ABSTRACT
A regio- and stereoselective intramolecular direct aldol reaction of 2,7-diketones derived from carbohydrates has been developed to construct cycloalkanones , which were dehydrated to obtain heavily oxygenated cycloalkenones .
ABSTRACT
A new class of human GST inhibitors has been identified via rational design approach; we report their discovery, synthesis, inhibitory activity, and synergetic effect in combination with cisplatin against A549 lung cancer cell line. The results of this effort show that the lead 4-O-decyl-gabosine D (24) has optimum synergetic effect in A549 human lung adenocarcinoma epithelial cell and that this activity involves inhibition of glutathione S-transferase M1, apparently consistent with siRNA-mediated knockdown of GSTM1 gene.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Cyclohexanones/pharmacology , Drug Resistance, Neoplasm/drug effects , Glutathione Transferase/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Cyclohexanones/chemical synthesis , Cyclohexanones/chemistry , Drug Screening Assays, Antitumor , Drug Synergism , Glutathione Transferase/genetics , Humans , Isoenzymes/antagonists & inhibitors , Lung Neoplasms , RNA, Small Interfering/genetics , Structure-Activity RelationshipABSTRACT
An alternative synthesis of 1,1'-bis-valienamine 5, which was demonstrated to be a potent trehalase inhibitor, has been achieved from d-glucose in 12 steps with 15% overall yield via enone 12 as the key intermediate, involving a direct aldol reaction of a glucose-derived diketone and a palladium-catalyzed allylic coupling reaction as the key steps.
Subject(s)
Cyclohexenes/chemical synthesis , Glucose/chemistry , Hexosamines/chemical synthesis , Cyclohexenes/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hexosamines/chemistry , Molecular Conformation , Stereoisomerism , Trehalase/antagonists & inhibitorsABSTRACT
(+)-Gabosines A (12), D (4), and E (5), which share the same trihydroxycyclohexenone skeleton, were synthesized from enone 11 as the common intermediate. The key building block 11 was accessed by an intramolecular aldol cyclization of a diketone derived from D-glucose (8).
Subject(s)
Cyclohexanones/chemical synthesis , Cyclization , Glucose/chemistry , Ketones/chemistryABSTRACT
A new and stereoselective intramolecular direct aldol reaction of diketones derived from carbohydrates has been developed to construct carbocycles with D-gluco-, D-galacto-, D-manno-, and L-ido-configurations. The stereochemical outcome of the aldol reaction of the diketone is dependent on the base used. Transformation of D-gluco-aldols readily affords valiolamine which also constitutes a formal synthesis of voglibose. Facile conversion of D-gluco-cyclohexanones into validoxylamine G has been achieved in 12 steps with 15.1% overall yield from D-glucose.
Subject(s)
Aldehydes/chemistry , Carbohydrates/chemistry , Inositol/analogs & derivatives , Ketones/chemistry , Enzyme Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors , Inositol/chemical synthesisABSTRACT
A pseudo-1,4'- N-linked disaccharide, pseudoacarviosin 5, was constructed via a key palladium-catalyzed coupling reaction of pseudoglycosyl chloride 8 (prepared from d-glucose via a novel direct intramolecular aldol addition in 12 steps) and pseudo-4-amino-4,6-dideoxy-alpha- d-glucose 9 (prepared from l-arabinose via an unusual trans-fused isoxazolidine-selective intramolecular nitrone-alkene cycloaddition in 11 steps). Pseudoacarviosin 5 has been shown to be a potent inhibitor of alpha-glucosidases, particularly the intestinal mucosal enzymes sucrase and glucoamylase of relevance to blood glucose control.
Subject(s)
Disaccharides/chemical synthesis , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents/chemical synthesis , Catalysis , Diabetes Mellitus/drug therapy , Disaccharides/chemistry , Disaccharides/pharmacology , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Molecular Structure , StereoisomerismABSTRACT
A short synthesis of gabosine I (1) from delta-D-gluconolactone (3) in four steps, involving a one-pot TPAP oxidation-K2CO3-mediated intramolecular Horner-Wadsworth-Emmons (HWE) olefination as the key step, is described. Regioselective acetylation of the primary alcohol in gabosine I (1) then furnished gabosine G (2).
Subject(s)
Cyclohexanones/chemical synthesis , Gluconates/chemistry , Lactones , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
[reaction: see text] Intramolecular nitrile oxide-alkene cycloaddition (INOC) of sugar derivatives with one to four free hydroxyl group(s) is reported. The INOC reaction, using chloramine-T, in the presence of silica gel, to generate nitrile oxides from oximes, proceeded smoothly to afford five- or six-membered carbocycles in good to excellent yields. This new methodology alleviates protection/deprotection steps and makes the synthetic route shorter and more efficient.
