Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Natural products as potential lead compounds to develop new antiviral drugs over the past decade.

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.

Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction.

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice. Moreover, the combination of compound 6 and morphine has a synergistic effect. We intended to explain the molecular mechanism of this effect. Therefore, 36 analgesic-related targets (including 15 G protein-coupled receptors, 6 enzymes, 13 ion channels, and 2 others) were systemically evaluated using reverse docking. The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase (AChE) or α4ß2 nicotinic acetylcholine receptor (nAChR). This study provides practitioners a new insight of analgesic effects.

Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity.

The proteolytic enzyme ß-secretase (BACE1) plays a central role in the synthesis of the pathogenic ß-amyloid peptides (Aß) in Alzheimer's disease (AD), antioxidants could attenuate the AD syndrome and prevent the disease progression. In this study, BACE1 inhibitors (D1-D18) with free radical-scavenging activities were synthesized by molecular hybridization of 2-aminopyridine with natural antioxidants. The biological activity evaluation showed that D1 had obvious inhibitory activity against BACE1, and strong antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS+• ) assay, which could be used as a lead compound for further study.

Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors.

Inhibition of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain ß-amyloid (Aß) peptide's formation is a potential effective approach to treat Alzheimer's disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 µM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 µM, logP = 2.49).

Synthesis and Biological Evaluation of Scutellarein Alkyl Derivatives as Preventing Neurodegenerative Agents with Improved Lipid Soluble Properties.

BACKGROUND: Exogenous antioxidants are considered as a promising therapeutic approach to treat neurodegenerative diseases since they could prevent and/or minimize the neuronal damage by oxidation. OBJECTIVE: Three series of lipophilic compounds structurally based on scutellarein (2), which is one metabolite of scutellarin (1) in vivo, have been designed and synthesized. METHODS: Their antioxidant activity was evaluated by detecting the 2-thiobarbituric acid reactive substance (TBARS) produced in the ferrous salt/ascorbate-induced autoxidation of lipids, which were present in microsomal membranes of rat hepatocytes. The lipophilicity of these compounds indicated as partition coefficient between n-octanol and buffer was investigated by ultraviolet (UV) spectrophotometer. RESULTS: This study indicated that compound 5e which had a benzyl group substituted at the C4'- OH position showed a potent antioxidant activity and good lipophilicity. CONCLUSION: 5e could be an effective candidate for preventing or reducing the oxidative status associated with the neurodegenerative processes.

Protective effect of 6-O-methyl-scutellarein on repeated cerebral ischemia/reperfusion in rats.

Scutellarin (1) possesses protective effects against neuronal injury, while 6-O-methyl-scutellarein (3), as the main metabolite of scutellarin in vivo, has not been reported about its protective effects previously. The present study mainly investigated whether the neural injury caused by ischemia/reperfusion would be influenced by different doses of 6-O-methyl-scutellarein (3). The results of behavioral, neurological, and histological examinations indicated that 6-O-methyl-scutellarein (3) could improve neuronal injury, and exhibit significant difference among the various doses. More importantly, 6-O-methyl-scutellarein (3) had better protective effects than scutellarin in rat cerebral ischemia.

Synthesis and Bioactivity Characterization of Scutellarein Sulfonated Derivative.

Scutellarin (1) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin (1) could be metabolized into scutellarein (2) in vivo. In this study, a sulfonic group was introduced at position C-8 of scutellarein (2) to enhance the aqueous solubility of the obtained derivative (3). DPPH (1,1-diphenyl-2-picrylhydrazyl)-radical scavenging ability and antithrombic activity were also conducted to determine its bioactivity. The result showed that scutellarein derivate (3) could be a better agent for ischemic cerebrovascular disease treatment.

Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism In Vivo.

Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2 O2 -induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.

Synthesis of scutellarein derivatives to increase biological activity and water solubility.

In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.