Organic Synthesis and Biological Signal Transduction

The understanding of cellular communication pathways in molecular detail is an important goal of bioorganic research. The synthesis of analogues of active substances (e.g. 1 ) to study the regulation of muscle contraction or the specific lipid modification of representative peptides (→ 2 ) to investigate their subcellular, targeted transfer to intracellular membranes are examples of the capability of organic synthesis is in the research of biological signal transduction mechanisms.     

Spontaneous Formation of the Bioactive Form of the Tuberculosis Drug Isoniazid

It works even without the enzyme : The formation of the bioactive form 1 of isoniazid inside Mycobacterium tuberculosis does not depend on specific interactions within the active site of the inhibited enzyme, but rather relies on the fast addition of acyl radicals to electron-deficient heterocycles such as NAD⁺.     

2-Nitrobenzylarsonium Compounds That Photorelease Heavy-Atom Cholinergic Ligands for Time-Resolved Crystallographic Studies on Cholinesterases

As heavy-atom analogues of caged cholinergic ligands, the arsonium compounds 1 – 3 were synthesized for potential time-resolved crystallographic studies on cholinesterases. Compounds 1 and 3 possess the desired properties for dynamic studies on the catalytic mechanism of cholinesterases: structural similarity with the N-homologue, strong X-ray diffracting effect of arsenic, inhibitory effects on cholinesterases, and excellent photofragmentation kinetics.     

New Tripodal, “Supercharged” Analogues of Adenosine Nucleotides: Inhibitors for the Fhit Ap3A Hydrolase

Methanetrisphosphonic acids provide a branch point for synthetic nucleotide analogues which can be exploited either to generate novel tripodal nucleotides or to incorporate additional negative charge into linear analogues relative to the parent nucleotide, as exemplified in the picture for ATP and diadenosine tetraphosphate (Ap₄A). These compounds show valuable discriminatory behavior as competitive inhibitors for the tumor suppressor protein Fhit and a second Ap_nA pyrophosphohydrolase. X=H, Cl, F.     

Natural Product Synthesis on Polymeric Supports—Synthesis and Biological Evaluation of an Indolactam Library

Potent activators of protein kinase C in fibroblasts: This property was determined for several indolactam V analogues ( 1 ) with a new cell-based assay system. This tumor-promoting indole alkaloid and analogues thereof can be synthesized efficiently on the solid phase. The key steps of the combinatorial approach are a regioselective amination of the indole ring and an enantioselective enzymatic reaction.     

Synthesis,In Vitro Biological Evaluation and In Silico Molecular Docking Studies of Indole Based Thiadiazole Derivatives as Dual Inhibitor of Acetylcholinesterase and Butyrylchloinesterase

The current study was conducted to obtain hybrid analogues of indole-based thiadiazole derivatives (1–16) in which a number of reaction steps were involved. To examine their biological activity in the presence of the reference drug Donepezil (0.21 ± 0.12 and 0.30 ± 0.32 M, respectively), the inhibitory potentials of AChE and BuChE were determined for these compounds. Different substituted derivatives showing a varied range of inhibitory profiles, when compared to the reference drug, analogue 8 was shown to have potent activity, with IC50 values for AchE 0.15 ± 0.050 M and BuChE 0.20 ± 0.10, respectively, while other substituted compounds displayed good to moderate potentials. Varied spectroscopic techniques including ¹H, ¹³CNMR and HREI-MS were used to identify the basic skeleton of these compounds. Furthermore, all analogues have a known structure–activity relationship (SAR), and molecular docking investigations have verified the binding interactions of molecule to the active site of enzymes.     

Chemoenzymatic Synthesis of a Characteristic Glycophosphopeptide from the Transactivation Domain of the Serum Response Factor

Glycopeptides, phosphopeptides, and glycophosphopeptides can be synthesized efficiently by a strategy based on a combination of suitable enzyme-labile protecting groups. Thus, probes for biological studies can be accessed. An example is the glycosylated and phosphorylated heptapeptide 1 from the transactivation domain of the human serum response factor, which contains an additional biotin label for detection with streptavidin.     

Synthesis of 2-substituted 2H-chromenes using potassium vinyltrifluoroborates

2H-Chromenes were synthesized from salicylaldehyde using potassium vinylic borates in the presence of secondary amines. We synthesized these 2H-chromene derivatives as a part of an ongoing project to develop inhibitors for TGF-β receptors. Potassium vinyl trifluoroborates react with salicylaldehydes at 80 °C in the presence of a secondary amine and produced 2-substituted 2H-chromene derivatives with a 70-90% yield.     

Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM²% and 31 µM²% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM² % to −176 µM² % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.     

Design,Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents

Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.     

Total Synthesis of the Marine Natural Product 7-Deoxy-okadaic Acid: A Potent Inhibitor of Serine/Threonine-Specific Protein Phosphatases

A small change to the structure of okadaic acid ( 1 ), the omission of the single hydroxy group at C7, facilitated substantially the first total synthesis of the derivative 7-deoxyokadaic acid ( 2 ). The conformation of 2 is in agreement with that of 1 and this minimal structural variation has been reported previously to have little effect on the inhibitory activity towards the serine/threonine-specific protein phosphatases PP-1 and PP-2A.     

Chemo‐Enzymatic Synthesis of Fluorescent Rab 7 Proteins: Tools to Study Vesicular Trafficking in Cells

The N ‐methylanthraniloylisoprenoid diphosphate derivatives 1 and 2 bind to RabGGTase II and are enzymatically transferred to Rab 7 (the Rab proteins are small G‐proteins that control events of docking and fusion of intracellular vesicles). The fluorescent Rab 7 proteins thus obtained may become important tools for further biological studies on vesicular trafficking in cells.     

Stereocontrolled Synthesis of (11Z)-Retinal and Its Analogues

Suzuki coupling of stereochemically pure (Z)-bromotetraene 1 —which is extremely unstable but can be kept in frozen benzene in the presence of a small amount of PPh₃ at &sminus 01;20°C—and (Z)-alkenylboronic acid 2 provides the stereocontrolled synthesis of (11Z)-retinal 3 . The 11Z configuration, which is introduced by selective catalytic debromination of the corresponding dibromo precursor of 1 , is retained in this step. TBDMS = tBuMe₂Si.     

抗流感病毒抑制剂Nucleozin衍生物的设计合成及抗病毒活性评价

小分子化合物Nucleozin作为靶向流感病毒核蛋白的抑制剂具有良好的抑制活性。本文围绕Nucleozin分子中与哌嗪环直接相连的芳环部分进行研究。通过钯催化偶联反应合成了一系列Nucleozin衍生物,通过检测所合成化合物对流感病毒H1N1的抑制活性,明确了Nucleozin分子中该部分的构效关系。利用甲基在药物分子设计中的作用,设计将分子中的氯原子替换为甲基,发现与原型分子Nucleozin相比其抑制活性有了明显的提高。本文的结果对该类分子成药性的提高具有积极意义。     

A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor

Potent modulators of RNA function can be assembled in cellulo by using the cell as a reaction vessel and a disease‐causing RNA as a catalyst. When designing small molecule effectors of function, a balance between permeability and potency must be struck. Low molecular weight compounds are more permeable whereas higher molecular weight compounds are more potent. The advantages of both types of compounds could be synergized if low molecular weight molecules could be transformed into potent, multivalent ligands by a reaction that is catalyzed by binding to a target in cells expressing a genetic defect. It was shown that this approach is indeed viable in cellulo. Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)^exp, the causative agent of myotonic dystrophy type 2 (DM2), and are transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction by a Huisgen 1,3‐dipolar cycloaddition reaction, a variant of click chemistry.     

The Concept of Docking/Protecting Groups in Biohydroxylation

A general principle for biohydroxylation , in which time-consuming screening and enrichment techniques are avoided, is demonstrated by the introduction of a docking/protecting group into the substrate. This facilitates acceptance by the microorganism and allows the use of a narrow range of microorganisms, for example Beauveria bassiana ATTC 7159 (B. b.), for the hydroxylation of compounds with diverse structures. After the biohydroxylation, the docking/protecting group is removed (see scheme).     

An Efficient and Practical Method for the Synthesis of 1-(2,6-Difluorobenzoyl)-3-(2-alkyl-3-oxopyridazin-4-yl)ureas as Potential Chitin Synthesis Inhibitors

Summary. A mild and efficient method for the synthesis of 4-amino-3(2H)-pyridazinones from their corresponding 4,5-dichloropyridazinones under microwave-assisted conditions is described. A series of novel chitin synthesis inhibitors, benzoylphenylureas containing the 3(2H)-pyridazinone, were synthesized. The biological activity of these target compounds was evaluated.