1,2,4-Oxadiazole-Based Bio-Isosteres of Benzamides: Synthesis,Biological Activity and Toxicity to Zebrafish Embryo

To discover new compounds with broad spectrum and high activity, we designed a series of novel benzamides containing 1,2,4-oxadiazole moiety by bioisosterism, and 28 benzamides derivatives with antifungal activity were synthesized. These compounds were evaluated against four fungi: Botrytis cinereal, FusaHum graminearum, Marssonina mali, and Thanatephorus cucumeris. The results indicated that most of the compounds displayed good fungicidal activities, especially against Botrytis cinereal. For example, 10a (84.4%), 10d (83.6%), 10e (83.3%), 10f (83.1%), 10i (83.3%), and 10l (83.6%) were better than pyraclostrobin (81.4%) at 100 mg/L. In addition, the acute toxicity of 10f to zebrafish embryo was 20.58 mg/L, which was classified as a low-toxicity compound.     

Design and Synthesis of N‐Acylated Aza‐Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin ( 1 ) and the evaluation of the potential antitumor activity of the compounds. N‐Acylation of aza‐goniothalamin ( 2 ) restored the in vitro antiproliferative activity of this family of compounds. 1‐(E)‐But‐2‐enoyl‐6‐styryl‐5,6‐dihydropyridin‐2(1H)‐one ( 18 ) displayed enhanced antiproliferative activity. Both goniothalamin ( 1 ) and derivative 18 led to reactive oxygen species generation in PC‐3 cells, which was probably a signal for caspase‐dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7‐aminoactinomycin D double staining, which indicated apoptosis, and also led to G₂/M cell‐cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin ( 1 ), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza‐goniothalamin ( 2 ) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.     

New Succinimides with Potent Anticancer Activity: Synthesis,Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.     

Synthesis of 9,9‐Dialkyl‐4,5‐diazafluorene Derivatives and Their Structure–Activity Relationships Toward Human Carcinoma Cell Lines

A homologous set of 9,9‐dialkyl‐4,5‐diazafluorene compounds were prepared by alkylation of 4,5‐diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB‐231 breast carcinoma, and SKHep‐1 hepatoma cells, were investigated; a structure–activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency [log(1/IC₅₀)] and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9‐dihexyl‐4,5‐diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in vitro cytotoxicity was not observed at clinically relevant concentrations.     

Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity

Herein we report the discovery of compound 6 [KST016366; 4‐((2‐(3‐(4‐((4‐ethylpiperazin‐1‐yl)methyl)‐3‐(trifluoromethyl)phenyl)ureido)benzo[d]thiazol‐6‐yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A . In vitro anticancer evaluation of 6 showed substantial broad‐spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI₅₀ values of 51.4 and 19 nm against leukemia K‐562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar‐level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC₅₀ values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL‐1 (wild‐type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.     

Alanine and Lysine Scans of the LL‐37‐Derived Peptide Fragment KR‐12 Reveal Key Residues for Antimicrobial Activity

The human host defence peptide LL‐37 is a broad‐spectrum antibiotic with immunomodulatory functions. Residues 18–29 in LL‐37 have previously been identified as a minimal peptide (KR‐12) that retains antibacterial activity with decreased cytotoxicity. In this study, analogues of KR‐12 were generated by Ala and Lys scans to identify key elements for activity. These were tested against a panel of human pathogens and for membrane permeabilisation on liposomes. Replacements of hydrophobic and cationic residues with Ala were detrimental for antibiotic potency. Substitutions by Lys increased activity, as long as the increase in cationic density did not disrupt the amphiphilic disposition of the helical structure. Importantly, substitutions showed differential effects against different organisms. Replacement of Gln5 with Lys and Asp9 with Ala or Lys improved the broad‐spectrum activity most, each resulting in up to an eightfold increase in potency against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The improved analogues displayed no significant toxicity against human cells, and thus, KR‐12 is a tuneable template for antibiotic development.     

Design,Synthesis, and Anticancer Activity of a Selenium-Containing Galectin-3 and Galectin-9N Inhibitor

Galectins are soluble β-D-galactoside-binding proteins whose implication in cancer progression and disease outcome makes them prominent targets for therapeutic intervention. In this frame, the development of small inhibitors that block selectively the activity of galectins represents an important strategy for cancer therapy which is, however, still relatively underdeveloped. To this end, we designed here a rationally and efficiently novel diglycosylated compound, characterized by a selenoglycoside bond and the presence of a lipophilic benzyl group at both saccharide residues. The relatively high binding affinity of the new compound to the carbohydrate recognition domain of two galectins, galectin 3 and galectin 9, its good antiproliferative and anti-migration activity towards melanoma cells, as well as its anti-angiogenesis properties, pave the way for its further development as an anticancer agent.     

Conjugation with Phospholipids as a Modification Increasing Anticancer Activity of Phenolic Acids in Metastatic Melanoma—In Vitro and In Silico Studies

Phenolic acids possess many beneficial biological activities, including antioxidant and anti-inflammatory properties. Unfortunately, their low bioavailability restricts their potential medical uses, as it limits the concentration of phenolic acids achievable in the organism. The conjugation with phospholipids constitutes one of the most effective strategies to enhance compounds bioavailability in biological systems. In the present study, the conjugates of anisic (ANISA) and veratric acid (VA) with phosphatidylcholine (PC) were investigated. Since both ANISA and VA are inhibitors of tyrosinase, a melanocyte enzyme, the expression of which increases during tumorigenesis, anticancer potential of the conjugates was tested in several metastatic melanoma cell lines. The conjugates proved to be antiproliferative, apoptosis-inducing and cell-cycle-affecting agents, selective for cancerous cells and not affecting normal fibroblasts. The conjugates substituted by ANISA and VA, respectively, at both the sn-1 and sn-2 positions of PC, appeared the most promising, since they were effective against the vast majority of metastatic melanoma cell lines. Additionally, the conjugation of phenolic acids to PC increased their antioxidant activity. Molecular modeling was employed for the first time to estimate the features of the investigated conjugates relevant to their anticancer properties and membrane permeation. Again, the conjugates substituted by phenolic acid at both the sn-1 and sn-2 positions of PC seemed to be presumably most bioavailable.     

Photocontrol of Protein Activity in Cultured Cells and Zebrafish with One‐ and Two‐Photon Illumination

We have implemented a noninvasive optical method for the fast control of protein activity in a live zebrafish embryo. It relies on releasing a protein fused to a modified estrogen receptor ligand binding domain from its complex with cytoplasmic chaperones, upon the local photoactivation of a nonendogenous caged inducer. Molecular dynamics simulations were used to design cyclofen‐OH, a photochemically stable inducer of the receptor specific for 4‐hydroxy‐tamoxifen (ER^T2). Cyclofen‐OH was easily synthesized in two steps with good yields. At submicromolar concentrations, it activates proteins fused to the ER^T2 receptor. This was shown in cultured cells and in zebrafish embryos through emission properties and subcellular localization of properly engineered fluorescent proteins. Cyclofen‐OH was successfully caged with various photolabile protecting groups. One particular caged compound was efficient in photoinducing the nuclear translocation of fluorescent proteins either globally (with 365 nm UV illumination) or locally (with a focused UV laser or with two‐photon illumination at 750 nm). The present method for photocontrol of protein activity could be used more generally to investigate important physiological processes (e.g., in embryogenesis, organ regeneration and carcinogenesis) with high spatiotemporal resolution.     

Total Synthesis of (−)‐Doliculide,Structure–Activity Relationship Studies and Its Binding to F‐Actin

Actin, an abundant protein in most eukaryotic cells, is one of the targets in cancer research. Recently, a great deal of attention has been paid to the synthesis and function of actin‐targeting compounds and their use as effective molecular probes in chemical biology. In this study, we have developed an efficient synthesis of (?)‐doliculide, a very potent actin binder with a higher cell‐membrane permeability than phalloidin. Actin polymerization assays with (?)‐doliculide and two analogues on HeLa and BSC‐1 cells, together with a prediction of their binding mode to F‐actin by unbiased computational docking, show that doliculide stabilizes F‐actin in a similar way to jasplakinolide and chondramide C.     

Design,Synthesis, and Antibacterial Activity of Demethylvancomycin Analogues against Drug‐Resistant Bacteria

Five novel N‐substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure‐based approach. The in vitro antibacterial activities against methicillin‐resistant Staphylococcus aureus (MRSA), gentamicin‐resistant Enterococcus faecalis (GRE), methicillin‐resistant Streptococcus pneumoniae (MRS), and vancomycin‐resistant Enterococcus faecalis (VRE) were evaluated. One of the compounds, N‐(6‐phenylheptyl)demethylvancomycin ( 12 a ), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12 a was also found to be ～18‐fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12 a exhibited a favorable pharmacokinetic profile with a half‐life of 5.11±0.52 h, which is longer than that of vancomycin (4.3±1.9 h). These results suggest that 12 a is a promising antibacterial drug candidate for further preclinical evaluation.     

Synthesis of N‐Substituted Iminosugar Derivatives and Evaluation of Their Immunosuppressive Activities

It is important to find more effective and safer immunosuppressants, because clinically used immunosuppressive agents have significant side effects. A series of N‐substituted iminosugar derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK‐8 assay. The results revealed that iminosugars 10 e and 10 i , that is, (3R,4S)‐1‐(4‐heptyloxylphenylethyl)pyrrolidine‐3,4‐diol and (3R,4S)‐1‐[2‐(2‐chloro‐4‐(p‐tolylthio)‐phenyl‐1‐yl)ethyl]pyrrolidine‐3,4‐diol, respectively, exhibited the strongest inhibitory effects on mouse splenocyte proliferation (IC₅₀=2.16 and 2.48 μm , respectively), whereas the iminosugars containing an amide group near the hydrophilic head (compounds 10 j – n ) exhibited no inhibitory effects. Further studies revealed that the inhibitory effects on splenocyte proliferation may have come from the suppression of both IFN‐γ and IL‐4 cytokines. Our results suggest that synthetic iminosugars, especially compounds 10 e and 10 i , hold potential as immunosuppressive agents.     

Development and Validation of a Pharmacophore‐Based QSAR Model for the Prediction of CNS Activity

A QSAR model for the prediction of CNS activity was developed and validated based on data from an in‐house database of “drug‐like” compounds. The model has demonstrated its applicability for novel chemical structures and its usefulness for the design of CNS‐focused compound libraries.

     

Synthesis and Structure–Activity Relationships of 1‐Benzyl‐4,5,6‐trimethoxyindoles as a Novel Class of Potent Antimitotic Agents

Combretastatin A‐4 derivatives : A series of combretastatin A‐4‐derived 1‐benzyl‐4,5,6‐trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site on the microtubule.

     

Synthesis of Schiff Base‐Ruthenium Complexes and Their Applications in Catalytic Processes

The synthesis of various Schiff base mononuclear and binuclear ruthenium complexes, whose additional ligands around the metal core have been selected from an array of motifs, is described. These types of ruthenium complexes, conveniently prepared from commonly available ruthenium sources, are rather stable, display good tolerance towards diverse organic functionalities and also to air and moisture. Remarkably, they exhibit a high activity and chemoselectivity in a variety of catalytic processes such as ring‐closing metathesis (RCM), Kharasch addition, alkyne dimerization, enol ester synthesis, ring‐opening metathesis polymerization (ROMP) and atom‐transfer radical polymerization (ATRP). This review covers both homogeneous and heterogeneous hybrid Schiff base‐ruthenium complexes.