Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer's disease.

The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer's disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-ß (Aß). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aß-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.

Therapeutic Effect of Ginsenoside Rd on Experimental Autoimmune Encephalomyelitis Model Mice: Regulation of Inflammation and Treg/Th17 Cell Balance.

Multiple sclerosis (MS) is an autoimmune inflammatory disease. Inflammatory infiltrates and demyelination of the CNS are the major characteristics of MS and its related animal model-experimental autoimmune encephalomyelitis (EAE). Immoderate autoimmune responses of Th17 cells and dysfunction of Treg cells critically contribute to the pathogenesis of MS and EAE. Our previous study showed that Ginsenoside Rd effectively ameliorated the clinical severity in EAE mice, but the mechanism remains unclear. In this study, we investigated the therapeutic effect of Ginsenoside Rd on EAE in vivo and in vitro and also explored the potential mechanisms for alleviating the injury of EAE. The results indicated that Ginsenoside Rd was effective for the treatment of EAE in mice and splenocytes. Ginsenoside Rd treatment on EAE mice ameliorated the severity of EAE and attenuated the characteristic signs of disease. Ginsenoside Rd displayed the therapeutic function to EAE by modulating inflammation and autoimmunity, via the downregulation of related proinflammatory cytokines IL-6 and IL-17, upregulation of inhibitory cytokines TGF-ß and IL-10, and modulation of Treg/Th17 imbalance. And the Foxp3/RORγt/JAK2/STAT3 signaling was found to be associated with this protective function. In addition, analysis of gut microbiota showed that Ginsenoside Rd also had modulation potential on gut microbiota in EAE mice. Based on this study, we hypothesize that Ginsenoside Rd could be a potential and promising agent for the treatment of MS.

HZ-A-005, a potent, selective, and covalent Bruton's tyrosine kinase inhibitor in preclinical development.

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec kinases family and is essential for B cell receptor (BCR) mediated signaling. BTK inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. Here we disclose a potent, selective, and covalent BTK inhibitor, HZ-A-005, currently in preclinical development. HZ-A-005 demonstrated dose-dependent activity in two xenograft models of lymphoma in vivo. It showed highly favourable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical studies. On the basis of its potency, selectivity, and covalent mode of inhibition, HZ-A-005 reveals the potential to be a promising BTK inhibitor for a wide range of cancer indications.

Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1).

Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

Progress on small-molecule proteolysis-targeting chimeras.

Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.

Novel phenanthridin-6(5H)-one derivatives as potent and selective BET bromodomain inhibitors: Rational design, synthesis and biological evaluation.

Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 µM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.

Development of the "hidden" multifunctional agents for Alzheimer's disease.

Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-ß (Aß) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Aß aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.

(+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFκB signaling.

BACKGROUND: Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear. RESULTS: In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1ß-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling. CONCLUSIONS: Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.

(2S,4R)-2-[(1R)-1-(4-Bromo-phen-yl)-2-nitro-eth-yl]-4-ethyl-cyclo-hexa-none.

The crystal structure of the title compound, C(16)H(20)BrNO(3), contains three chiral centers in the configuration 1R,2S,6R. The cyclo-hexane ring is in a chair conformation. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming chains along the a-axis direction.

(1R,2R)-N,N'-Bis(ferrocenylmeth-yl)-1,2-diphenyl-ethane-1,2-diamine.

The title compound, [Fe(2)(C(5)H(5))(2)(C(26)H(26)N(2))], was synthesized from a chiral diamine and ferrocenecarboxaldehyde and subsequent reduction with NaBH(4). It has two chiral centers which both exhibit an R configuration. Two ferrocene groups are present in the mol-ecular structure, with their cyclo-penta-dienyl ring planes showing an almost perpen-dicular arrangement [dihedral angle 88.6 (1)°].