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Blocking the System X c −_ GSH_GPX4 pathway to induce ferroptosis in tumor cells is a novel strategy for cancer treatment. GPX4 serves as the core of the System Xc-/GSH/GPX4 pathway and is a predominant target for inducing ferroptosis in tumor cells. This article summarizes compounds identified in current research that directly target the GPX4 protein, including inhibitors, activators, small molecule degraders, chimeric degraders, and the application of combination therapies with other drugs, aiming to promote further research on the target and related diseases. [Display omitted] • This article provides an overview and research progress of the small molecules targeting GPX4. • The characteristics, advantages and limitations of these compounds are summarized. • The application of combination therapies with other drugs are also mentioned. [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]

Abstract: Synthesis and biological evaluation of glucoconjugates of oleanolic acid, linked by either a triazole moiety or an ester function, as novel inhibitors of glycogen phosphorylase have been described. Several triterpene–glycoside conjugates exhibited moderate-to-good inhibitory activity against rabbit muscle GPa. Compound 12 showed the best inhibition with an IC50 value of 1.14μM. Structure–activity relationship (SAR) analysis of these inhibitors is also discussed. Possible binding modes of compound 12 were explored by molecular docking simulations. [Copyright &y& Elsevier]

• Nitric oxide donating chelidonine derivatives were synthesized. • 11j showed selectivity against cancer and normal cell lines. • 11j induced apoptosis through mitochondria related pathway. • 11j influenced the intrinsic pathway by regulating apoptosis-related proteins. To get chelidonine derivatives with enhanced antiproliferative activity and selectivity, a series of nitric oxide donating derivatives (10a-f and 11a-j) were designed, synthesized and biologically evaluated. Compared with chelidonine, these compounds exhibited lower IC 50 values against human hepatoma cells HepG2, breast cancer cells MCF-7, colon cancer cells HCT-116, as well as leukemia cells K562. Compound 11j displayed the strongest antiproliferative activity with IC 50 values of 3.91, 6.90, 4.36 and 1.12 μM against the above four cells, respectively. Nevertheless, it showed an IC 50 value >40 μM against human peripheral blood mononuclear cells (PBMCs), which demonstrated high selectivity between normal and cancer blood cells. In further mechanism studies, 11j showed the capability to induce K562 cells apoptosis, S phase cell cycle arrest and mitochondrial membrane potential disorder. Besides, 11j was found to be effective in promoting the expression of proapoptotic protein Bad and suppressing the expression of anti-apoptotic proteins Bcl-xL, catalase, survivin, claspin and clusterin. [ABSTRACT FROM AUTHOR]

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]

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]

Abstract: The synthesis and biological evaluation of corosolic acid derivatives and related compounds as inhibitors of rabbit muscle glycogen phosphorylase a is described. Within this series of compounds, 8 (IC50 =7.31μM), 12d (IC50 =3.26μM), and 12e (IC50 =5.1μM) exhibited more potent activities than the parent compound 1 (IC50 =20μM). SAR of these compounds is also discussed. [Copyright &y& Elsevier]

Oxazolidin-2-one served as a class of highly important nitrogen-containing five-membered heterocycles has been found in a wide range of biologically active molecules and chiral ligands. Consequently, its synthesis has attracted significant attention from chemists, leading to extensive investigations in this area. In this study, we developed a novel and more sustainable synthetic approach, using BF 3 ·Et 2 O as the catalyst to facilitate intramolecular oxo-Michael addition reactions of Boc-protected p -quinoamines. This approach allowed for the efficient construction of diverse polycyclic fused oxazolidin-2-one compounds and yields up to 98 %. Furthermore, the anti-tumor activity of these structurally unique oxazolidin-2-one derivatives was reported. [Display omitted] [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]

Abstract To explore antitumor agents with potent efficacy and low toxicity, scutellarein derivatives with benzoic acid mustard (10a − c , 11a − c and 13a − c) were designed and synthesized. The antiproliferative activities of the target derivatives against A549, MCF-7 and Bel-7402 cancer cell lines were tested. Compound 10a showed the strongest potency with an IC 50 value of 1.50 μM against MCF-7 cell line, and displayed low toxicity against human liver L-O2 normal cells (IC 50 > 50 μM), showing specificity between normal and malignant cells. The mechanism studies revealed that 10a could induce apoptosis in MCF-7 cells, arrest MCF-7 cell cycle at the G1 phase and cause mitochondrial dysfunction in a concentration-dependant manner. Furthermore, the enhanced expression of the pro-apoptotic proteins caspase-9, caspase-3, Bax and cytochrome c , and the reduced expression of the anti-apoptotic protein Bcl-2 confirmed that 10a induced the intrinsic apoptosis pathway in MCF-7 cells. The potent antiproliferative activity and good selectivity guaranteed 10a a lead compound for the further development into anticancer therapeutics, especially for breast cancer. Graphical abstract Image 1 Highlights • Hybrids of scutellarein and benzoic acid mustard were designed and synthesized. • Some exhibited potent antiproliferative activities with low IC 50 values. • Compound 10a showed good selectivity between human normal and tumor cells. • 10a induced apoptosis and arrest cell cycle at G1 phase in MCF-7 cells. • 10a induced MCF-7 cells apoptosis via the mitochondria-dependent pathways. [ABSTRACT FROM AUTHOR]

Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase. It is emerging as a promising target for the development of drugs to treat cancer and metabolism-related diseases. In this study, we screened 5000 compounds and identified a hit compound 14 bearing a pyrazolone functional group as a novel SIRT5-selective inhibitor. Structure-based optimization of 14 resulted in compound 47 with an IC 50 value of 0.21 ± 0.02 μM and a 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 over SIRT1-3 and SIRT6. Biochemical studies suggest that 47 does not occupy the NAD + -binding pocket and acts as a substrate-competitive inhibitor. The identified potent and selective SIRT5 inhibitors allow further studies as research tools and therapeutic agents. [Display omitted] • Hit compound 14 bearing a pyrazolone skeleton was identified as a SIRT5 inhibitor. • Extensive SAR studies guided by molecular docking were conducted. • Compound 47 showed a 100-fold increased potency as compared to the original hit. [ABSTRACT FROM AUTHOR]

To explore novel antitumor agents with high efficiency and low toxicity, a series of NO-donating scutellarin derivatives ( 14 – 17 ) were synthesized and the antiproliferative activities against MCF-7, HCT-116, PC-3 and HepG2 cancer cell lines were assessed. Among them, compound 14b was the strongest with IC 50 values of 2.96 μ M, 7.25 μ M, 0.09 μ M and 0.50 μ M, respectively, and displayed low toxicity against normal human liver L-O2 cells with an IC 50 of 47.96 μ M, showing good selectivity between normal and malignant liver cells. Moreover, NO releasing ability of the derivatives has been studied. Mechanism studies of the most promising compounds 14b and 15a were carried out. The results indicated that 14b and 15a could induce apoptosis, cell cycle arrest at the S phase and led to mitochondrial dysfunction in the HepG2 and PC-3 cell lines, respectively. Furthermore, Human Apoptosis Protein Array kit assay demonstrated that 14b could induce apoptosis through down-regulating the levels of procaspase-3 and inhibiting the expression of survivin, c-IAP1, HSP27, HSP60, HSP70, HO-1/HMOX1/HSP32 and HO-2/HMOX2 in HepG2 cell line. These results guaranteed compound 14b to be a drug candidate against liver cancer for further investigation. [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]

The newly synthesized glycine- l -phenylalanine conjugates 11 and 16 have good anticancer activity. In vivo and in vitro experiments showed that both compounds inhibit the growth of solid tumors by inducing apoptosis of cancer cells. [Display omitted] • 37 triterpenoid acid derivatives linked to l -phenylalanine or l -proline were synthesized. • Glycyrrhetinic acid (GA) derivatives 11 (IC 50 = 0.2 μM) and 16 (IC 50 = 0.7 μM) are much more potent than GA. • 11 and 16 showed significant tumor growth inhibition in A549 and T24 tumor xenograft model, respectively. • 16 showed low toxicity in vitro and in vivo experiments. • The mechanisms of action of compounds 11 and 16 were extensively investigated. Extensive research effort has been put in pentacyclic triterpenoids due to their numerous biological activities. However, their poor water solubility and low oral bioavailability limit their antitumor effects in vivo. To address these issues, 37 triterpenoid acid derivatives linked to l -phenylalanine or l -proline were designed and synthesized in this study. Structure-activity relationship (SAR) studies found two promising glycyrrhetinic acid (GA) derivatives 11 and 16. Compound 11 was obtained by C3-OH esterification and C30-COOH modification with l -phenylalanine while 16 was obtained by attaching C3-OH with l -phenylalanine. Compounds 11 and 16 exhibit up to 48- and 120-fold improvement respectively compared with the IC 50 values of naturally occurring GA in the cellular assay. Fluorescence microscope and flow cytometric analysis suggested that both compounds 11 and 16 increased the content of ROS and Ca2+ in cancer cells, decreased mitochondrial membrane potential (JC-1), and activated the regulator caspase-3/8/9 to trigger cell apoptosis. RNA-seq analysis and western blot analysis indicated that compounds 11 and 16 may promote apoptosis by upregulating the functions of pro-apoptotic factors while inhibiting the proteasome activity. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) and its auto-oxidation products are known to disrupt normal bacterial function and NO releasing molecules have the potential to be developed as antibacterial leads in drug discovery. We have designed and synthesized a series of novel nitrated compounds by combining NO releasing groups with ocotillol-type triterpenoids, which have previously demonstrated activity only against Gram-positive bacteria. The in vitro NO release capacity and antibacterial activity were sequentially evaluated and the data showed that most of the synthesized compounds could release nitric oxide. Compound 16a , 17a and 17c , with nitrated aliphatic esters at C-3 position, displayed higher NO release than other analogues, correlating to their good antibacterial activity, in which 17c demonstrated broad-spectrum activity against both Gram positive and -negative bacteria, as well as excellent synergism at sub-minimum inhibitory concentration when using with kanamycin and chloramphenicol. Furthermore, the epifluorescent microscopic study indicated that the ocotillol-type triterpenoid core may induce NO release on the bacterial membrane. Our results demonstrate that nitrated substitutions at C-3 of ocotillol-type derivatives could provide an approach to expand their antibacterial spectrum, and that ocotillol-type triterpenoids may also be developed as appropriate carriers for NO donors in antibacterial agent discovery with low cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure–activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1μM. [Copyright &y& Elsevier]

Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation. Image 1 • The synthetic strategies, structural modification sites and potent derivatives of renieramycins were summarized. • The structures and their features were listed. • Anti-tumor activities and mechanisms were reviewed. [ABSTRACT FROM AUTHOR]

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases. Image 1 • δ-Oleanolic acid was identified as a potent AMPK activator. • 23 new saponin derivatives of δ-oleanolic acid were synthesized and biologically evaluated. • The bioavailability of saponins 29 and 33 was much better than their aglycon. • Saponin 29 exhibited significant in vitro and in vivo anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease. Image 1 • A series of novel AdipoRon analogues were designed and synthesized. • Six analogues exhibited much more potency of AMPK activation than AdipoRon. • B10 exhibited significant in vitro and in vivo hypoglycemic effects in mice. • B10 did not inhibit mitochondrial complex I. • B10 did not cause cardiac hypertrophy in mice. [ABSTRACT FROM AUTHOR]

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC 50 = 40.8 nM, K D = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC 50 = 29.6 nM) and RS4; 11 (IC 50 = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors. Image 1 • Fifty-five piperidinol derivatives were synthesized and biologically evaluated. • Compound L55 exhibited potent USP7 inhibitory activity (IC 50 = 40.8 nM). • X-ray crystallographic studies revealed a new pose for L55 to bind to USP7. • L55 downregulated MDM2 and DNMT1 and upregulated p53 and p21 in RS4; 11 cells. • LNCaP (IC 50 = 29.6 nM) and RS4; 11 (IC 50 = 41.6 nM) were highly sensitive to L55. [ABSTRACT FROM AUTHOR]