Pressure Driven Fractionalization of Ionic Spins Results in Cupratelike High-T_{c} Superconductivity in La_{3}Ni_{2}O_{7}.

Beyond 14 GPa of pressure, bilayered La_{3}Ni_{2}O_{7} was recently found to develop strong superconductivity above the liquid nitrogen boiling temperature. An immediate essential question is the pressure-induced qualitative change of electronic structure that enables the exciting high-temperature superconductivity. We investigate this timely question via a numerical multiscale derivation of effective many-body physics. At the atomic scale, we first clarify that the system has a strong charge transfer nature with itinerant carriers residing mainly in the in-plane oxygen between spin-1 Ni^{2+} ions. We then elucidate in electron-volt scale and sub-electron-volt scale the key physical effect of the applied pressure: it induces a cupratelike electronic structure via fractionalizing the Ni ionic spin from 1 to 1/2. This suggests a high-temperature superconductivity in La_{3}Ni_{2}O_{7} with microscopic mechanism and (d-wave) symmetry similar to that in the cuprates.

Geometric frustration produces long-sought Bose metal phase of quantum matter.

Two of the most prominent phases of bosonic matter are the superfluid with perfect flow and the insulator with no flow. A now decades-old mystery unexpectedly arose when experimental observations indicated that bosons could organize into the formation of an entirely different intervening third phase: the Bose metal with dissipative flow. The most viable theory for such a Bose metal to date invokes the use of the extrinsic property of impurity-based disorder; however, a generic intrinsic quantum Bose metal state is still lacking. We propose a universal homogeneous theory for a Bose metal in which geometric frustration confines the essential quantum coherence to a lower dimension. The result is a gapless insulator characterized by dissipative flow that vanishes in the low-energy limit. This failed insulator exemplifies a frustration-dominated regime that is only enhanced by additional scattering sources at low energy and therefore produces a Bose metal that thrives under realistic experimental conditions.

Discovery of a tetrahydroisoquinoline-based HDAC inhibitor with improved plasma stability.

Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t1/2=630min) was over 5-fold improved than its parent 1 (t1/2=103min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model.

LJNK, an indoline-2,3-dione-based aminopeptidase N inhibitor with promising antitumor potency.

In our previous study, we found that LJNK showed potent aminopeptidase N (APN)-inhibitory activity. In the current study, we further evaluated the antitumor effects of LJNK both in vitro and in vivo. Enzyme experiments showed that LJNK showed better inhibitory activity than bestatin against APN both from human carcinoma cells' surface and from porcine kidney microsomes. In addition, LJNK could suppress rat aortic ring microvessel growth and HUVEC tubular structure formation, which showed its stronger antiangiogenesis effects than bestatin. [(3-[4,5-Dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide)] assay and clonogenic assay showed that LJNK suppressed cancer cell growth both in the short and the long term. Mice bearing H22 transplantation tumor proved its antitumor effects in vivo. Annexin V-fluorescein isothiocyanate/propidium iodide assay showed that LJNK could induce 28.1% PLC/PRF/5 cell apoptosis and the apoptotic pathway was probably identified by western blot. The above-mentioned results suggested that LJNK inhibited cell proliferation and angiogenesis, and induced apoptosis by decreasing APN activity.

Discovery of a novel chimeric ubenimex-gemcitabine with potent oral antitumor activity.

Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of gemcitabine in vitro. Further characterization also demonstrated that compound BC-A1 exhibited significant anti-invasion and anti-angiogenesis effects in vitro. The preliminary stability test of BC-A1 revealed that it could release gemcitabine in vitro. The in vivo anti-tumor results in liver cancer showed that at the same dosage, oral administration of BC-A1 was as potent as intraperitoneal administration of gemcitabine. This warranted the further research and development of the orally active prodrug BC-A1 because gemcitabine can not be orally administrated in clinic.

Synthesis and biological evaluation of novel histone deacetylases inhibitors with nitric oxide releasing activity.

A novel series of histone deacetylases inhibitors (HDACIs) containing benzofuroxan pharmacophore as nitric oxide (NO) donor were designed based on the combination principle and 'multifunctional drugs' theory. As a novel study on embedding NO donor into the structure of HDACIs, all designed hybrid compounds, especially 19d and 24d, displayed remarkable HDACs inhibitory activity and outstanding antiproliferative activity on tumor cells. Besides, they could produce high levels of NO in HCT-116 cells; furthermore, their antiproliferative activity on HCT-116 cells could be diminished by pretreatment with hemoglobin, as the NO scavenger, in a dose-dependent manner. All in all, our designed compounds displayed great inhibitory activities and might offer a prospective avenue to discover novel anti-cancer drugs.

[Preparation and in vitro characterization of apigemin-loaded nanostructured lipid carriers].

OBJECTIVE: To prepare Apigemin-loaded nanostructured lipid carriers (Api-NLCs) and evaluate their characteristics. METHODS: Api-NLCs were prepared by the method of emulsion evaporation-solidification at low temperature. The physicochemical properties such as morphology, size distribution, zeta potential, entrapment efficiency, drug loading and drug release in vitro were evaluated. RESULTS: The obtained nanoparticles were spherical under transmission electron microscope. The mean diameter was 212.1 nm, the zeta potential was - 14.65 mV, the mean entrapment efficiency was 82.4% and the mean drug loading was 0.97%. The total drug release was 30% in 2 hours followed by a slow and sustained release in vitro. CONCLUSION: The optimal Api-NLCs show stable characteristics and broad prospects for application.

Design, Synthesis, and Biological Evaluation of Pyrazoline-Based Hydroxamic Acid Derivatives as Aminopeptidase†N (APN) Inhibitors.

Aminopeptidase N (APN) has been recognized as a target for anticancer treatment due to its overexpression on diverse malignant tumor cells and association with cancer invasion, metastasis and angiogenesis. Herein we describe the synthesis, biological evaluation, and structure-activity relationship study of two new series of pyrazoline analogues as APN inhibitors. Among these compounds, 5-(2-(2-(hydroxyamino)-2-oxoethoxy)phenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (compound 13 e) showed the best APN inhibition with an IC50 value of 0.16±0.02 µm, which is more than one order of magnitude lower than that of bestatin (IC50 =9.4±0.5 µm). Moreover, compound 13 e was found to inhibit the proliferation of diverse carcinoma cells and to show potent anti-angiogenesis activity. At the same concentration, compound 13 e presents significantly higher anti-angiogenesis activity than bestatin in human umbilical vein endothelial cells (HUVECs) capillary tube formation assays. The putative binding mode of 13 e in the active site of APN is also discussed.

Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy.

Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex-fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13+ cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer.

Design, synthesis, and preliminary bioactivity evaluation of N1 -hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors.

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1 -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50  = 0.074 µm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50  = 0.131 µm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.

Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study.

Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compound 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compounds exhibited high HDACs inhibitory potency. Compound 11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In vivo studies revealed that compound 11a displayed potent oral antitumor activity in both hematological tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide 3, 11a and 19 afforded new thienyl and phenyl compounds (50a, 50b, 63a, 63b and 63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine containing compound 56, with moderate HDAC3 selectivity.

PXD101 analogs with L-phenylglycine-containing branched cap as histone deacetylase inhibitors.

Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L-phenylglycine-containing branched cap group could not change the isoform selectivity of PXD101 dramatically.

Discovery of Multi-target Anticancer Agents Based on HDAC Inhibitor MS-275 and 5-FU.

Histone deacetylases (HDACs) inhibitors have multiple effects targeting the cancer cells and have become one of the promising cancer therapeutics with possibly broad applicability. Combination of HDAC inhibitors with the cytotoxic fluorouracil (5-FU) showed additive and synergistic effects both in vitro and in vivo. To explore the possibility in cancer therapy of a bivalent agent that combines two bioactive groups within a single molecular architecture, we designed and synthesized new dual-acting compounds by combining the bioactive fragment of MS-275, a clinical HDACs inhibitor, with cytotoxic agent 5-FU. The target compounds 9a and 9b showed comparable HDACs inhibition with MS-275 and moderate antiproliferative acitivities against six cancer cells lines.

Discovery of BC-01, a novel mutual prodrug (hybrid drug) of ubenimex and fluorouracil as anticancer agent.

We designed and synthesized a novel mutual prodrug, named BC-01 (3), by integrating ubenimex and Fluorouracil (5-FU) into one molecule based on prior research results that showed that a combination of the aminopeptidase N (CD13) inhibitor, ubenimex, and the cytotoxic antitumor agent, 5-FU, exhibited improved in vitro and in vivo antitumor efficiency. 3 showed potent inhibitory activity against CD13 enzymatic activity. Compared with ubenimex, 3 exhibited more potent anti-angiogenesis effects, and compared with the approved 5-FU prodrug, capecitabine, 3 exhibited more potent tumor growth inhibitory and anti-metastasis effects. Additionally, compared with 5-FU or 5-FU plus ubenimex, 3 also exhibited a superior antitumor efficiency even in our 5-FU-resistant mice model. Other antitumor agents could be conjugated with ubenimex using this strategy to obtain novel mutual prodrugs with promising antitumor potency.

Design, synthesis, and antitumor evaluation of histone deacetylase inhibitors with L-phenylglycine scaffold.

In our previous research, a novel series of histone deacetylase (HDAC) inhibitors with L-phenylglycine scaffold were designed and synthesized, among which amides D3 and D7 and ureido D18 were far superior to the positive control (suberoylanilide hydroxamic acid [SAHA]) in HDAC inhibition, but were only comparable to SAHA in antiproliferation on tumor cell lines. Herein, further structural derivation of lead compounds D3, D7, and D18 was carried out to improve their cellular activities. Most of our newly synthesized compounds exhibited more potent HDAC inhibitory activities than the positive control SAHA, and several derivatives were even better than their parent compounds. However, compared with SAHA and our lead compounds, only secondary amine series compounds exhibited improved antiproliferative activities, likely due to their appropriate topological polar surface area values and cell permeabilities. In a human histiocytic lymphoma (U937) xenograft model, the most potent secondary amine 9d exhibited similar in vivo antitumor activity to that of SAHA.

Enhanced anticancer activity of 5-FU in combination with Bestatin: Evidence in human tumor-derived cell lines and an H22 tumor-bearing mouse.

The clinical use of 5-fluorouracil (5-FU) is increasingly limited by low response rates, adverse reactions, and toxicity. A drug combination offers a new strategy for appropriate use of 5-FU. Bestatin, an aminopeptidase N (APN) inhibitor, has been used as an adjuvant chemotherapy drug because of its actions to suppress tumorigenesis and invasion. The current study evaluated the anticancer efficacy of 5-FU plus Bestatin at the cellular and animal level. The combination killed more colonic cancer, hepatic carcinoma, and ovarian cancer cells and fewer nonmalignant human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells than 5-FU or Bestatin alone. Moreover, 41.58% of ES-2 and 20.86% of PLC/PRF/5 cell apoptosis was caused by the combination of the two, while 5-FU caused apoptosis of 20.86% of ES-2 cells and 8.85% of PLC/PRF/5 cells. The cell cycle was arrested in the S and G0/G1 phases when a combination of the two was used. In an experiment involving mice bearing tumors, a combination of the two had a rate of tumor inhibition of 61.98%, while 5-FU alone had a rate of tumor inhibition of just 49.17%. In addition, the combination of the two was safer than either drug alone and did not cause weight loss or death. In conclusion, combining 5-FU and Bestatin could enhance the anticancer activity of 5-FU and decrease its cytotoxicity. These results suggest that 5-FU plus Bestatin has greater efficacy as a tumor therapy.

Development of 3-hydroxycinnamamide-based HDAC inhibitors with potent in vitro and in vivo anti-tumor activity.

Inhibition of histone deacetylases (HDACs) has diverse effects on cell function, such as causing differentiation, growth arrest and apoptosis in nearly all types of tumor cell lines. In our previous work, we have designed and synthesized a novel series of 4-hydroxycinnamamide-based and 3-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which, 3-hydroxycinnamamide-based HDACIs 1a-1c exhibited moderate inhibition against HDACs. In this article, we report the development of a more potent class of 3-hydroxycinnamamide-based HDACIs, compound 7o exhibited much higher pan-HDAC inhibitory activity than positive control SAHA. In addition, compound 7h showed excellent in vitro growth inhibitory activity against more than ten cell lines and induced U937 cells apoptosis in micromolar concentration. In vivo assay in U937 xenograft model identified compound 7h as a potent, orally active HDACI.

Histone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activities.

In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results show that representative compounds can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, (S)-4-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-phenylacetamido)-N-hydroxybenzamide (D17) showed better performance than SAHA in blocking U937 tumor growth. Western blot analysis revealed that representative molecules can block the function of both class I HDACs and HDAC6. More importantly, our western blot results reveal that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by our compounds in the U937 cell line rather than MDA-MB-231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA-MB-231 cell line.

Discovery of the first N-hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oral antitumor activity.

In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which the representative compound 14a exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using 14a as lead, among which, compound 11r gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Compounds 11e, 11r, 11w, and 11y showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compound 11r as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.