Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in presence Zn2+, Co2+ or Cu2+ as a dimer forms via metal-ion interactions and interlocked hydrophobic surfaces. SAXS, NMR size exclusion chromatography analyses confirm formation solution Co2+, Cd2+ Cu2+. Since metal-induced dimerization masks VEGFs surface, investigated ability metal ions...

Vascular endothelial growth factors (VEGF), factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological pathological angiogenesis. In the last 20 years, many drugs have been developed based on VEGF/VEGFR treat diverse cancers retinopathies, new with improved properties continue emerge at fast rate. consist of different molecular structures characteristics, which enable them...

Described is an efficient heterologous expression system for Sulfolobus solfataricus ADH-10 (Alcohol Dehydrogenase isozyme 10) and its use in the dynamic reductive kinetic resolution (DYRKR) of 2-arylpropanal (Profen-type) substrates. Importantly, among 12 aldehydes tested, a general preference (S)-antipode was observed, with high ee's substrates corresponding to NSAIDs (nonsteroidal anti-inflammatory drugs) naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen. To our knowledge, this...

The human sirtuin silent information regulator 1 (SIRT1) is a NAD+-dependent deacetylase enzyme. It deacetylates many protein substrates, including histones and transcription factors, thereby controlling physiological pathological processes. Several synthetic inhibitors activators of SIRT1 have been developed, some therapeutic applications explored. indole EX-527 its derivatives are among the most potent selective inhibitors. has often used as pharmacological tool to explore effect...

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on interaction between VEGFB VEGFR1 that unexpectedly binds neutralizes VEGFR2. Investigation of cyclic linear structures VGB3 (named C-VGB3 L-VGB3, respectively) using binding cell proliferation assays, molecular docking, evaluation antiangiogenic antitumor activities in 4T1 mouse mammary carcinoma tumor (MCT)...

ABSTRACT The antituberculosis drug isoniazid (INH) is quickly oxidized by stoichiometric amounts of manganese(III) pyrophosphate. In the presence nicotinamide coenzymes (NAD + , NADH, mononucleotide [NMN ]) and nicotinic acid adenine dinucleotide (DNAD ), INH oxidation produced formation INH-coenzyme adducts in addition to known biologically inactive products (isonicotinic acid, isonicotinamide, isonicotinaldehyde). A pool INH-NAD(H) preformed solution allowed rapid strong inhibition vitro...

The use of NADH- and NADPH-dependent ketoreductases to access enantioenriched pharmaceutical building blocks is reported. Seven structurally diverse synthons are obtained, including those for atomoxetine (KRED 132), talampanel (RS1-ADH CPADH), Dolastatin fluoxetine 108/132). Ethanol may be used as stoichiometric reductant, regenerating both nicotinamide cofactors, particularly under four-electron redox conditions. Its favorable thermodynamic economic profile, coupled with its advantageous...

For the big screen: An alcohol oxidase/peroxidase-based screen for combinatorial catalysis produces a signal in visible region and real time. A targeted high-throughput uncovered bromometalation/carbocyclization route to bicyclic terpenoid cores thiocyano palladation/carbocyclization ready installation of vinyl thiocyanates. Detailed facts importance specialist readers are published as ”Supporting Information”. Such documents peer-reviewed, but not copy-edited or typeset. They made available...

The degeneracy of the guanine radical cation, which is formed in DNA by oxidation electron transfer, was studied a detailed analysis products on oligonucleotide duplexes and labeling experiments. It shown that imidazolone, major product oxidation, through one-electron process incorporates one oxygen atom from O2. formation 8-oxo-7,8-dihydroguanine two-electron minor pathway. mechanism also evidenced tris(hydroxymethyl)aminomethane adduct.

[reaction: see text] An isoniazid-NAD adduct has been recently proposed as the ultimate metabolite responsible for antituberculous activity of isoniazid (INH). Its structure results from binding isonicotinoyl radical at C4 position nicotinamide ring NAD with further possible and debated cyclization to form a cyclic hemiamidal derivative. Replacing pyridine cycle INH in INH-NAD by phenyl (BH-NAD adduct) was shown previously still retain activity. On these bases, core...

Cancer angiogenesis is mainly initiated by vascular endothelial growth factors (VEGFs). On the basis of reported crystal structures three natural ligands (VEGF-A, -B, and PlGF) with major receptors VEGFR-1 VEGFR-2, we scanned receptor-binding epitopes these designing linear cyclic peptides aim to disrupt VEGF-A/VEGFR-1 interaction, which implicated in cancer development. The ability inhibit this interaction was evaluated an ELISA-based assay. Several peptides, especially those mimicking loop...

Previously designed cyclic peptide antagonist c[YYDEGLEE]-NH2 disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). It represents a promising tool in fight against cancer age-related macular degeneration. We described this paper optimization of lead by C-terminal modification. A new strategy for synthesis peptides is developed, improving cyclisation efficiency. At 100 µM, several with an aromatic group flexibly linked at end showed...

The v114* cyclic peptide has been identified as a tight vascular endothelial growth factor (VEGF) ligand. Here we report on the use of isothermal titration calorimetry (ITC), 96-well plate competition assay, and circular dichroism (CD) to explore binding determinants new set related peptides. Anti-VEGF antibodies are currently used in clinic for regulating angiogenesis cancer age-related macular degeneration treatment. In this context, our aim is develop smaller molecular entities with high...

Abstract A flexible route towards five‐membered ring imino sugars starting from a chiral α,β‐epoxy aldehyde has been developed. The approach relies on the use of versatile epoxyamine intermediate 4 , which regiocontrolled epoxide opening affords diastereoselective access to trisubstituted pyrrolidines. Described here is nucleophilic attack at C‐2 pivotal epoxypyrrolidine 10 leading biologically relevant 1,4‐dideoxy‐1,4‐imino‐ D ‐arabinitol ( 2 ) and L ‐galactitol 3 as well their novel...

Isoniazid (INH) is easily oxidized with manganese(III) pyrophosphate, a chemical model of the KatG protein involved in activation INH inside bacteria Mycobacterium tuberculosis. Performed presence NAD(+), this oxidation generates family isomeric INH-NAD(H) adducts, which have been shown to be effective inhibitors InhA, an enzyme essential mycolic acid biosynthesis. In work, we fully characterized by (1)H and (13)C NMR spectroscopy four main species adducts that coexist solution. Two them are...

Macrocyclization constraints are widely used in the design of protein ligands to stabilize their bioactive conformation and increase affinities. However, resulting changes binding entropy can be puzzling uncorrelated affinity gains. Here, thermodynamic (Isothermal Titration Calorimetry) structural (X-ray, NMR CD) analysis a complete series lactam-bridged peptide vascular endothelial growth factor, unconstrained analogs reported. It is shown that differences thermodynamics arise mainly from...

Short peptides composed of naturally occurring amino acids are usually unstructured in aqueous media. The installation covalent constraints within their side chains or backbones, resulting the formation macrocyclic peptides, is an appealing approach to stabilize them defined secondary structures. Therefore, with objective α-turn conformation, we designed, synthesized and characterized constrained 13-membered peptides. Their design was inspired by previous work using replacement a hydrogen...

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on interaction between VEGFB VEGFR1 that unexpectedly binds neutralizes VEGFR2. Investigation of cyclic linear structures VGB3 using binding cell proliferation assays, molecular docking, evaluation antiangiogenic antitumor activities in 4T1 mouse mammary tumor model showed loop formation is essential for...

Macromolecular ligands targeting vascular endothelial growth factor A (VEGF) to inhibit pathological angiogenesis are used in the clinic for treatment of cancers and ocular diseases. To develop smaller retaining high affinity through an avidity effect, here we design homodimer peptides two symmetrical binding sites VEGF homodimer. series 11 dimers were synthesized with flexible poly(ethylene glycol) (PEG) linkers increasing lengths. The mode was determined by size exclusion chromatography,...

This study introduces new methods of screening for and tuning chiral space in so doing identifies a promising set ligands asymmetric synthesis. The carbafructopyranosyl-1,2-diamine(s) salens constructed therefrom are particularly compelling. It is shown that by removing the native anomeric effect this ligand family, one can tune shape improve bias. concept demonstrated combination (i) x-ray crystallographic structure determination, (ii) assessment catalytic performance, (iii) consideration...

An ortho-metallation–electrophilic substitution sequence was employed as a key step to build the 4-benzoylpyridine framework. It found that 4-benzoylpyridine-3-carboxamide and an N-pyridyl alkylated derivative both exist in unique cyclized hemiamidal structure, not usually expected keto-amide open form. These structures represent fragment models of Isoniazid–NAD adducts involved mechanism action antituberculous drug Isoniazid.