General information All reactions, sensitive to air or moisture, were carried out in flame-dried ... more General information All reactions, sensitive to air or moisture, were carried out in flame-dried glassware under positive pressure of argon using standard techniques. For the photoreactions, the compounds were dissolved in the corresponding solvent, degassed by purging with Ar in an ultrasonicator for 15 minutes and irradiated in a Rayonet RPR 100 merry-goround reactor, equipped with 16 Rayonet RPR-2537 Å lamps (λ = 254 nm). Unless otherwise stated, the reactions were stopped when the starting material was fully consumed according to thin layer chromatography (TLC) and gas chromatography (GC) analysis. The solvent was then removed and the residue was purified by column chromatography. Except as otherwise noted; only one reaction product could be determined. Typically, an immobile spot could be seen on TLC, which we tentatively attribute to polymeric side-products. Flash chromatography was performed on silica gel 60 (Merck, 230-400 mesh) with the eluent mixtures given for the corresponding procedures. TLC was performed on silica coated glass plates (silca gel 60 F 254). Compounds were detected by UV (λ = 254 nm), CAM (cerium ammonium molybdate solution) or KMnO 4. All solvents for chromatography were destilled prior to use. Analytical gas chromatography was performed at a HP 6890 Series GC (Agilent, achiral stationary phase: HP-5 column, polydimethyl/diphenyl-siloxane, 95/5) with a flame ionisation detector. IR: JASCO IR-4100. MS /HRMS: Finnigan MAT 8200. 1 H and 13 C NMR: Bruker AV-250, AV-360 and AV-500 recorded at 300 K unless otherwise indicated. Chemical shifts are reported relative to the solvent [CHCl 3 : δ (1 H) = 7.26 ppm, δ (13 C) = 77.0 ppm, DMSO: δ (1 H) = 2.50 ppm, δ (13 C) = 39.5 ppm] as reference. Apparent multiplets which occur as a result of accidental equality of coupling constants to those of magnetically non-equivalent protons are marked as virtual (virt.). The relative configuration of the products and the multiplicity of the 13 C-NMR signals were determined by two-dimensional NMR spectra (COSY, NOESY, HSQC, HMBC). Melting points were measured on a Büchi 510 and are not corrected.
Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29... more Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29 Temperature 89(2) K Wavelength 0.70000 A Crystal system, space group Monoclinic, P2(1)/n Unit cell dimensions a = 10.633(2) A alpha = 90 deg. b = 6.3900(13)A beta = 102.39(3)deg. c = 20.622(4) A gamma = 90 deg. Volume 1368.5(5) A^3 Z, Calculated density 4, 1.229 Mg/m^3 Absorption coefficient 0.091 mm^-1 F(000) 544 Crystal size 0.2 x 0.1 x 0.07 mm Theta range for data collection 2.00 to 26.38 deg. Limiting indices-13<=h<=13,-7<=k<=7,-25<=l<=25 Reflections collected / unique
Tandem radical reactions listed in the title afford a convergent and flexible pathway to function... more Tandem radical reactions listed in the title afford a convergent and flexible pathway to functionalized, heteroannular tricyclic acetals which are of relevance in natural product chemistry. The cycloi.somtization of the 1,5enyne was carried out under exceptioually mild conditions at-50 to-6YC. For the first time, consecutive 5-exodigonal ! 5-exo-digonal cyclizadons using 1,5diyne systems have been accomplished, again under full stereocontrol. Academic insight into radical reactions has facilitated advances in organic synthesis and vice versa. Radical cascade reactions, in particular, are useful for constructing natural products and their precursors1 We here describe convergent routes to functional&d, heteroannular tricychc acetals via the title methodology. Acetylenes and allenes, unlike alkenes, have been used much less as acceptors in radical cyclizations. Alkynes offer the opportunity of generating reactive vinyl radicals by a radical addition under very mild conditions,* as an alternative to the homolytic fission of a vinyl-halogen bond, which is energetically more costly and accordingly, requires more demanding experimental conditions.
Heterocycles : an international journal for reviews and communications in heterocyclic chemistry, 2014
Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29... more Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29 Temperature 89(2) K Wavelength 0.70000 A Crystal system, space group Monoclinic, P2(1)/n Unit cell dimensions a = 10.633(2) A alpha = 90 deg. b = 6.3900(13)A beta = 102.39(3)deg. c = 20.622(4) A gamma = 90 deg. Volume 1368.5(5) A^3 Z, Calculated density 4, 1.229 Mg/m^3 Absorption coefficient 0.091 mm^-1 F(000) 544 Crystal size 0.2 x 0.1 x 0.07 mm Theta range for data collection 2.00 to 26.38 deg. Limiting indices-13<=h<=13,-7<=k<=7,-25<=l<=25 Reflections collected / unique
The s-BuLi-sparteine base combination deprotonated the C-2&amp;amp;amp;amp;amp;amp;amp;amp;am... more The s-BuLi-sparteine base combination deprotonated the C-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; position of 1,2,3,4,5-pentamethylazaferrocene and subsequent reaction with a range of electrophiles gave C-2 substituted products in 76-93% yield and approximately 80% ee. The products could be recrystallised to enrich ee&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s to…
The synthesis of five sialyl Lewis X mimetics was described. Mimetics 2 6 were easily synthesiz... more The synthesis of five sialyl Lewis X mimetics was described. Mimetics 2 6 were easily synthesized from readily available starting materials. Mimics 4 and 6 showed activities five-fold better than sialyl Lewis X. ... The synthesis of five readily prepared sialyl Lewis X mimetics was ...
We present a series of small molecule drug discovery case studies where computational methods wer... more We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequencedriven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.
The metabotropic glutamate receptor 2 (mGlu 2) plays an important role in the presynaptic control... more The metabotropic glutamate receptor 2 (mGlu 2) plays an important role in the presynaptic control of glutamate release and several mGlu 2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu 2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu 2 PAMs are therefore carried out here using the radiolabeled mGlu 2 agonist 3 [H]-LY354740 and mGlu 2 PAM 3 [H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu 2 PAMs increase the affinity of 3 [H]-LY354740 for the orthosteric site of mGlu2 as well as the number of 3 [H]-LY354740 binding sites. 3 [H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr 3.40 and Asn 5.46. Also of remark, in the described experimental conditions S731A (Ser 5.42) residue is important only for the mGlu 2 PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu 2 PAMs. This study provides a summary of the information generated in the past decade on mGlu 2 PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu 2 PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu 2 PAM and NAM agents and residues driving mGlu2 PAM selectivity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
A variety of the title benzodiazepine derivatives (I) are synthesized and evaluated as metabotrop... more A variety of the title benzodiazepine derivatives (I) are synthesized and evaluated as metabotropic glutamate receptor antagonists.
The biological activity of a potent selectin antagonist could be 40-fold enhanced by attachment o... more The biological activity of a potent selectin antagonist could be 40-fold enhanced by attachment of a lipid moiety. Also an enantioselective synthesis of β,ω-dihydroxyamino acids by Sharpless asymmetric dihydroxylation (AD-reaction) allowed general access to this important class of compounds.
The in vitro binding of [ 3 H]LY354740, the first high affinity group II-selective metabotropic g... more The in vitro binding of [ 3 H]LY354740, the first high affinity group II-selective metabotropic glutamate (mGlu) receptor radioligand, was characterized in rat cortical, hippocampal, and thalamic membranes as well as in rat brain sections. [ 3 H]LY354740 binding was saturable in all regions investigated. Nonspecific binding (in the presence of 10 M DCG-IV) was Ϸ8% of the total. Ionotropic glutamate receptor agonists, N-methyl-Daspartate, (R,S)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate, a Na ϩ-dependent glutamate uptake blocker as well as a group I-selective mGlu receptor agonist (all up to 1 mM) did not inhibit [ 3 H]LY354740 binding to cortical membranes. However, several known metabotropic receptor ligands inhibited the binding with the following rank order of potency: LY354740 ϭ LY341495 Ͼ (2S,2ЈR,3ЈR)-2-(2Ј,3Јdicarboxycyclopropyl)glycine ϭ (2S,1ЈS,2ЈS)-2-(2-carboxycyclopropyl)glycine Ͼ glutamate ϭ (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid Ͼ (2S,1ЈS,2ЈS)-2-methyl-2-(2carboxycyclopropyl)-glycine Ͼ quisqualate Ͼ ibotenate Ͼ L-2-amino-3-phosphonopropionic acid ϭ (S)-␣-methyl-4carboxyphenylglycine Ͼ L-(ϩ)-2-amino-4-phosphonobutyric acid. N-Acetyl-aspartyl-glutamate, (2S)-␣-ethylglutamic acid, and (R,S)-␣-methyl-4-phosphonophenylglycine inhibited [ 3 H]LY354740 binding in a biphasic manner. Guanosine-5Ј-O-(3-thiotriphosphate concentration-dependently and almost completely inhibited the binding. Finally, in parasagittal sections of rat brain, a high density of specific binding was observed in the accessory olfactory bulb, cortical regions (layers 1-3 Ͼ 4-6), caudate putamen, molecular layers of the hippocampus and dentate gyrus, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer, reflecting its preferential (perhaps not exclusive) affinity for presynaptic and postsynaptic mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to guanosine-5Ј-O-(3-thiotriphosphate show that [ 3 H]LY354740 binding probably occurs to group II mGlu receptors in rat brain.
Herein we describe the facile generation of novel benzimidazoles starting from 5-chloro-4-iodo-2-... more Herein we describe the facile generation of novel benzimidazoles starting from 5-chloro-4-iodo-2-nitroaniline. A synthesis protocol was established which allows the parallel synthesis of compound arrays as well as the rapid generation of single representatives thereof.
The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control ... more The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2 PAMs are therefore carried out here using the radiolabeled mGlu2 agonist 3[H]-LY354740 and mGlu2 PAM 3[H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu2 PAMs increase the affinity of 3[H]-LY354740 for the orthosteric site of mGlu2 as well as the number of 3[H]-LY354740 binding sites. 3[H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr3.40 and Asn5.46. Also of remark, in the described experimental conditions S731A (Ser5.42) residue is important only for the mGlu2 PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu2 PAMs. This study provides a summary of the information generated in the past decade on mGlu2 PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu2 PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu2 PAM and NAM agents and residues driving mGlu2 PAM selectivity.
Several aryl substituted C-fucopeptides have been developed as sialyl Lewis X mimetics. Although ... more Several aryl substituted C-fucopeptides have been developed as sialyl Lewis X mimetics. Although the compounds have a much simpler structure compared to SLex, up to 3-times higher binding affinity toward E-selectin and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 times toward P-selectin was observed. Furthermore, a convenient strategy for generating a number of analogues from a SLex mimetic template at a very late stage of the
Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3... more Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks. Objective: In the present primate study, we used radioautography to describe the distribution and intensity of 3 H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated. Methods: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3-10 mg/kg, and on the CDMP, subjects were tested at 1-3 or 3-10 mg/kg. Results: Radioautog-raphy revealed a relatively low level of 3 H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP. Conclusions: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.
General information All reactions, sensitive to air or moisture, were carried out in flame-dried ... more General information All reactions, sensitive to air or moisture, were carried out in flame-dried glassware under positive pressure of argon using standard techniques. For the photoreactions, the compounds were dissolved in the corresponding solvent, degassed by purging with Ar in an ultrasonicator for 15 minutes and irradiated in a Rayonet RPR 100 merry-goround reactor, equipped with 16 Rayonet RPR-2537 Å lamps (λ = 254 nm). Unless otherwise stated, the reactions were stopped when the starting material was fully consumed according to thin layer chromatography (TLC) and gas chromatography (GC) analysis. The solvent was then removed and the residue was purified by column chromatography. Except as otherwise noted; only one reaction product could be determined. Typically, an immobile spot could be seen on TLC, which we tentatively attribute to polymeric side-products. Flash chromatography was performed on silica gel 60 (Merck, 230-400 mesh) with the eluent mixtures given for the corresponding procedures. TLC was performed on silica coated glass plates (silca gel 60 F 254). Compounds were detected by UV (λ = 254 nm), CAM (cerium ammonium molybdate solution) or KMnO 4. All solvents for chromatography were destilled prior to use. Analytical gas chromatography was performed at a HP 6890 Series GC (Agilent, achiral stationary phase: HP-5 column, polydimethyl/diphenyl-siloxane, 95/5) with a flame ionisation detector. IR: JASCO IR-4100. MS /HRMS: Finnigan MAT 8200. 1 H and 13 C NMR: Bruker AV-250, AV-360 and AV-500 recorded at 300 K unless otherwise indicated. Chemical shifts are reported relative to the solvent [CHCl 3 : δ (1 H) = 7.26 ppm, δ (13 C) = 77.0 ppm, DMSO: δ (1 H) = 2.50 ppm, δ (13 C) = 39.5 ppm] as reference. Apparent multiplets which occur as a result of accidental equality of coupling constants to those of magnetically non-equivalent protons are marked as virtual (virt.). The relative configuration of the products and the multiplicity of the 13 C-NMR signals were determined by two-dimensional NMR spectra (COSY, NOESY, HSQC, HMBC). Melting points were measured on a Büchi 510 and are not corrected.
Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29... more Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29 Temperature 89(2) K Wavelength 0.70000 A Crystal system, space group Monoclinic, P2(1)/n Unit cell dimensions a = 10.633(2) A alpha = 90 deg. b = 6.3900(13)A beta = 102.39(3)deg. c = 20.622(4) A gamma = 90 deg. Volume 1368.5(5) A^3 Z, Calculated density 4, 1.229 Mg/m^3 Absorption coefficient 0.091 mm^-1 F(000) 544 Crystal size 0.2 x 0.1 x 0.07 mm Theta range for data collection 2.00 to 26.38 deg. Limiting indices-13<=h<=13,-7<=k<=7,-25<=l<=25 Reflections collected / unique
Tandem radical reactions listed in the title afford a convergent and flexible pathway to function... more Tandem radical reactions listed in the title afford a convergent and flexible pathway to functionalized, heteroannular tricyclic acetals which are of relevance in natural product chemistry. The cycloi.somtization of the 1,5enyne was carried out under exceptioually mild conditions at-50 to-6YC. For the first time, consecutive 5-exodigonal ! 5-exo-digonal cyclizadons using 1,5diyne systems have been accomplished, again under full stereocontrol. Academic insight into radical reactions has facilitated advances in organic synthesis and vice versa. Radical cascade reactions, in particular, are useful for constructing natural products and their precursors1 We here describe convergent routes to functional&d, heteroannular tricychc acetals via the title methodology. Acetylenes and allenes, unlike alkenes, have been used much less as acceptors in radical cyclizations. Alkynes offer the opportunity of generating reactive vinyl radicals by a radical addition under very mild conditions,* as an alternative to the homolytic fission of a vinyl-halogen bond, which is energetically more costly and accordingly, requires more demanding experimental conditions.
Heterocycles : an international journal for reviews and communications in heterocyclic chemistry, 2014
Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29... more Data deposition Roche CSD structure No. 2685 Empirical formula C13 H19 N O4 Formula weight 253.29 Temperature 89(2) K Wavelength 0.70000 A Crystal system, space group Monoclinic, P2(1)/n Unit cell dimensions a = 10.633(2) A alpha = 90 deg. b = 6.3900(13)A beta = 102.39(3)deg. c = 20.622(4) A gamma = 90 deg. Volume 1368.5(5) A^3 Z, Calculated density 4, 1.229 Mg/m^3 Absorption coefficient 0.091 mm^-1 F(000) 544 Crystal size 0.2 x 0.1 x 0.07 mm Theta range for data collection 2.00 to 26.38 deg. Limiting indices-13<=h<=13,-7<=k<=7,-25<=l<=25 Reflections collected / unique
The s-BuLi-sparteine base combination deprotonated the C-2&amp;amp;amp;amp;amp;amp;amp;amp;am... more The s-BuLi-sparteine base combination deprotonated the C-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; position of 1,2,3,4,5-pentamethylazaferrocene and subsequent reaction with a range of electrophiles gave C-2 substituted products in 76-93% yield and approximately 80% ee. The products could be recrystallised to enrich ee&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s to…
The synthesis of five sialyl Lewis X mimetics was described. Mimetics 2 6 were easily synthesiz... more The synthesis of five sialyl Lewis X mimetics was described. Mimetics 2 6 were easily synthesized from readily available starting materials. Mimics 4 and 6 showed activities five-fold better than sialyl Lewis X. ... The synthesis of five readily prepared sialyl Lewis X mimetics was ...
We present a series of small molecule drug discovery case studies where computational methods wer... more We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequencedriven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.
The metabotropic glutamate receptor 2 (mGlu 2) plays an important role in the presynaptic control... more The metabotropic glutamate receptor 2 (mGlu 2) plays an important role in the presynaptic control of glutamate release and several mGlu 2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu 2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu 2 PAMs are therefore carried out here using the radiolabeled mGlu 2 agonist 3 [H]-LY354740 and mGlu 2 PAM 3 [H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu 2 PAMs increase the affinity of 3 [H]-LY354740 for the orthosteric site of mGlu2 as well as the number of 3 [H]-LY354740 binding sites. 3 [H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr 3.40 and Asn 5.46. Also of remark, in the described experimental conditions S731A (Ser 5.42) residue is important only for the mGlu 2 PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu 2 PAMs. This study provides a summary of the information generated in the past decade on mGlu 2 PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu 2 PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu 2 PAM and NAM agents and residues driving mGlu2 PAM selectivity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
A variety of the title benzodiazepine derivatives (I) are synthesized and evaluated as metabotrop... more A variety of the title benzodiazepine derivatives (I) are synthesized and evaluated as metabotropic glutamate receptor antagonists.
The biological activity of a potent selectin antagonist could be 40-fold enhanced by attachment o... more The biological activity of a potent selectin antagonist could be 40-fold enhanced by attachment of a lipid moiety. Also an enantioselective synthesis of β,ω-dihydroxyamino acids by Sharpless asymmetric dihydroxylation (AD-reaction) allowed general access to this important class of compounds.
The in vitro binding of [ 3 H]LY354740, the first high affinity group II-selective metabotropic g... more The in vitro binding of [ 3 H]LY354740, the first high affinity group II-selective metabotropic glutamate (mGlu) receptor radioligand, was characterized in rat cortical, hippocampal, and thalamic membranes as well as in rat brain sections. [ 3 H]LY354740 binding was saturable in all regions investigated. Nonspecific binding (in the presence of 10 M DCG-IV) was Ϸ8% of the total. Ionotropic glutamate receptor agonists, N-methyl-Daspartate, (R,S)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate, a Na ϩ-dependent glutamate uptake blocker as well as a group I-selective mGlu receptor agonist (all up to 1 mM) did not inhibit [ 3 H]LY354740 binding to cortical membranes. However, several known metabotropic receptor ligands inhibited the binding with the following rank order of potency: LY354740 ϭ LY341495 Ͼ (2S,2ЈR,3ЈR)-2-(2Ј,3Јdicarboxycyclopropyl)glycine ϭ (2S,1ЈS,2ЈS)-2-(2-carboxycyclopropyl)glycine Ͼ glutamate ϭ (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid Ͼ (2S,1ЈS,2ЈS)-2-methyl-2-(2carboxycyclopropyl)-glycine Ͼ quisqualate Ͼ ibotenate Ͼ L-2-amino-3-phosphonopropionic acid ϭ (S)-␣-methyl-4carboxyphenylglycine Ͼ L-(ϩ)-2-amino-4-phosphonobutyric acid. N-Acetyl-aspartyl-glutamate, (2S)-␣-ethylglutamic acid, and (R,S)-␣-methyl-4-phosphonophenylglycine inhibited [ 3 H]LY354740 binding in a biphasic manner. Guanosine-5Ј-O-(3-thiotriphosphate concentration-dependently and almost completely inhibited the binding. Finally, in parasagittal sections of rat brain, a high density of specific binding was observed in the accessory olfactory bulb, cortical regions (layers 1-3 Ͼ 4-6), caudate putamen, molecular layers of the hippocampus and dentate gyrus, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer, reflecting its preferential (perhaps not exclusive) affinity for presynaptic and postsynaptic mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to guanosine-5Ј-O-(3-thiotriphosphate show that [ 3 H]LY354740 binding probably occurs to group II mGlu receptors in rat brain.
Herein we describe the facile generation of novel benzimidazoles starting from 5-chloro-4-iodo-2-... more Herein we describe the facile generation of novel benzimidazoles starting from 5-chloro-4-iodo-2-nitroaniline. A synthesis protocol was established which allows the parallel synthesis of compound arrays as well as the rapid generation of single representatives thereof.
The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control ... more The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2 PAMs are therefore carried out here using the radiolabeled mGlu2 agonist 3[H]-LY354740 and mGlu2 PAM 3[H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu2 PAMs increase the affinity of 3[H]-LY354740 for the orthosteric site of mGlu2 as well as the number of 3[H]-LY354740 binding sites. 3[H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr3.40 and Asn5.46. Also of remark, in the described experimental conditions S731A (Ser5.42) residue is important only for the mGlu2 PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu2 PAMs. This study provides a summary of the information generated in the past decade on mGlu2 PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu2 PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu2 PAM and NAM agents and residues driving mGlu2 PAM selectivity.
Several aryl substituted C-fucopeptides have been developed as sialyl Lewis X mimetics. Although ... more Several aryl substituted C-fucopeptides have been developed as sialyl Lewis X mimetics. Although the compounds have a much simpler structure compared to SLex, up to 3-times higher binding affinity toward E-selectin and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 times toward P-selectin was observed. Furthermore, a convenient strategy for generating a number of analogues from a SLex mimetic template at a very late stage of the
Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3... more Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks. Objective: In the present primate study, we used radioautography to describe the distribution and intensity of 3 H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated. Methods: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3-10 mg/kg, and on the CDMP, subjects were tested at 1-3 or 3-10 mg/kg. Results: Radioautog-raphy revealed a relatively low level of 3 H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP. Conclusions: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.
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Papers by Thomas Woltering