ABSTRACT
A simple and versatile method for the enantio- and diastereoselective synthesis of mono- or disubstituted 3-aminoazepanes is described. The key step involves a highly regio- and diastereoselective tandem ring-enlargement/alkylation or reduction process. This novel synthetic route provides enantiomerically pure constrained diamines interesting as scaffolds for medicinal chemistry.
ABSTRACT
The first total synthesis of coscinosulfate 1, a metabolite isolated from a sea sponge, starting from (+)-sclareolide 3 is described. The convergent synthesis strategy relies on the coupling of sulfone 21 with the bromide 26. The sulfone fragment 21 was obtained by successive asymmetric aldol reaction with aldehyde 2 to introduce the stereocenters at C-12 and C-13, followed by one-carbon homologation via Horner-Wadsworth-Emmons olefination. The selective sulfatation at C-12 was accomplished through the quinone intermediate 31 obtained by selective oxidation of hydroquinone 30; this, when followed by reduction, furnished the desired coscinosulfate 1. X-ray analysis of the intermediate aldehyde 18 confirmed the proposed structure.
Subject(s)
Terpenes/chemical synthesis , cdc25 Phosphatases/antagonists & inhibitors , Animals , Antifungal Agents/chemistry , Diterpenes/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Conformation , Porifera/chemistry , Sesterterpenes , Stereoisomerism , Terpenes/chemistryABSTRACT
Three new limonoids, named haperforins C2 (1), F (2), and G (3), were isolated from a sample of Harrisonia perforata leaves collected in Central Vietnam. Their structures were determined by single-crystal X-ray diffraction analyses, and their NMR and mass spectral data are reported.
Subject(s)
Limonins , Plants, Medicinal/chemistry , Triterpenes/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Plant Extracts/chemistry , Plant Leaves/chemistry , Triterpenes/isolation & purification , Vietnam , X-Ray DiffractionABSTRACT
Bridged tetracyclic tetrahydroquinoline is synthesized by a novel one-pot three component condensation of an ortho-amino cinnamate, alpha-isocyano acetamide and an aldehyde.
ABSTRACT
The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.
Subject(s)
Drug Design , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor Modulators/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Binding, Competitive/drug effects , Cell Division/drug effects , Crystallography, X-Ray , Estrogen Receptor Modulators/chemistry , Estrogen Receptor Modulators/metabolism , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Conformation , Molecular Structure , Quinolines/chemistry , Quinolines/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tumor Cells, CulturedSubject(s)
Furans/chemical synthesis , GABA Modulators/chemical synthesis , Isoquinolines/chemical synthesis , Receptors, GABA-A/drug effects , Tetrahydroisoquinolines , Allosteric Regulation , Animals , Brain/metabolism , Electrophysiology , Furans/chemistry , Furans/pharmacology , GABA Modulators/chemistry , GABA Modulators/pharmacology , In Vitro Techniques , Isoquinolines/chemistry , Isoquinolines/pharmacology , Molecular Conformation , Oocytes/metabolism , Oocytes/physiology , Radioligand Assay , Rats , Receptors, GABA-A/genetics , Receptors, GABA-A/physiology , Stereoisomerism , Structure-Activity Relationship , XenopusABSTRACT
Two new rearranged limonoids, named haperforine A (1) and haperforine E (2), were isolated from a sample of Harrisonia perforata leaves collected in Center Vietnam and their structures determined by X-ray diffraction analysis. The structure of a minor compound was established as 12-desacetylhaperforine A (3) by chemical correlation. Their NMR and mass spectroscopic properties are reported.
Subject(s)
Flavonoids/chemistry , Flavonoids/isolation & purification , Plants, Medicinal/chemistry , Crystallography, X-Ray , Molecular Structure , Spectrum AnalysisABSTRACT
Bioassay-guided fractionation of a leaf extract of G. bracteata has yielded six new prenylxanthones, bractatin (1), isobractatin (2), 1-O-methylbractatin (3), 1-O-methylisobractatin (4), 1-O-methyl-8-methoxy-8,8a-dihydrobractatin (5), and 1-O-methylneobractatin (6). The structures of these compounds have been elucidated by spectroscopic means (NMR, MS), literature data, and X-ray crystallographic analysis of 2. These compounds possess significant cytotoxicity against the KB cell line.
Subject(s)
Antineoplastic Agents, Phytogenic/isolation & purification , Plants, Medicinal/chemistry , Xanthenes/isolation & purification , Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Humans , KB Cells , Magnetic Resonance Spectroscopy , Mass Spectrometry , Plant Leaves/chemistry , Spectrophotometry, Ultraviolet , Xanthenes/pharmacologyABSTRACT
The X-ray crystal structure of 3-(methoxycarbonyl) amino-beta-carboline, a selective antagonist of the sedative effects of diazepam having a high affinity for the benzodiazepine receptor, has been determined. The results were compared with structural information obtained from this compound, both in the solid state and in dilute solution, by use of Fourier transform infrared spectroscopy. Its X-ray structure was also compared with those of two other active beta-carbolines, methyl beta-carboline-3-carboxylate and N-ethyl-3-carbamoyl-beta-carboline. The crystal packing characteristics of 3-(methoxycarbonyl) amino-beta-carboline differ from those of these two beta-carbolines in both the pattern of intermolecular hydrogen bonding and the quality of their pi-pi stacking interactions. The relevance this may have to the selective activity of 3-(methoxycarbonyl) amino-beta-carboline is discussed.
Subject(s)
Carbolines , Diazepam/antagonists & inhibitors , Carbolines/pharmacology , Crystallography , Models, Molecular , Molecular Conformation , Receptors, GABA-A/drug effects , X-Ray DiffractionABSTRACT
The optically active lignan (-)-steganol was prepared from natural (-)-steganacin by selective deacetylation and was transformed, via a three-step sequence, into the corresponding 4', 6'-O-ethylidene- and thenylidene-beta-D-glucopyranosides, 3b and 3c, respectively, which are the analogues, in the steganol series, of the podophyllotoxin derived, and clinically useful, anticancer drugs, VP16-213 and VM26. Formation of the dimeric compound distegyl ether as a minor by-product was established. Complete elucidation of all the asymmetric centres was performed with the help of high resolution 1H-nmr studies at 400 MHz, COSY experiment at 500 MHz and X-ray analysis. Contrary to the podophyllotoxin series, the glycosylation of (-)-steganol occurred with retention of configuration, and all the synthesized compounds, including distegyl ether, exhibited the starting natural R configuration at C-5.
