The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs ... more The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs are described. These prodrugs were designed as potential candidates in more selective chemotherapy by targeting hypoxic tumour tissue. Aromatic nitro and azide groups were used as the bioreductive trigger. Generation of paclitaxel occurs after reduction and subsequent 1,6-elimination or 1,8-elimination. All prodrugs are stable in buffer and indeed give paclitaxel after chemical reduction of the aromatic nitro or azide functionality. In aerobic cytotoxicity assays several prodrugs exhibit diminished cytotoxicity. These compounds are interesting candidates for further biological evaluation.
The selective C-10 acylation of 10-deacetylbaccatin III to baccatin III and derivatives is very e... more The selective C-10 acylation of 10-deacetylbaccatin III to baccatin III and derivatives is very efficiently catalysed by lanthanide trifluoromethanesulfonates. Baccatin III, now readily available through this procedure, is an important precursor for an economically viable semisynthesis of paclitaxel and its derivatives.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT 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.
ChemInform Abstract Dimethoxypropen (I) reagiert mit den Acyloxy-carbonylverbindungen (II) zu den... more ChemInform Abstract Dimethoxypropen (I) reagiert mit den Acyloxy-carbonylverbindungen (II) zu den Oxetanen (III), die mit KOH zu den Hydroxyoxetanen (IV) hydrolysiert werden; (IV) lagern sich in neutralem oder schwach saurem Medium in die Hydroxytetrahydrofurane (V) um. Durch HC1-Hydrolyse erhält man aus (IV) oder (V) die Hydroxy-y-butyrolactone (VI), deren Dehydratisierung die Butenolide (VII) liefert. Die Stereochemie der Verbindungen (V) und (VI) wird untersucht.
European Journal of Organic Chemistry, Sep 1, 2002
Pyran derivatives Pyran derivatives R 0340 High Pressure Promoted Cycloadditions of Enol Ethers a... more Pyran derivatives Pyran derivatives R 0340 High Pressure Promoted Cycloadditions of Enol Ethers and 3-Aryl-2-cyano-2-propenoates.-The title reaction offers an efficient approach to pyranocarbonitriles. The latter which are prepared with high endo selectivity can smoothly be transformed into different compounds like aldehydes, ketones, acetals, β-amino acid esters, and piperidines.
A series of new receptor molecules derived from 2,4,6,8-tetraazabicyclo[3.3.1]nonane-3,7-dione (p... more A series of new receptor molecules derived from 2,4,6,8-tetraazabicyclo[3.3.1]nonane-3,7-dione (propanediurea) is described. These molecules possess a cavity which is defined by two nearly parallel aromatic side walls positioned on top of a bis-urea framework. The resulting "U-shaped" clip molecules are ideal hosts for the complexation of flat aromatic guest molecules. The affinity of these new propanediurea based molecular clips for dihydroxybenzene derivatives is exceptionally high, with association constants up to K a) 2 400 000 L mol-1. Comparison of the binding mechanism of a variety of clip and half clip hosts, in conjunction with NMR, IR, and X-ray studies, has enabled the reason for this high binding to be elucidated. It is shown that subtle sub-angstrom changes in the geometry of the clip molecules have a great impact on their binding properties.
Journal of the American Chemical Society, Jun 11, 2020
Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are pote... more Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators of antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from the site of injection into systemic circulation. Here, we report on the design and synthesis of an amphiphilic polymer-prodrug conjugate of an imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures of 200 nm. The conjugate contains an endosomal enzyme-responsive linker enabling degradation of the vesicles and release of the TLR7/8 agonist in native form after endocytosis, which results in high in vitro TLR agonist activity. In a mouse model, locally administered vesicles provoke significantly more potent and long-lasting immune stimulation in terms of interferon expression at the injection site and in draining lymphoid tissue compared to a nonamphiphilic control and the native TLR agonist. Moreover, the vesicles induce robust activation of dendritic cells in the draining lymph node in vivo.
The (3+2] cyclouddition reactions of nitriles with f,3-dipoles containing an arthogonal double bo... more The (3+2] cyclouddition reactions of nitriles with f,3-dipoles containing an arthogonal double bond (nitrilium betaims, diauHlium bctaincs) arc well documntedl and afford useful syntktic mutes to a variety of five-membered hctcrmyclic ring systems. In contrast, relatively few examples of the cycloaddition of nitriles to 1,3-dipoles lacking a double bond (the class of ammthinium betaints) are known.' Recently we ~~pmtcd~ that 1, a nibme dcrivai f?mn N-hydroxytryptophanc as well as several other nitmncs undmvent cycloaddition to geminuf dinitriles with complete r@~~lcctivity to give A'-1 &GoxAiam1ims. In general the k~~~wlalgc and undastanding of tbc remion 9Xi.k of l$dipolcS and dipolamphilcs are intimately connected with mechanistic qucstims. It is generally ~~~cptcd that 1,3dipolar cycloadditions of nitroncs to alktncs arc single-step cmcmed four-center rcaction~.~ However, it is suggtstadl that polari& dipolamphiks (e.g. nitriles) may undergo cmcatcd but not nczssarily synchronous cycloadditions. We now report an extensive investigation of the scope as well as a mc&nistic study of the nimnt-nitrik cyckmddition. Synfhetlc scope The nitrmes l-6 wm used as 1,3dip0les in this investigatbn. The rmv nitmms 3 and 4 were
ChemInform Abstract Behandelt man Alkylsulfinyl-oder I-Alkylsulfonyl-CS-chlor-2-propanole mit alk... more ChemInform Abstract Behandelt man Alkylsulfinyl-oder I-Alkylsulfonyl-CS-chlor-2-propanole mit alkoholisch-wässriger Natronlauge oder Natriumalkoholat-Lösung, so erfolgt eine intermolekulare Cyclisierung zu ZS-Dialkylsulfinyl-bzw. 2,5-Dialkylsulfonylmethyl-l ,4-dioxanen, was im Formelschema anhand der Butylverbindungen (I) gezeigt ist.
ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)über... more ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)übergeführt, die Wirkung gegen Leukämiezellen der Maus besitzen. Am wirksamsten ist die Verbindung (IIIa). (UV-spektroskopische Daten).
European Journal of Organic Chemistry, Feb 1, 2001
At 15 kbar the 1-nitro-2-heteroarylethenes 2a−c reacted in a one-pot three-component cycloadditio... more At 15 kbar the 1-nitro-2-heteroarylethenes 2a−c reacted in a one-pot three-component cycloaddition with p-methoxybenzyl vinyl ether (1) and methyl acrylate to yield novel heteroaromatic-substituted six/five-membered bicyclic nitroso acetals. In the reaction of 3-[(E)-2-nitroeth-1-enyl]pyridine (2 equiv.) and 1 a competition between the formation of the tandem [4 + 2]/[3 + 2] cycloadducts and the formation of a novel five-membered cyclic nitronate was observed. The ratio of product formation was strongly pressure and solvent dependent. A mechanistic explanation for the formation of the novel five-membered cyclic nitronate has been proposed. 1-Nitro-4-[(E)-2-nitroeth-1-enyl]benzene (2d) reacted with 1 in the same manner as 2a in accordance with the proposed mechanism. The five-membered cyclic nitronate reacted as an 1,3-dipole in a high-pressure promoted [3 + 2] cycloaddition with both electron-rich and electron-poor olefins and yielded a novel class of pyridyl-substituted five/five-membered bicyclic nitroso acetals.
Page 1. N N N N O O R2 R2 R2 R2 R1 R1 N N N N O O R2 R2 R2 R2 R1 NH HN HN NH O O R1 1a R1 = Ph, R... more Page 1. N N N N O O R2 R2 R2 R2 R1 R1 N N N N O O R2 R2 R2 R2 R1 NH HN HN NH O O R1 1a R1 = Ph, R2 = H b R1 = Ph, R2 = OMe c R1 = Me, R2 = H 2a R1 = H, R2 = H b R1 = Me, R2 = H c R1 = H, R2 = OMe 3a R1 = H b R1 = Me R ...
Abstract The diastereoselectivity of the intramolecular Pictet-Spengler condensation in the synth... more Abstract The diastereoselectivity of the intramolecular Pictet-Spengler condensation in the synthesis of tetracyclic eudistomins is described. Nb-Alkoxytryptamines 15a–m were synthesized with different sized groups R2. Closure of the 7-membered oxathiazepine ring was accomplished in 66–98% yield. With the intramolecular approach diastereoselectivity can be achieved for the unnatural trans isomer. An indole methylated derivative was also synthesized giving the interesting cis/trans pentacyclic spiro compounds 19 and 20. These results are interpreted in terms of a kinetically favoured electrophilic attack at the indole-3 position, whereas β-carboline formation is the result of a slower route via electrophilic attack at the indole-2 position.
Methods Activation of nitrodiol 6 to give doubly activated 7. Nitrodiol 6 (130 mg, 0.621 mmol) wa... more Methods Activation of nitrodiol 6 to give doubly activated 7. Nitrodiol 6 (130 mg, 0.621 mmol) was dissolved in 3 mL of dry THF under an argon atmosphere and the solution was cooled to 0 °C. Diisopropylethylamine (DIPEA) (865 µL, 8 equiv), 4-nitrophenyl chloroformate (751 mg, 6 equiv), and pyridine (25 μL, 0.5 equiv) were added to the solution. The reaction mixture was allowed to reach room temperature (Rt) and stirred for 16 h. Dichloromethane was added and the organic layer was washed with water, saturated sodium bicarbonate, and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The product was purified by means of column chromatography (EtOAc/heptane 2/5) to afford 280 mg (84%) of doubly activated 7. 1 H-NMR (300 MHz, CDCl 3) δ 5.
Bridging inorganic medicinal chemistry and nanomedicine in cancer therapy: nanoformulations to im... more Bridging inorganic medicinal chemistry and nanomedicine in cancer therapy: nanoformulations to improve the clinical translation of metallodrugs.
The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs ... more The syntheses and preliminary evaluation of the first potential bioreductive paclitaxel prodrugs are described. These prodrugs were designed as potential candidates in more selective chemotherapy by targeting hypoxic tumour tissue. Aromatic nitro and azide groups were used as the bioreductive trigger. Generation of paclitaxel occurs after reduction and subsequent 1,6-elimination or 1,8-elimination. All prodrugs are stable in buffer and indeed give paclitaxel after chemical reduction of the aromatic nitro or azide functionality. In aerobic cytotoxicity assays several prodrugs exhibit diminished cytotoxicity. These compounds are interesting candidates for further biological evaluation.
The selective C-10 acylation of 10-deacetylbaccatin III to baccatin III and derivatives is very e... more The selective C-10 acylation of 10-deacetylbaccatin III to baccatin III and derivatives is very efficiently catalysed by lanthanide trifluoromethanesulfonates. Baccatin III, now readily available through this procedure, is an important precursor for an economically viable semisynthesis of paclitaxel and its derivatives.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT 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.
ChemInform Abstract Dimethoxypropen (I) reagiert mit den Acyloxy-carbonylverbindungen (II) zu den... more ChemInform Abstract Dimethoxypropen (I) reagiert mit den Acyloxy-carbonylverbindungen (II) zu den Oxetanen (III), die mit KOH zu den Hydroxyoxetanen (IV) hydrolysiert werden; (IV) lagern sich in neutralem oder schwach saurem Medium in die Hydroxytetrahydrofurane (V) um. Durch HC1-Hydrolyse erhält man aus (IV) oder (V) die Hydroxy-y-butyrolactone (VI), deren Dehydratisierung die Butenolide (VII) liefert. Die Stereochemie der Verbindungen (V) und (VI) wird untersucht.
European Journal of Organic Chemistry, Sep 1, 2002
Pyran derivatives Pyran derivatives R 0340 High Pressure Promoted Cycloadditions of Enol Ethers a... more Pyran derivatives Pyran derivatives R 0340 High Pressure Promoted Cycloadditions of Enol Ethers and 3-Aryl-2-cyano-2-propenoates.-The title reaction offers an efficient approach to pyranocarbonitriles. The latter which are prepared with high endo selectivity can smoothly be transformed into different compounds like aldehydes, ketones, acetals, β-amino acid esters, and piperidines.
A series of new receptor molecules derived from 2,4,6,8-tetraazabicyclo[3.3.1]nonane-3,7-dione (p... more A series of new receptor molecules derived from 2,4,6,8-tetraazabicyclo[3.3.1]nonane-3,7-dione (propanediurea) is described. These molecules possess a cavity which is defined by two nearly parallel aromatic side walls positioned on top of a bis-urea framework. The resulting "U-shaped" clip molecules are ideal hosts for the complexation of flat aromatic guest molecules. The affinity of these new propanediurea based molecular clips for dihydroxybenzene derivatives is exceptionally high, with association constants up to K a) 2 400 000 L mol-1. Comparison of the binding mechanism of a variety of clip and half clip hosts, in conjunction with NMR, IR, and X-ray studies, has enabled the reason for this high binding to be elucidated. It is shown that subtle sub-angstrom changes in the geometry of the clip molecules have a great impact on their binding properties.
Journal of the American Chemical Society, Jun 11, 2020
Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are pote... more Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators of antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from the site of injection into systemic circulation. Here, we report on the design and synthesis of an amphiphilic polymer-prodrug conjugate of an imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures of 200 nm. The conjugate contains an endosomal enzyme-responsive linker enabling degradation of the vesicles and release of the TLR7/8 agonist in native form after endocytosis, which results in high in vitro TLR agonist activity. In a mouse model, locally administered vesicles provoke significantly more potent and long-lasting immune stimulation in terms of interferon expression at the injection site and in draining lymphoid tissue compared to a nonamphiphilic control and the native TLR agonist. Moreover, the vesicles induce robust activation of dendritic cells in the draining lymph node in vivo.
The (3+2] cyclouddition reactions of nitriles with f,3-dipoles containing an arthogonal double bo... more The (3+2] cyclouddition reactions of nitriles with f,3-dipoles containing an arthogonal double bond (nitrilium betaims, diauHlium bctaincs) arc well documntedl and afford useful syntktic mutes to a variety of five-membered hctcrmyclic ring systems. In contrast, relatively few examples of the cycloaddition of nitriles to 1,3-dipoles lacking a double bond (the class of ammthinium betaints) are known.' Recently we ~~pmtcd~ that 1, a nibme dcrivai f?mn N-hydroxytryptophanc as well as several other nitmncs undmvent cycloaddition to geminuf dinitriles with complete r@~~lcctivity to give A'-1 &GoxAiam1ims. In general the k~~~wlalgc and undastanding of tbc remion 9Xi.k of l$dipolcS and dipolamphilcs are intimately connected with mechanistic qucstims. It is generally ~~~cptcd that 1,3dipolar cycloadditions of nitroncs to alktncs arc single-step cmcmed four-center rcaction~.~ However, it is suggtstadl that polari& dipolamphiks (e.g. nitriles) may undergo cmcatcd but not nczssarily synchronous cycloadditions. We now report an extensive investigation of the scope as well as a mc&nistic study of the nimnt-nitrik cyckmddition. Synfhetlc scope The nitrmes l-6 wm used as 1,3dip0les in this investigatbn. The rmv nitmms 3 and 4 were
ChemInform Abstract Behandelt man Alkylsulfinyl-oder I-Alkylsulfonyl-CS-chlor-2-propanole mit alk... more ChemInform Abstract Behandelt man Alkylsulfinyl-oder I-Alkylsulfonyl-CS-chlor-2-propanole mit alkoholisch-wässriger Natronlauge oder Natriumalkoholat-Lösung, so erfolgt eine intermolekulare Cyclisierung zu ZS-Dialkylsulfinyl-bzw. 2,5-Dialkylsulfonylmethyl-l ,4-dioxanen, was im Formelschema anhand der Butylverbindungen (I) gezeigt ist.
ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)über... more ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)übergeführt, die Wirkung gegen Leukämiezellen der Maus besitzen. Am wirksamsten ist die Verbindung (IIIa). (UV-spektroskopische Daten).
European Journal of Organic Chemistry, Feb 1, 2001
At 15 kbar the 1-nitro-2-heteroarylethenes 2a−c reacted in a one-pot three-component cycloadditio... more At 15 kbar the 1-nitro-2-heteroarylethenes 2a−c reacted in a one-pot three-component cycloaddition with p-methoxybenzyl vinyl ether (1) and methyl acrylate to yield novel heteroaromatic-substituted six/five-membered bicyclic nitroso acetals. In the reaction of 3-[(E)-2-nitroeth-1-enyl]pyridine (2 equiv.) and 1 a competition between the formation of the tandem [4 + 2]/[3 + 2] cycloadducts and the formation of a novel five-membered cyclic nitronate was observed. The ratio of product formation was strongly pressure and solvent dependent. A mechanistic explanation for the formation of the novel five-membered cyclic nitronate has been proposed. 1-Nitro-4-[(E)-2-nitroeth-1-enyl]benzene (2d) reacted with 1 in the same manner as 2a in accordance with the proposed mechanism. The five-membered cyclic nitronate reacted as an 1,3-dipole in a high-pressure promoted [3 + 2] cycloaddition with both electron-rich and electron-poor olefins and yielded a novel class of pyridyl-substituted five/five-membered bicyclic nitroso acetals.
Page 1. N N N N O O R2 R2 R2 R2 R1 R1 N N N N O O R2 R2 R2 R2 R1 NH HN HN NH O O R1 1a R1 = Ph, R... more Page 1. N N N N O O R2 R2 R2 R2 R1 R1 N N N N O O R2 R2 R2 R2 R1 NH HN HN NH O O R1 1a R1 = Ph, R2 = H b R1 = Ph, R2 = OMe c R1 = Me, R2 = H 2a R1 = H, R2 = H b R1 = Me, R2 = H c R1 = H, R2 = OMe 3a R1 = H b R1 = Me R ...
Abstract The diastereoselectivity of the intramolecular Pictet-Spengler condensation in the synth... more Abstract The diastereoselectivity of the intramolecular Pictet-Spengler condensation in the synthesis of tetracyclic eudistomins is described. Nb-Alkoxytryptamines 15a–m were synthesized with different sized groups R2. Closure of the 7-membered oxathiazepine ring was accomplished in 66–98% yield. With the intramolecular approach diastereoselectivity can be achieved for the unnatural trans isomer. An indole methylated derivative was also synthesized giving the interesting cis/trans pentacyclic spiro compounds 19 and 20. These results are interpreted in terms of a kinetically favoured electrophilic attack at the indole-3 position, whereas β-carboline formation is the result of a slower route via electrophilic attack at the indole-2 position.
Methods Activation of nitrodiol 6 to give doubly activated 7. Nitrodiol 6 (130 mg, 0.621 mmol) wa... more Methods Activation of nitrodiol 6 to give doubly activated 7. Nitrodiol 6 (130 mg, 0.621 mmol) was dissolved in 3 mL of dry THF under an argon atmosphere and the solution was cooled to 0 °C. Diisopropylethylamine (DIPEA) (865 µL, 8 equiv), 4-nitrophenyl chloroformate (751 mg, 6 equiv), and pyridine (25 μL, 0.5 equiv) were added to the solution. The reaction mixture was allowed to reach room temperature (Rt) and stirred for 16 h. Dichloromethane was added and the organic layer was washed with water, saturated sodium bicarbonate, and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The product was purified by means of column chromatography (EtOAc/heptane 2/5) to afford 280 mg (84%) of doubly activated 7. 1 H-NMR (300 MHz, CDCl 3) δ 5.
Bridging inorganic medicinal chemistry and nanomedicine in cancer therapy: nanoformulations to im... more Bridging inorganic medicinal chemistry and nanomedicine in cancer therapy: nanoformulations to improve the clinical translation of metallodrugs.
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Papers by Hans Scheeren