Optimization and antifungal activity of quinoline derivatives linked to chalcone moiety combined with FLC against Candida albicans.

In present work, a series of quinoline derivatives linked to chalcone moiety have been prepared, and their in vitro and in vivo antifungal activities against C. albicans have been evaluated. The results indicated that quinoline combined with fluconazole (FLC) showed good inhibitory activity against C. albicans. Especially, compound PK-10 combined with FLC displayed the best antifungal activity against 14 FLC-resistant C. albicans strains with almost no cytotoxicity. Preliminary mechanistic studies proved that PK-10 combined with FLC could inhibit the hyphae formation of C. albicans, induce the accumulation of reactive oxygen species (ROS), the damage of mitochondrial membrane potential and the decrease of intracellular ATP content, which led to mitochondrial dysfunction. In vivo studies found obvious effects of the co-treatment regimen had obvious effects based on histological analysis, body weight curves, and coefficients of major organs. Therefore, the optimization of quinolone-chalcone derivatives combined with FLC could exert the potent antifungal activity in vitro and in vivo obviously, suggesting them as new agents to treat drug-resistant C. albicans infection.

Enhanced antibacterial activity of dimethyl gallium quinolinolates toward drug-resistant Klebsiella pneumoniae in low iron environments.

A series of dimethylgallium quinolinolate [GaMe2L] (L = 5-chloroquinolinolate, 5, 7-dichloroquinolinolate, 5, 7-dibromoquinolinolate or 5, 7-doiodoquinolinolate) complexes, shown previously to be active toward the Leishmania parasite, have been studied for their antibacterial activity toward a reference and drug resistant strain of Klebsiella pneumoniae (KP). The assays were conducted in standard iron-rich LB media and in the iron depleted RPMI and RPMI-HS media to better understand the effect of Fe concentration on the activity of the Ga complexes. In LB broth the parent quinolinols and the gallium complexes were inactive up to the highest concentration tested, 100 µM. In the more physiologically relevant 'iron-poor' RPMI-HS media the quinolonols remained inactive, however, the gallium complexes showed exceptional activity in the range 48-195 nM. Only in RPMI without any added HS did both the quinolinols and the gallium complexes show good activity. The significant differences in activity across the various media types suggest that the unnaturally high iron content of conventional LB media may provide false negative results for potentially potent Ga therapeutics. A protein binding assay on the organometallic gallium complexes showed a much slower uptake of Ga by Fe-binding proteins than is typically observed for gallium salts. This indicates that their greater lipophilicity and greater hydrolytic stability could account for their increased biological activity in RPMI-HS media.

Synthesis of new antiproliferative 1,3,4-substituted-pyrrolo[3,2-c]quinoline derivatives, biological and in silico insights.

A series of biologically unexplored substituted 1,3,4-subtituted-pyrrolo[3,2-c]quinoline derivatives (PQs) was evaluated against a panel of about 60 tumor cells (NCI). Based on the preliminary antiproliferative data, the optimizations efforts permitted us to design and synthesize a new series of derivatives allowing us to individuate a promising hit (4g). The insertion of a 4-benzo[d] [1,3]dioxol-5-yl moiety on increased and extended the activity towards five panel tumor cell lines such as leukemia, CNS, melanoma, renal and breast cancer, reaching IG50 in the low µM range. Replacement of this latter with a 4-(OH-di-Cl-Ph) group (4i) or introduction a Cl-propyl chain in position 1 (5), selectively addressed the activity against the entire leukemia sub-panel (CCRF-CEM, K-562, MOLT-4, RPMI-8226, SR). Preliminary biological assays on MCF-7 such as cell cycle, clonogenic assay, ROS content test alongside a comparison of viability between MCF-7 and non-tumorigenic MCF-10 were investigated. Among the main anticancer targets involved in breast cancer, HSP90 and ER receptors were selected for in silico studies. Docking analysis revealed a valuable affinity for HSP90 providing structural insights on the binding mode, and useful features for optimization.

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation.

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198-0.096 µM, compared to IC50 value of 0.19420 µM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 µM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

Design, synthesis and bioactivity evaluations of 8-substituted-quinoline-2-carboxamide derivatives as novel histone deacetylase (HDAC) inhibitors.

The inhibition of histone deacetylases (HDACs) has been considered a promising therapeutic strategy for treatment of many diseases, especially cancer. In the current study, a series of 8-substituted quinoline-2-carboxamide derivatives were designed and synthesized as potent HDAC inhibitors. The most potent compound 21 g (IC50 = 0.050 µM) exhibited 3-fold greater HDAC inhibitory activity compared to the known HDAC inhibitor Vorinostat (IC50 = 0.137 µM). Additionally, compound 21g exhibited low toxicity against normal cells(IC50 in HUVEC cell > 50 µM) and showed good liver microsomal stability, therefore, may serve as a new lead compound for further development.

The Neuroprotective Activities of the Novel Multi-Target Iron-Chelators in Models of Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Aging.

The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques. These novel iron chelators exhibit neuroprotective activities by attenuating relevant neurodegenerative pathology, promoting positive behavior changes, and up-regulating neuroprotective signaling pathways. Taken together, these results suggest that our multifunctional iron-chelating compounds can upregulate several neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders, such as PD, AD, ALS, and aging-related cognitive decline, in which oxidative stress and iron-mediated toxicity and dysregulation of iron homeostasis have been implicated.

Design, Synthesis and Biological Evaluation of Novel Quinoline Derivatives as Potential Anti-Proliferative Agents Against PC-3 and KG-1 Cells.

BACKGROUND: Cancer is a major public health problem worldwide, and is the leading cause of death. The discovery and development of cancer therapeutic drugs have become the most urgent measure, which significantly benefited from the usage of small molecule compounds. The quinoline core possessed a vast number of biological activities that were found to be imperative. OBJECTIVE: The aim is to design, synthesize and perform the biological evaluation of novel quinoline derivatives as potential anti-proliferative agents. METHODS: Quinoline as a privileged scaffold was adopted to introduce diverse effective nitrogen heterocycles through different linkers. The synthesized compounds were spectroscopically characterized and evaluated for their anti-proliferative activity using the CCK8 assay. The mechanism of action was investigated by flow cytometry and the inhibitory activity against Pim-1 kinase was measured by mobility shift assay. Molecular docking analysis was performed to rationalize biochemical potency as well. RESULTS: The majority of these quinolines displayed potent growth inhibitory effects, among which compounds 13e, 13f and 13h were the most effective ones, with GI50 values of 2.61/3.56, 4.73/4.88 and 4.68/2.98 µM, respectively. Structure-activity relationships indicated that both appropriate heterocycles at the C4 position of pyridine and suitable substituent at quinoline had a significant impact on improving activity. Compounds 13e and 24d exhibited moderate Pim-1 kinase inhibitory activity. CONCLUSION: In this study, three series of novel molecules bearing quinoline scaffold were designed, synthesized and evaluated for their in-vitro anti-proliferative activity. The most promising candidate, 13e, caused cell cycle arrest in a concentration-dependent manner and further induced apoptosis, which might represent a novel antiproliferative agent working through Pim-1 kinase inhibition to a certain extent.

Evaluation of potential bacterial protease inhibitor properties of selected hydroxyquinoline derivatives: an in silico docking and molecular dynamics simulation approach.

Antimicrobial drug resistance (AMR) is a severe global threat to public health. The increasing emergence of drug-resistant bacteria requires the discovery of novel antibacterial agents. Quinoline derivatives have previously been reported to exhibit antimalarial, antiviral, antitumor, antiulcer, antioxidant and, most interestingly, antibacterial properties. In this study, we evaluated the binding affinity of three newly designed hydroxyquinolines derived from sulfanilamide (1), 4-amino benzoic acid (2) and sulfanilic acid (3) towards five bacterial protein targets (PDB ID: 1JIJ, 3VOB, 1ZI0, 6F86, 4CJN). The three derivatives were designed considering the amino acid residues identified at the active site of each protein involved in the binding of each co-crystallized ligand and drug-likeness properties. The ligands displayed binding energy values with the target proteins ranging from -2.17 to -8.45 kcal/mol. Compounds (1) and (3) showed the best binding scores towards 1ZI0/3VOB and 1JIJ/4CJN, respectively, which may serve as new antibiotic scaffolds. Our in silico results suggest that sulfanilamide (1) or sulfanilic acid (3) hydroxyquinoline derivatives have the potential to be developed as bacterial inhibitors, particularly MRSA inhibitors. But before that, it must go through the proper preclinical and clinical trials for further scientific validation. Further experimental studies are warranted to explore the antibacterial potential of these compounds through preclinical and clinical studies.Communicated by Ramaswamy H. Sarma.

Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1).

Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.

Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity.

This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 µM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI50 and total growth inhibition (TGI) values against the cell lines. Three of the tested molecules exerted higher potency against most of the cell lines than the reference drug, sorafenib. Compound 1l indicated a higher potency than sorafenib against 53 of tested cancer cell lines. Compounds 1j-l demonstrated promising selectivity against cancer cells than normal cells. Moreover, compound 1l induced apoptosis and necrosis in RPMI-8226 cell line in a dose-dependent manner. In addition, compounds 1j-l were tested against C-RAF kinase as a potential molecular target. The three compounds showed high potency, and the most potent C-RAF kinase inhibitor was compound 1j with an IC50 value of 0.067 µM. In addition, Compounds 1j-l were further tested at 1 µM concentration against a panel of another twelve kinases and they showed a high selectivity for C-RAF kinase. Molecular modeling studies were performed to illuminate on the putative binding interactions of these motifs in the active site of C-RAF kinase. Additional studies were conducted to measure aqueous solubility, partition coefficient, and Caco-2 permeability of the most promising derivatives.

Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity.

Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.

Chemical Constituents of the Deep-Sea-Derived Penicillium solitum.

A systematic chemical investigation of the deep-sea-derived fungus Penicillium solitum MCCC 3A00215 resulted in the isolation of one novel polyketide (1), two new alkaloids (2 and 3), and 22 known (4-25) compounds. The structures of the new compounds were established mainly on the basis of exhaustive analysis of 1D and 2D NMR data. Viridicatol (13) displayed moderate anti-tumor activities against PANC-1, Hela, and A549 cells with IC50 values of around 20 µM. Moreover, 13 displayed potent in vitro anti-food allergic activity with an IC50 value of 13 µM, compared to that of 92 µM for the positive control, loratadine, while indole-3-acetic acid methyl ester (9) and penicopeptide A (10) showed moderate effects (IC50 = 50 and 58 µM, respectively).

In silico and multi-spectroscopic analyses on the interaction of 5-amino-8-hydroxyquinoline and bovine serum albumin as a potential anticancer agent.

5-Amino-8-hydroxyquinoline (5A8HQ), an amino derivative of 8-hydroxyquinoline, has become a potential anticancer candidate because of its promising proteasome inhibitory activity to overcome and yet synergize bortezomib for fighting cancers. Therefore, in this study, its physicochemical properties and interaction activities with serum protein have extensively been elucidated by both in vitro and in silico approaches to fulfill the pharmacokinetic and pharmacodynamic gaps. 5A8HQ exhibited the drug-likeness properties, where oral administration seems to be a route of choice owing to its high-water solubility and intestinal absorptivity. Multi-spectroscopic investigations suggested that 5A8HQ tended to associate with bovine serum albumin (BSA), a representative of serum protein, via the ground-state complexation. It apparently bound in a protein cleft between subdomains IIA and IIIA of BSA as suggested by the molecular docking and molecular dynamics simulations. The binding was mainly driven by hydrogen bonding and electrostatic interactions with a moderate binding constant at 104 M-1, conforming with the predicted free fraction in serum at 0.484. Therefore, 5A8HQ seems to display a good bioavailability in plasma to reach target sites and exerts its potent pharmacological activity. Likewise, serum albumin is a good candidate to be reservoir and transporter of 5A8HQ in the circulatory system.

7-[[(4-methyl-2-pyridinyl)amino](2-pyridinyl)methyl]-8-quinolinol (compound 30666) inhibits enhancer activity and reduces B-cell lymphoma growth - A question of specificity.

B-cell non-Hodgkin lymphoma (NHL) is among the ten most common malignancies. Survival rates range from very poor to over 90% and highly depend on the stage and subtype. Characteristic features of NHL are recurrent translocations juxtaposing an oncogene (e.g. MYC, BCL2) to the enhancers in the immunoglobulin heavy chain (IGH) locus. Survival and proliferation of many B-cell lymphomas depend on the expression of the translocated oncogene. Thus, targeting IGH enhancers as an anti-lymphoma treatment seems a promising strategy. Recently, a small molecule - 7-[[(4-methyl-2-pyridinyl)amino](2-pyridinyl)methyl]-8-quinolinol (compound 30666) was identified to decrease activity of the Eµ enhancer and reduce the expression of translocated oncogenes in multiple myeloma and some NHL cell lines (Dolloff, 2019). Here, we aimed to test the effect of compound 30666 in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) and shed light on its mechanism of action. We report that both IGH-translocation positive NHL cells as well as IGH-translocation negative B cells and non-B cell controls treated with compound 30666 exhibited consistent growth inhibition. A statistically significant increase in cell percentage in sub-G1 phase of cell cycle was observed, suggesting induction of apoptosis. Compound 30666 downregulated MYC levels in BL cell lines and altered IGH enhancer RNA expression. Moreover, a global decrease of H3K27ac and an increase of H3K4me1 was observed upon 30666 treatment, which suggests switching enhancers to a poised or primed state. Altogether, our findings indicate that 30666 inhibitor affects enhancer activity but might not be as specific for IGH enhancers as previously reported.

O-prenylated carbostyrils as a novel class of 15-lipoxygenase inhibitors: Synthesis, characterization, and inhibitory assessment.

Catalyzed peroxidation of unsaturated lipid in animals and plants intimately is linked to the activity of 15-Lipoxygenase enzymes. Lipoxygenases (LOXs) are well known to play an important role in many acute and chronic syndromes such as inflammation, asthma, cancer, and allergy. In this study, a series of mono prenyloxycarbostyrils were synthesized and evaluated as potential inhibitors of soybean 15-Lipoxygenase (SLO) and their inhibitory potencies were compared to mono prenyloxycoumarins which had been reported in the previous works. The synthetic compounds inhibit lipoxygenase enzyme by competitive mechanism like the prenyloxy coumarins. The results showed that position and length of the prenyl moiety play the important role in lipoxygenase inhibitory activity. Among all of the synthetic compounds (coumarin and carbostyril derivatives), 5-farnesyloxycoumarin and 8-farnesyloxycarbostyril demonstrated the best inhibitory activity by IC50  values of 1.1 µM and 0.53 µM, respectively.

Identification and Synthesis of DDI-6, a Quinolinol Analog Capable of Activating Both Caenorhabditis elegans and Mouse Spermatozoa.

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.

Development of new combination anti-leishmanial complexes: Triphenyl Sb(V) mono-hydroxy mono-quinolinolates.

In seeking to develop single entity combination anti-Leishmanial complexes six heteropletic organometallic Sb(V) hydroxido quinolinolate complexes of general formula [SbPh3(C9H4NORR')(OH)] have been synthesised and characterised, derived from a series of halide substituted quinolinols (8-hydroxyquinolines). Single crystal X-ray diffraction on all the complexes show a common distorted six-coordinate octahedral environment at the Sb(V) centre, with the aryl groups and nitrogen atom of quinolinolate ligand bonding in the equatorial planes, with the two oxygen atoms (hydroxyl and quinolinolate) occupying the axial plane in an almost linear configuration. Each complex was tested for their anti-promastigote activity and mammalian cytotoxicity and a selectivity indices established. The complexes displayed excellent anti-promastigote activity (IC50: 2.03-3.39 µM) and varied mammalian cytotoxicity (IC50: 12.7-46.9 µM), leading to a selectivity index range of 4.52-16.7. All complexes displayed excellent anti-amastigote activity with a percentage infection range of 2.25%-9.00%. All complexes performed substantially better than the parent quinolinols and comparable carboxylate complexes [SbPh3(O2CRR')2] indicating the synergistic role of the Sb(V) and quinolinol moieties in increasing parasite mortality. Two of the complexes [SbPh3(C9H4NOBr2)(OH)] 4, [SbPh3(C9H4NOI2)(OH)] 5, provide an ideal combination of high selective and good activity towards the leishmanial amastigotes and offer the potential as good lead compounds.

Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy.

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream ß-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells' P-glycoproteins (P-gp) through the JMJD1A/ß-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

Myricetin and M10, a myricetin-3-O-ß-d-lactose sodium salt, modify composition of gut microbiota in mice with ulcerative colitis.

Our previous studies found that M10, a myricetin-3-O-ß-d-lactose sodium salt, possessed higher effects of ameliorating ulcerative colitis (UC) than Myricetin in mice. Here, we aim to investigate whether the inhibition of UC is the consequence of the effects of M10 that leads to the changed microbiota. Mice model of UC was induced by dextran sulfate sodium (DSS) treatment. M10 and Myricetin were orally administrated for 12 weeks. We performed 16S rDNA sequencing assay to analyze the composition of gut microbiota isolated from ileocecum. Both M10 and Myricetin normalized the composition of Firmicutes and Actinobacteria as healthy mice had. At genus level, the effects of M10 and Myricetin on colitis were associated to the increase of probiotics, such as Akkermansia, and the inhibition of pathogenic microorganisms, such as Ruminococcus and Parabacteroides. M10 had stronger activity than Myricetin in the improvement of biosynthesis and degradation activities, resulting to increasing metabolism of sulfur, pyruvate, steroid biosynthesis and unsaturated fatty acid biosynthesis in gut. Furthermore, M10 normalized the proportion of Firmicutes and Actinobacteria in gut microbiota. It suggests that the improvements in UC are the consequence of the effect of M10 that leads to the changed intestinal microbiota. Conclusion: M10 contributed the pharmacological effects on UC by modification of the intestinal microbiota.

The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.

GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analogue, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analogue conjugated with BODIPY showed colocalization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (proteolysis targeting chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress, with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer. SIGNIFICANCE: This study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth in vitro and in vivo, demonstrating its potential as a therapeutic agent for pancreatic cancer.