Vortioxetine Derivatives with Amino Acid as Promoiety: Synthesis, Activity, Stability and Preliminary Pharmacokinetic Study.

Vortioxetine (Vot) is an effective antidepressant with unique mechanisms exerting multi-target effects. However, severe side-effects such as nausea and vomiting are commonly experienced under conditions of long-term administration. Eight amino acid modified Vot derivatives were designed and prepared in this study. Similar or lower binding affinities of the modified compounds to the serotonin transporter (SERT) than Vot was observed in the 4-(4-(dimethylamino)-styrl)-N-methylpyridinium (ASP+) uptake assay on RBL-2H3 cells. Additionally, the majority of derivatives remained sufficiently stable in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), indicating achievement of intestinal absorption in the modified form. Afterwards, all derived compounds exhibited slower hepatic clearance and a longer half-life, compared to the parent drug Vot. Notably, threonine-modified 3f exhibited significantly lower activity to SERT, serine-modified 3e showed the fastest degradation rate in rat plasma, with hydrolysis to an extent of 50% in 10 min, and better pharmacokinetic properties in rat, including Cmax, t1/2, and especially AUC0-t, which was ~3-fold higher relative to the parent compound. Although, no clear understanding of SARs has been obtained, modification of Vot with amino acids containing hydroxyl groups may be beneficial to reduce the gastrointestinal side effect of Vot or obtain better pharmacokinetic properties, providing some ideas for the further study in the future.

Novel glucagon- and OXM-based peptides acting through glucagon and GLP-1 receptors with body weight reduction and anti-diabetic properties.

Oxyntomodulin (OXM) is an endogenous gastrointestinal hormone, which activates both the Glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). However, OXM has shortcomings including poor GLP-1R agonism to control glycemia, short half-life and others. Inspired from the sequence relationship between OXM and glucagon, in this study, we introduced different C-terminus residues of GLP-1, exenatide and OXM to glucagon to get a series of hybrid peptides with enhanced GLP-1R activation. The formed glucagon-exenatide hybrid peptide shows higher GLP-1R activation properties than OXM. Then the peptides based on the glucagon-exenatide hybrid peptide were coupled with fatty acid side chains to prolong their half-lives. As a result, the most potent compound 16a could stimulate insulin secretion and maintain blood glucose in normal level for ~42.6 h in diabetic mice. 16a exhibited reduced HbA1c level in diabetic mice, lowered body weight significantly in obesity mice on chronic treatment assay. 16a, combined efficient GCGR/GLP-1R activity, is potential as novel treatment for obesity and diabetes. This finding provides new insights into balancing GLP-1/GCGR potency of glucagon-exenatide hybrid peptide and is helpful for discovery of novel anti-diabetic and bodyweight-reducing drugs.

Novel lipid side chain modified exenatide analogs emerged prolonged glucoregulatory activity and potential body weight management properties.

Exenatide is known as the first marketed GLP-1 agonist for antidiabetic treatment, but it need twice injection a day because of its fast clearance. This work aims to prolong the half-life of exenatide by modified with novel lipid chain. Four optimized exenatide analogs named as Cys12-Exenatide (1-39)-NH2, Cys40-Exenatide (1-39)-NH2, Cys12-Tyr22-Gln24-Glu28-Arg35-Exenatide (1-39)-NH2 and Tyr22-Gln24-Glu28-Arg35-Cys40-Exenatide (1-39)-NH2 were selected and applied for conjugation. Then a series of evaluations including GLP-1R activation assay were conducted, conjugation C2 was selected for further investigation. Glucoregulatory and insulin secretion assay and hypoglycemic duration test were accessed and showed that C2 was capable of comparable insulinotropic activities and glucose-lowering abilities with those of liraglutide and exenatide. Cell protective effects in INS-1 cells confirmed that C2 had relatively protection effects. Meanwhile, once daily injection of C2 to STZ-induced diabetic mice achieved long-term beneficial effects on glucose tolerance, body weight and blood chemistry. Acute feeding studies were evaluated in DIO mice. These results suggested that C2 is a promising agent for further investigation of its potential to treat diabetes patients with obese.

Synthesis and evaluation of redox-sensitive gonadotropin-releasing hormone receptor-targeting peptide conjugates.

Lytic peptides have been demonstrated to exhibit obvious advantages in cancer therapy with binding ability toward tumor cells via electrostatic attractions, which are lack of active targeting and aggregation to tumor tissue. In the present study, five conjugated lytic peptides were redesigned and constructed to target gonadotropin releasing hormone receptors (GnRHr), meanwhile, the disulfide bridge was introduced to achieve redox sensitive delivery based on the experience from the preliminary work of lytic peptides P3 and P7. YX-1, was considered to be the most promising for in-depth study. YX-1 possessed high potency (IC50 = 3.16 ±â€¯0.3 µM), low hemolytic effect, and cell membrane permeability in human A2780 ovarian cancer cells. Moreover, YX-1 had prominent pro-apoptotic activity by activating the mitochondria-cytochrome c-caspase apoptotic pathway. The study yielded the conjugate YX-1 with superior properties for antineoplastic activity, which makes it a promising potential candidate for targeting cancer therapy.

Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4 inhibitors.

Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC50 of 1.53 µM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.

Synthesis and anti-cancer evaluation of folic acid-peptide- paclitaxel conjugates for addressing drug resistance.

The drug resistance and the poor water solubility are major limitations of paclitaxel (PTX) of based chemotherapy. To conquer the two problems, targeting folate (FA) receptor PTX-lytic peptides conjugates were synthesized and evaluated. Compared with PTX, FA-P3-PTX and FA-P7-PTX displayed significantly enhanced cell toxicity in many cancer cells, particularly drug resistant cancer cells MCF-7/PTX. FA-P7-PTX possessed stronger effect on cell toxicity (IC50 = 2.92 ±â€¯0.2 µM), membrane disrupting activity and pro-apoptosis in MCF-7/PTX cells than FA-P3-PTX. Further investigation displayed that the anti-cancer mechanisms of FA-P3-PTX and FA-P7-PTX might be a mitochondrial impairment and caspase-3-dependent apoptotic cell death. Furthermore, the in vivo antitumor efficacy study confirmed that FA-P7-PTX performed more stronger potency in inhibition of tumors growth than PTX. The study demonstrated that conjugate FA-P7-PTX with superior properties for antineoplastic activity, which makes it a promising potential candidate for drug-resistant cancer therapy.

Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.

c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ±â€¯0.1 nM and 5.0 ±â€¯0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ±â€¯0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ±â€¯0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.

pH-Sensitive micelles with mitochondria-targeted and aggregation-induced emission characterization: synthesis, cytotoxicity and biological applications.

Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria targeting micelle (PEG-AIE-TPP) by conjugating a triphenylphosphonium (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). At first, the in vitro and in vivo properties of the PEG-AIE-TPP micelle were characterized in detail. It was found that the micelle was reasonably stable at physiological pH and highly sensitive to mildly acidic pH stimuli. Importantly, this micelle could selectively localize and accumulate in the mitochondria, thus generating an aggregation-induced emission (AIE) effect as confirmed by the green fluorescence. Additionally, the micelle exhibited selective cytotoxicity to cancer cells and negligible toxicity to normal cells in vitro. The in vivo imaging and ex vivo imaging results showed that the accumulation tendency of the micelle at the tumor region was obvious. We also further proved the biocompatible, tumor targeting ability and antitumor activity of the PEG-AIE-TPP micelle in MCF-7 tumor-bearing mice. Accordingly, this mitochondria-targeted therapeutic micelle with good stability, biocompatibility, and tumor-targeting and antitumor activity provides a potentially unique tumor-targeted system for cancer therapy.

Design, synthesis and evaluation of a novel series of inhibitors reversing P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is still the main barrier to attaining effective results with chemotherapy. Discovery of new chemo-reversal agents is needed to overcome MDR. Our study focused on a better way to obtain novel drugs with triazole rings that have an MDR reversal ability through click chemistry. Among 20 developed compounds, compound 19 had a minimal cytotoxic effect compared to tariquidar and verapamil (VRP) and showed a higher reversal activity than VRP through increased accumulation in K562/A02 cells. Compound 19 also played an important role in the P-gp efflux function of intracellular Rh123 and doxorubicin (DOX) accumulation in K562/A02 cells. Moreover, compound 19 exhibited a long lifetime of approximately 24 hr. These results indicated that compound 19 is a potential lead compound for the design of new drugs to overcome cancer MDR.

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors.

Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.

Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.

Pro-apoptotic cationic host defense peptides rich in lysine or arginine to reverse drug resistance by disrupting tumor cell membrane.

Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro-apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (ΔΨm) demonstrated that the peptides induced ΔΨm dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy.