tumor redox heterogeneity, thus enriching the design theory of prodrug-based nanomedicines.

Design, synthesis, and evaluation of novel 3,4-isoxazolediamide derivatives for the combination treatment of azole-resistant candidiasis.

Invasive fungal infections are emerging as serious infectious diseases worldwide. Due to the frequent emergence of resistance, the cure for invasive fungal infections is often unachievable. The molecular chaperone Hsp90 provides a promising target because it supports survival, virulence, and drug resistance in a variety of pathogens. Herein, we report on the structural optimization and structure-activity relationship studies of 3,4-isoxazolediamide analogs. As a new class of fungal Hsp90 inhibitor, compound B25 was found to have good synergistic effects with fluconazole and to avoid potential mammalian toxicity. It also showed remarkable metabolic stability in vitro. Collectively, B25 could be a promising lead compound for drug discovery targeting fungal Hsp90 and deserves further investigation.

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis.

Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5-diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.

Recent progress on betulinic acid and its derivatives as antitumor agents: a mini review.

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.

Design, synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors.

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 µM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 µM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.

Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii.

Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of R. chingii fruits exhibited significant PTP1B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1B inhibitory ursane-type triterpenes: ursolic acid (1), 2-oxopomolic acid (2), and 2α, 19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3). Kinetics analyses revealed that 1 was a non-competitive PTP1B inhibitor, and 2 and 3 were mixed type PTP1B inhibitors. Compounds 1-3 and structurally related triterpenes (4-8) were further analyzed the structure-activity relationship, and were evaluated the inhibitory selectivity against four homologous protein tyrosine phosphatases (TCPTP, VHR, SHP-1 and SHP-2). Molecular docking simulations were also carried out, and the result indicated that 1, 3-acetoxy-urs-12-ene-28-oic acid (5), and pomolic acid-3ß-acetate (6) bound at the allosteric site including α3, α6, and α7 helix of PTP1B.

Identification of caffeoylquinic acid derivatives as natural protein tyrosine phosphatase 1B inhibitors from Artemisia princeps.

Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1-10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC50 11.1 µM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B. Furthermore, compound 3 showed remarkable selectivity against four homologous PTPs. According to these findings, compound 3 might be potentially valuable for further drug development.

Allergy-preventive effects of linarinic acid and its tetrahydropyrrolo[2,1-b]quinazoline derivatives isolated from Linaria vulgaris.

Linarinic acid, (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid (4a), was isolated from the ethanol extract of Linaria vulgaris Mill. In our previous study, a series of tetrahydropyrrolo[2,1-b]quinazoline derivatives 4b, 4c, 5a, 5b, 6a and 6b that were structurally related to 4a and evaluated as neuroprotective agents were synthesized. The aim of the present study was to investigate the novel features of these compounds. We examined their allergy-preventive effects using an in vivo assay system we developed previously, that monitors a decrease in blood flow in the tail vein of mice subjected to sensitization with hen egg-white lysozyme. We observed that 4a and its three derivatives, amide (6a), ester (5a), bromine (4b), and alcohol substituent (6b), showed significant allergy-preventive activities. The study confirmed the allergy-preventive activity of tetrahydropyrrolo[2,1-b]quinazoline derivatives by comprehensively monitoring the specific blood flow decrease occurring in the induction phase of allergy. This finding may aid in the development of new agents for the treatment of allergic diseases such as atopic dermatitis, allergic asthma, and hay fever.

(-)-ß-hydrastine suppresses the proliferation and invasion of human lung adenocarcinoma cells by inhibiting PAK4 kinase activity.

(-)-ß-hydrastine is one of the main active components of the medicinal plant, Hydrastis canadensis, which is used in many dietary supplements intended to enhance the immune system. However, whether (-)-ß-hydrastine affects the tumor signaling pathway remains unexplored. In the present study, we found that (-)-ß-hydrastine inhibited the kinase activity of p21-activated kinase 4 (PAK4), which is involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. In the present study, (-)-ß-hydrastine suppressed lung adenocarcinoma cell proliferation by inhibiting expression of cyclin D1/D3 and CDK2/4/6, leading to cell cycle arrest at the G1 phase, in a PAK4 kinase-dependent manner. Moreover, inhibition of PAK4 kinase activity by (-)-ß-hydrastine also promoted the early apoptosis of lung adenocarcinoma cells through the mitochondrial apoptosis pathway. In addition, (-)-ß-hydrastine significantly suppressed the migration and invasion of human lung adenocarcinoma cells in conjunction with concomitant blockage of the PAK4/LIMK1/cofilin, PAK4/SCG10 and PAK4/MMP2 pathways. All of these data indicate that (-)-ß-hydrastine, as a novel PAK4 inhibitor, suppresses the proliferation and invasion of lung adenocarcinoma cells. Taken together, these results provide novel insight into the development of a PAK4 kinase inhibitor and a potential therapeutic strategy for lung cancer.

In vitro and in vivo studies of the metabolic activation of 8-epidiosbulbin E acetate.

Furanoid 8-epidiosbulbin E acetate (EEA) is a major constituent of herbal medicine Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Our preliminary studies demonstrated that administration of EEA caused acute hepatotoxicity in mice, and the observed toxicity required cytochromes P450-mediated metabolism. Metabolic activation studies of EEA were performed in vitro and in vivo. Microsomal incubations of EEA supplemented with N-acetyl lysine (NAL) and glutathione (GSH) generated six metabolites (M1-M6). M1-M4 were characterized as pyrrole derivatives, and M5 and M6 were pyrrolinones. M2-M6 were detected in bile and/or urine of rats given EEA. Dimethyldioxirane-mediated oxidation of EEA in the presence of NAL and GSH produced M1-M6, all of which were generated in microsomal incubations. The structures of M3 and M6 were confirmed by (1)H and (13)C NMR. These findings provide evidence for the metabolic activation of EEA to the corresponding cis-enedial intermediate both in vitro and in vivo. Ketoconazole inhibited the microsomal production of the cis-enedial, and P450 3A4 was found to be the primary enzyme involved in the bioactivation of EEA.

Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors.

A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC50 value of 1.04nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity.

Desoxyrhapontigenin up-regulates Nrf2-mediated heme oxygenase-1 expression in macrophages and inflammatory lung injury.

Heme oxygenase-1 (HO-1) is an important anti-inflammatory, antioxidative and cytoprotective enzyme that is regulated by the activation of the major transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In the present study, six stilbene derivatives isolated from Rheum undulatum L. were assessed for their antioxidative potential. In the tert-butylhydroperoxide (t-BHP)-induced RAW 264.7 macrophage cell line, desoxyrhapontigenin was the most potent component that reduced intracellular reactive oxygen species (ROS) and peroxynitrite. In response to desoxyrhapontigenin, the mRNA expression levels of antioxidant enzymes were up-regulated. An electrophoretic mobility shift assay (EMSA) confirmed that desoxyrhapontigenin promoted the DNA binding of Nrf2 and increased the expression of antioxidant proteins and enzymes regulated by Nrf2. Further investigation utilizing specific inhibitors of Akt, p38, JNK and ERK demonstrated that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediates HO-1 expression. Moreover, the increase in Nrf2 expression mediated by treatment with desoxyrhapontigenin was reversed by Nrf2 or Akt gene knock-down. In the LPS-induced in vivo lung inflammation model, pretreatment with desoxyrhapontigenin markedly ameliorated LPS-induced lung inflammation and histological changes. Immunohistochemical analysis of Nrf2, HO-1 and p65 was conducted and confirmed that treatment with desoxyrhapontigenin induced Nrf2 and HO-1 expression but reduced p65 expression. These findings suggest that desoxyrhapontigenin may be a potential therapeutic candidate as an antioxidant or an anti-inflammatory agent.

Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors.

A series of novel quinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC50]=1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-ß, c-Kit, and EGFR. Structure-activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.

Synthesis and activity of tetrapeptidic HTLV-I protease inhibitors possessing different P3-cap moieties.

The causative agent behind adult T-cell leukemia and tropical spastic paraparesis/HTLV-I-associated myelopathy is the human T-cell leukemia virus type 1 (HTLV-I). Tetrapeptidic HTLV-I protease inhibitors were designed on a previously reported potent inhibitor KNI-10516, with modifications at the P(3)-cap moieties. All the inhibitors showed high HIV-1 protease inhibitory activity (over 98% inhibition at 50nM) and most exhibited highly potent inhibition against HTLV-I protease (IC(50) values were less than 100nM).

Synthesis and antitumor activity of two natural N-acetylglucosamine-bearing triterpenoid saponins: lotoidoside D and E.

Two natural triterpenoid saponins bearing N-acetylglucosamine, lotoidoside D and lotoidoside E, which had been available only from Glinus lotoides growing in Egyptian desert, were facilely synthesized from readily available oleanolic acid. Preliminary pharmacological research showed their antitumor activity against HeLa cell.

A new pyrroloquinazoline alkaloid from Linaria vulgaris.

A new alkaloid, 1,2,3,9-tetrahydropyrrolo(2,1-b)quinazolin-1-carboxylic acid (1), together with eight known compounds, 7-hydroxy vasicine (2), benzyl alcohol beta-D-(2'-O-beta-xylopyranosyl)glucopyranoside (3), benzyl alcohol O-beta-D-glucopyranoside (4), benzyl alcohol O-beta-D-primveroside (5), 3,5-dimethyl-4-hydroxy benzaldehyde (6), gluco-syringic acid (7), syringin (8), and liriodendrin (9), were isolated from the plants of Linaria vulgaris. Their structures were established by spectroscopic methods.