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Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a key enzyme involved in the trimming of antigenic peptides presented by Major Histocompatibility Complex class I. It is a target of growing interest for the treatment of autoimmune diseases and in cancer immunotherapy. However, the discovery of potent and selective ERAP2 inhibitors is highly challenging. Herein, we have used kinetic target‐guided synthesis (KTGS) to identify such inhibitors. Co‐crystallization experiments revealed the binding mode of three different inhibitors with increasing potency and selectivity over related enzymes. Selected analogues engage ERAP2 in cells and inhibit antigen presentation in a cellular context. 4 d (BDM88951) displays favorable in vitro ADME properties and in vivo exposure. In summary, KTGS allowed the discovery of the first nanomolar and selective highly promising ERAP2 inhibitors that pave the way of the exploration of the biological roles of this enzyme and provide lead compounds for drug discovery efforts. [ABSTRACT FROM AUTHOR]

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H 2 S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H 2 S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H 2 S are thought to promote cancer, whereas high doses of exogenous H 2 S suppress tumor proliferation. Similarly, inhibition of endogenous H 2 S production also suppresses tumor proliferation. Accordingly, H 2 S biosynthesis inhibitors and H 2 S supplementation (H 2 S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H 2 S on pancreatic cancer has not been studied so far. However, H 2 S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H 2 S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H 2 S donors and NO–H 2 S dual donors on pancreatic cancer were summarized in this paper. Exogenous H 2 S donors may be promising compounds for pancreatic cancer treatment. The review summarizes the antitumor mechanisms of H 2 S donating derivatives against pancreatic cancer by modulating signaling pathways, including PI3K/AKT/mTOR, SHH, NF- κ B, MAPK, NOTCH, STAT3, DR4, etc. Perspectives on future directions and challenges are also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Propargyl esters of the C-28 carboxylic acids of pentacyclic triterpenes (oleanolic, ursolic, and maslinic acids) were coupled with 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide as well as N-(ω-azido-[C-2, C-6, and C-11]alkanoyl)-β-d-glucopyranosylamines under conditions of copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) to give tethered d-glucose–triterpene heteroconjugates. The O-acetyl protecting groups were removed by base-catalyzed hydrolysis. N-(ω-Azido-[C-2, C-6, C-11, and C-16]alkanoyl)-β-d-glucopyranosylamines were also tethered by 1,7-octadiyne under CuAAC conditions to furnish d-glucose homoconjugates. O-Deacetylation was carried out by the Zemplén protocol. The new compounds were assayed against rabbit muscle glycogen phosphorylase (RMGP) a or b enzymes. Some of the heteroconjugates inhibited the enzyme in the low micromolar range (IC50values 40–70 μM), while the homoconjugates proved inefficient as inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights: • A series of quinazolines have been designed to occupy three zones of colchicine domain. • 19c showed the most potent in vitro anti-proliferative activity. • 19c was identified as a tubulin polymerization inhibitor with potent vascular disrupting activity. • 19c was validated to occupy three zones of colchicine domain on in silico studies. • 19c exhibited potent tumor growth inhibition in H22 liver cancer xenograft mouse model. Abstract A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modeling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers. [ABSTRACT FROM AUTHOR]

In order to discover more effective and less toxic drugs in the field of anti-tumor, the backbone structure of 17 β -estradiol was modified, and 11 target compounds were synthesized. Compounds 5 and 10 , which exhibited better anti-tumor activity and higher selectivity (more than 10-fold), were chosen for further biological investigation. Flow cytometry results indicated that 5 and 10 could arrest MCF-7 cells in the G2 phase and induce apoptosis. Immunohistochemical analysis revealed that 5 and 10 could bind to the estradiol receptor alpha in MCF-7 cells. Western blotting and real-time PCR assays were performed to detect the effects of compounds on apoptosis-related targets at the protein and gene levels. These results showed that both 5 and 10 could dosed-dependently increase the expression of Apaf-1, Bax, caspase-3,8,9 and reduce the expression levels of the anti-apoptotic factors Bcl-2 and Bcl-xL. Besides, the Human apoptosis array assay demonstrated the expression level of death receptor Trail R2/DR5 was upregulated obviously while the expression of TNF R1, IAPs and Hsp27/60/70 were downregulated. On the whole, 5 induced MCF-7 cell death through the endogenous pathway in mitochondria and the exogenous pathway with death receptor Trail R2/DR5. • Eleven 17 β -estradiol derivatives from modification were synthesized. • 5 and 10 possessed much better antiproliferative activities and higher selectivity than 17 β -estradiol. • 5 and 10 could arrest cell cycle at the G2 phase in MCF-7 cells and partly bind with the estradiol receptor alpha. • 5 induced MCF-7 cells death through both endogenous and exogenous pathways. [ABSTRACT FROM AUTHOR]

Background Elimination half-life is an important pharmacokinetic parameter that determines exposure duration to approach steady state of drugs and regulates drug administration. The experimental evaluation of half-life is time-consuming and costly. Thus, it is attractive to build an accurate prediction model for half-life. Methods In this study, several machine learning methods, including gradient boosting machine (GBM), support vector regressions (RBF-SVR and Linear-SVR), local lazy regression (LLR), SA, SR, and GP, were employed to build high-quality prediction models. Two strategies of building consensus models were explored to improve the accuracy of prediction. Moreover, the applicability domains (ADs) of the models were determined by using the distance-based threshold. Results Among seven individual models, GBM showed the best performance ( R 2 = 0.820 and RMSE = 0.555 for the test set), and Linear-SVR produced the inferior prediction accuracy ( R 2 = 0.738 and RMSE = 0.672). The use of distance-based ADs effectively determined the scope of QSAR models. However, the consensus models by combing the individual models could not improve the prediction performance. Some essential descriptors relevant to half-life were identified and analyzed. Conclusions An accurate prediction model for elimination half-life was built by GBM, which was superior to the reference model (R 2 = 0.723 and RMSE = 0.698). General significance Encouraged by the promising results, we expect that the GBM model for elimination half-life would have potential applications for the early pharmacokinetic evaluations, and provide guidance for designing drug candidates with favorable in vivo exposure profile. This article is part of a Special Issue entitled “System Genetics” Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. [ABSTRACT FROM AUTHOR]

Despite the importance of monofluoroalkyl groups in pharmaceutically relevant molecules, catalytic protocols for their incorporation into alkenes remain limited. We describe herein a three-component acylmonofluoroalkylation of alkenes for the introduction of such moieties through an unprecedented cooperativity between the N-heterocyclic carbene catalyst and earth-abundant Mn(II) complex. This general method can be applied to a variety of alkenes, including styrenes, 1,3-enynes, and allenes, as well as complex substrates containing natural product and drug motifs.

USP7 has been regarded as a potential therapeutic target for cancer. In this study, virtual screening, molecular dynamics (MD) simulation, and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. Among the obtained compounds, compound 12 with a novel scaffold structure exhibited certain USP7 inhibitory activity (Ub-AMC assay IC 50 = 18.40 ± 1.75 μM, Ub-Rho assay IC 50 = 7.75 μM). The binding affinity between USP7 CD (USP7 catalytic domain) and this hit compound was confirmed with a K D value of 4.46 ± 0.86 μM. Preliminary in vitro studies disclosed its antiproliferative activity on human prostate cancer cell line LNCaP with an IC 50 value of 15.43 ± 3.49 μM. MD simulation revealed the detailed differences of protein-ligand interactions between USP7 CD and the ligands, including the reference compound ALM4 and compound 12 , providing some important information for improving the bioactivity of 12 . This hit compound will serve as a promising starting point for facilitating the further discovery of novel USP7 inhibitors.

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.

Background: Recently, we devoted to disclosing the antibacterial activities of enmein-type 6,7-seco-ent-kauranoid derivatives., Objective: Eleven new enmein-type diterpenoid derivatives with different substituents and drug-like properties were designed and synthesized., Method: The antimicrobial activities against E. coli, S. aureus, B. subtilis and M. albicans were disclosed. The antiproliferative activities against human cancer Bel-7402, K562, MGC-803 and CaEs-17 cells and non-cancerous L-02 cells were also measured by MTT method., Results: The results revealed that enmein-type diterpenoids showed more promising activities against tested gram-positive bacteria than gram-negative bacterium and fungus. Compound 9 with R of 2-quinolyl group exhibited the strongest antimicrobial activities with MIC values of 7.81 µg/ml and 0.98 µg/ml against S. aureus and B. subtilis, respectively. All the target derivatives exhibited superior cytotoxic activities to compounds 1 and 2 against tumor cells, and slight selectivity between cancerous cells and normal liver cells. Compound 12 with R of 3-(2-chloropyridyl) group and IC50 values of 0.7 µM, 0.9 µM, 0.8 µM and 2.0 µM agaist four tumor cells, respectively, was selected for further mechanism study in Bel-7402 cell line., Conclusion: Compound 12 could induce S phase cell cycle arrest and apoptosis at low concentrations via mitochondria-related pathways. The effects of compound 12 on some apoptosis related proteins showed that CDK2 was up regulated and ATM and cyclin A1 were down-regulated which confirmed the apoptosis and cell cycle effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oridonin belongs to ent-kaurane tetracyclic diterpenoid and was first isolated from Isodon species. It exhibits inhibitory activities against a variety of tumor cells, and pharmacological study shows that oridonin could inhibit cell proliferation, DNA, RNA and protein synthesis of cancer cells, induce apoptosis and exhibit an antimutagenic effect. In addition, the large amount of the commercially-available supply is also very important for the natural lead oridonin. Moreover, the good stability, suitable molecular weight and drug-like property guarantee its further generation of a natural-like compound library. Oridonin has become the hot molecule in recent years, and from the year 2010, more than 200 publications can be found. In this review, we summarize the synthetic medicinal chemistry work of oridonin from the first publication 40 years ago and share our research experience of oridonin for about 10 years, which may provide useful information to those who are interested in this research field., Competing Interests: The authors declare no conflict of interest.

Herein, we reported on a series of synthetic nitric oxide-releasing enmein-type diterpenoid hybrids (9a-i). All the target compounds showed potent antibacterial activity against selected Gram-positive bacteria S. aureus and B. subtilis. The antiproliferative activity against human tumor K562, MGC-803, CaEs-17 and Bel-7402 cells, and human normal liver cells L-02 was tested and the structure activity relationships (SARs) were also concluded. Compounds 9b and 9d showed the best activity against S. aureus and B. subtilis with the same minimal inhibitory concentrations (MICs) of 4 and 2 μg/mL, respectively. The derivative 9f displayed IC50 values of 1.68, 1.11, 3.60 and 0.72 μM against the four cancer cell lines above and 18.80 μM against normal liver cells L-02; meanwhile, 9f also released a high level of NO at the time point of 60 min of 22.24 μmol/L. Furthermore, it was also found that 9f induced apoptosis via the mitochondria-related pathway and arrested cell cycle of Bel-7402 cells at S phase. These findings might be important to explore new chemical entities for the main causes of in-hospital mortality of S. aureus infection, combined with a solid tumor.

Isodon rubescens has been used as a traditional green tea for more than 1000 years and many medicinal functions of I. rubescens are also very useful, such as its well-known antitumor and antibacterial activities. Oridonin, a bioactive ent-kaurane diterpenoid, is the major ingredient of this medicinal tea. Herein, 22 novel oridonin derivatives were designed and synthesized. The antibacterial activity was evaluated for the first time. Compound 12 was the most promising one with MIC of 2.0 μg/mL against B. subtilis, which was nearly 3-fold stronger than positive control chloromycetin. The antiproliferative property was also assayed and compound 19 showed stronger activity than taxol. The apoptosis-inducing ability, cell cycle arrest effect at S phase and influence of mitochondrial membrane potential by 19 in CaEs-17 cancer cells were first disclosed. Based on the above results, the cell apoptosis induced by compound 19 in CaEs-17 cells was most probably involved in the intrinsic apoptotic pathway.

Bredemolic acid (3) is a naturally occurring 2β,3α-isomer of maslinic acid (1) that is an allosteric site inhibitor of glycogen phosphorylase (GP). A practical synthesis of 3 was accomplished (18% yield) in five steps starting from the readily available 2β,3β-diol 6a. In a similar fashion, 2β,3α-dihydroxyurs-12-en-28-oic acid (4) was synthesized as a natural 2β,3α-isomer of corosolic acid (2). Compounds 3 and 4 exhibited significant inhibitory activity against rabbit muscle GPa with IC(50) values of 6.25 and 1.1 μM, respectively.

Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity ( 7, 18- 20) or no activity ( 21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.