Alexey Yu. Sukhorukov

Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (−)-, and (±)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via Reductive Domino Transformations of 3-β-Carbomethoxyethyl-Substituted Six-Membered Cyclic Nitronates

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKlines highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.

Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

Asymmetric synthesis of GlaxoSmithKlines highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-dihydro-4H-1,2-oxazine and subsequent stereoselective reduction of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone framework with the recovery of chiral auxiliary alcohol.

Synthesis and characterization of novel 1,2-oxazine-based small molecules that targets acetylcholinesterase.

Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2a) showed inhibitory activity towards 5-LOX and AChE with an IC50 values of 1.88, and 2.5 μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of -1.18 kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (logP=2.66), suggesting a potential ability to penetrate the blood-brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimers agents.

Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2.

In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 μM) over COX1 (40.4 μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.

Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo

Aberrant activation of nuclear factor kappa B (NF-κB) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis inducing effect of API was demonstrated using flow cytometry analysis and measuring the caspase 3/7 activity in API treated cells. Based on the literature on inhibition of NF-κB by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-κB binding to DNA, NF-κB-dependent luciferase expression and IκBα phosphorylation. We found that, API abrogate constitutive activation of NF-κB and inhibits IκBα phosphorylation in HCT116 cells. Our in silico analysis revealed the binding of oxazines to the hydrophobic cavity that present between the interface of p65 and IκBα. Given the relevance with aberrant activation of NF-κB in inflammation bowel disease (IBD), we evaluated the effect of API on dextran sulphate sodium-induced IBD mice model. The treatment of IBD induced mice with API decreased the myeloperoxidase activity in colonic extract, modulated the colon length and serum levels of pro- and anti-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-1β and IL-10. Furthermore, the histological analysis revealed the restoration of the distorted cryptic epithelial structure of colon in the API treated animals. In conclusion, we comprehensively validated the NF-κB inhibitory efficacy of API that targets NF-κB in in vitro colon cancer and an in vivo inflammatory bowel disease model.

Unusual Intramolecular Cyclization of Tris(β-oximinoalkyl)amines. The First Synthesis of 1,4,6,10-Tetraazaadamantanes

An unusual intramolecular cyclization of tris(beta-oximinoalkyl)amines 1 into 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes 2 was discovered. Compounds 2 are related to a previously unknown type of heteroadamantanes that contain the cage isomeric to urotropin. A simple three-step synthesis of tetraazaadamantanes 2 and their N-substituted derivatives 3 and 4 from ammonia and aliphatic nitro compounds via the intermediacy of available tris-oximes 1 was developed.

Synthesis of B,O,N-Doped Adamantanes and Diamantanes by Condensation of Oximes with Boronic Acids.

Condensation of oximes with boronic acids RB(OH)2 or B(OH)3 affords remarkably stable 2,4,10-trioxa-1,5,7-triaza-3-boroadamantanes via an unprecedented multicomponent process. The mechanism involves the reversible generation of unstable oxime cyclotrimers, which are readily intercepted by boronic acids.

Synthesis and Structure of N,N-Dinitroamidoborane Complexes

A general approach to the synthesis of borohydride complexes containing one or two dinitroamide fragments has been suggested. Based on a smooth substitution of halide in haloborane or dibromoborane complexes with N,N-dinitroamide salts, this method provides various N,N-dinitroamidoboranes complexes in good yields and in analytically pure form. By means of spectroscopic and computational methods, it was demonstrated that dinitroamidoborane complexes could form as both B,N- and B,O-isomers, which did not interconvert at ambient temperature.

Synthesis of Tris(ɣ-oximinoalkyl)amines, New Tripodal N4 Ligands

Abstract An original approach to the synthesis of tris(γ-oximinoalkyl)amines was proposed. The suggested synthetic sequence is based on aza-Michael addition of ammonia to methyl vinyl ketone and oximation of obtained products with hydroxylamine or O-alkhylhydroxylamines. The tris(γ-oximinoalkyl)amines may be considered as prospective N4 tripodal ligands. GRAPHICAL ABSTRACT

Acylation of Nitronates: [3,3]-Sigmatropic Rearrangement of in Situ Generated N-Acyloxy,N-oxyenamines

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown N-acyloxy, N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N-O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.