There's a huge gap between the sequence and structural knowledge of proteins. Determining protein... more There's a huge gap between the sequence and structural knowledge of proteins. Determining proteins structures experimentally is expensive and not always amenable. Computational tools such as homology modeling have been successful at bridging this gap. However, they are still subject to database information and they don't have a principled way of selecting structures. This and other issues are treated in the blind CASP competition (Critical Assessment of Structure Prediction). We took part in the recent CASP11 competition by using a new physics based approach called MELD[1,2] and combining with either proposed data during CASP or with general insights coming from our knowledge of globular protein structures (e.g. they have hydrophobic cores). Physics based methods are usually too computationally demanding for the tight deadlines in CASP, which has mostly excluded them from participation. In this talk I will show how MELD was useful during CASP. In some cases MELD provided value beyond what database methods could do-including the best blind prediction for one of the proteins in CASP. As such, physics based methods are starting to be useful for structure prediction to complement existing methods. 1.MacCallum, J. L., Perez, A. & Dill, K. Determining protein structures by combining semireliable data with atomistic physical models by Bayesian inference.
Beuerle F, Krueger A, Lehmann M, et al. Organic Chemistry 2012. Nachrichten aus der Chemie . 2013... more Beuerle F, Krueger A, Lehmann M, et al. Organic Chemistry 2012. Nachrichten aus der Chemie . 2013;61(3):265-297
Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al.,... more Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem. Sci., 2020, 11, 2627–2639.
There are currently fewer than ten antifungal drugs in clinical development, but new fungal strai... more There are currently fewer than ten antifungal drugs in clinical development, but new fungal strains, which are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains, compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or haemolytic pr...
A synthesis of benzo[e][1,2,4]triazines and 1,2,4-triazolospiro[4,5]deca-2,6,9-trien-8-ones has b... more A synthesis of benzo[e][1,2,4]triazines and 1,2,4-triazolospiro[4,5]deca-2,6,9-trien-8-ones has been developed from reactions of amidrazones with 2-chloro-1,4-benzoquinone in EtOAc containing 0.5 mL of piperidine. This highly regioselective and one-pot process provided rapid access to 1,2,4-triazolospiro[4,5]deca-2,6,9-trien-8-ones (60%-70%) and benzo[e][1,2,4]triazines (11%-18%). On reacting amidrazones with 5-hydroxy-1,4-naphthoquinone in an EtOAc/piperidine mixture, the reaction proceeded to give 5-hydroxy-2-(piperidin-1-yl)naphthalene-1,4-dione. The structures of the isolated products were proved by infrared, NMR (2D-NMR), mass spectra, and elemental analyses in addition to X-ray structure analysis. The reaction mechanisms are discussed. The anticancer screening of selected compounds showed broad-spectrum anticancer activity against most melanoma cancer cell lines, ovarian cancer OVCAR-3, central nervous system cancer SF-295 and U251, non-small cell lung cancer NCI-H23, renal cancer SN12C, and colon cancer HCT-15 and HCT-116. The selected compounds exhibited moderate to weak anticancer activity to other cell lines.
Improved One-Pot Synthesis of C 3-Symmetric ClickPhos and Related Ligands: Structures of Unique T... more Improved One-Pot Synthesis of C 3-Symmetric ClickPhos and Related Ligands: Structures of Unique Triazole-Zinc Complexes.-Mono-, bis-, and tris(triazolyl)phosphanes are prepared by in three steps without isolation of the intermediates. The route involves the generation of an alkynylmagnesium bromide, the conversion into a triazolylmagnesium bromide by reaction with an azide, and the direct treatment of this salt with the chlorophosphanes. The method can be carried out on a gram scale.
Starting from salicylaldehydes and α,β-unsaturated aldehydes, a new coumarin synthesis in ionic l... more Starting from salicylaldehydes and α,β-unsaturated aldehydes, a new coumarin synthesis in ionic liquids is presented. The key feature is the generation of N-heterocyclic carbenes (NHC) and an Umpolung reaction. During the last decade, N-heterocyclic carbenes (NHCs) have been successfully introduced as ligands for transitionmetal catalysis [1] and recently NHCs have been effectively applied as organocatalysts [2] in a large number of chemical transformations, including transesterification/acylation, [3] benzoin [4] and Stetter [5] reactions. The generation of homoenolate equivalents, by NHC-catalyzed Umpolung of α,βunsaturated aldehydes, was independently described by Glorius [6] and Bode [7] in the synthesis of γ-butyrolactones. Subsequently, this methodology has been extended towards the synthesis of β-lactones, [8] spiro γ-butyrolactones, [9] γlactams [10] and to redox esterification of α,β-unsaturated al-Scheme 1. Reaction path a: synthesis of 2,2-dimethyl-2H-chromene-3-carbaldehydes 3 and 9-methyl-8,12-dioxatricyclo[7.3.1.0 2,7 ]trideca-2,4,6-trien-11-ols 4. [15] Reaction path b: preliminary synthesis of coumarin 6d-H.
The core structural unit of marmycins is prepared by vinylogous aldol—aza-Michael reaction of o-a... more The core structural unit of marmycins is prepared by vinylogous aldol—aza-Michael reaction of o-aminobenzaldehydes (I) with prenal (II).
Synthesis of Novel Spiro[indol-2,2'-pyrroles] Using Isocyanide-Based Multicomponent Reaction.-An ... more Synthesis of Novel Spiro[indol-2,2'-pyrroles] Using Isocyanide-Based Multicomponent Reaction.-An efficient and facile method for the synthesis of novel spiro[indole-2,2'-pyrroles] (IV) from N-methyl-3-isatin imines, alkyl isocyanide, and dialkyl acetylenedicarboxylate is achieved by [3 + 2] cycloaddition reaction. Structure of spiro compound (IVa) is elucidated by X-ray analysis. Isatin product (V) is retained by hydrolysis of (IVd) whereby, yield is not given.-(JALLI*, V.;
Metal-Free Radical Perfluoroalkylation of (Hetero)arenes.-Inexpensive and commercially available ... more Metal-Free Radical Perfluoroalkylation of (Hetero)arenes.-Inexpensive and commercially available perfluorocarboxylic anhydrides are used as source of perfluoroalkyl radicals for the perfluoroalkylation of various arenes, such as benzene derivatives, furans, thiophenes, and pyrroles.-(
Synthesis of Some New Heterocyclic Systems Bearing 2-Phenyl-6iodo-4(3H)-quinazolinon-3-yl Moiety ... more Synthesis of Some New Heterocyclic Systems Bearing 2-Phenyl-6iodo-4(3H)-quinazolinon-3-yl Moiety as Antibacterial Agents.-A variety of new quinazoline derivatives containing an additional heterocyclic moiety [cf. (IV), (VI), (VIII), (X), (XII), (XIV)] are synthesized starting from 3-amino-2-phenylquinazolinone (I). Some of the obtained heterocycles show
There's a huge gap between the sequence and structural knowledge of proteins. Determining protein... more There's a huge gap between the sequence and structural knowledge of proteins. Determining proteins structures experimentally is expensive and not always amenable. Computational tools such as homology modeling have been successful at bridging this gap. However, they are still subject to database information and they don't have a principled way of selecting structures. This and other issues are treated in the blind CASP competition (Critical Assessment of Structure Prediction). We took part in the recent CASP11 competition by using a new physics based approach called MELD[1,2] and combining with either proposed data during CASP or with general insights coming from our knowledge of globular protein structures (e.g. they have hydrophobic cores). Physics based methods are usually too computationally demanding for the tight deadlines in CASP, which has mostly excluded them from participation. In this talk I will show how MELD was useful during CASP. In some cases MELD provided value beyond what database methods could do-including the best blind prediction for one of the proteins in CASP. As such, physics based methods are starting to be useful for structure prediction to complement existing methods. 1.MacCallum, J. L., Perez, A. & Dill, K. Determining protein structures by combining semireliable data with atomistic physical models by Bayesian inference.
Beuerle F, Krueger A, Lehmann M, et al. Organic Chemistry 2012. Nachrichten aus der Chemie . 2013... more Beuerle F, Krueger A, Lehmann M, et al. Organic Chemistry 2012. Nachrichten aus der Chemie . 2013;61(3):265-297
Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al.,... more Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem. Sci., 2020, 11, 2627–2639.
There are currently fewer than ten antifungal drugs in clinical development, but new fungal strai... more There are currently fewer than ten antifungal drugs in clinical development, but new fungal strains, which are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains, compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or haemolytic pr...
A synthesis of benzo[e][1,2,4]triazines and 1,2,4-triazolospiro[4,5]deca-2,6,9-trien-8-ones has b... more A synthesis of benzo[e][1,2,4]triazines and 1,2,4-triazolospiro[4,5]deca-2,6,9-trien-8-ones has been developed from reactions of amidrazones with 2-chloro-1,4-benzoquinone in EtOAc containing 0.5 mL of piperidine. This highly regioselective and one-pot process provided rapid access to 1,2,4-triazolospiro[4,5]deca-2,6,9-trien-8-ones (60%-70%) and benzo[e][1,2,4]triazines (11%-18%). On reacting amidrazones with 5-hydroxy-1,4-naphthoquinone in an EtOAc/piperidine mixture, the reaction proceeded to give 5-hydroxy-2-(piperidin-1-yl)naphthalene-1,4-dione. The structures of the isolated products were proved by infrared, NMR (2D-NMR), mass spectra, and elemental analyses in addition to X-ray structure analysis. The reaction mechanisms are discussed. The anticancer screening of selected compounds showed broad-spectrum anticancer activity against most melanoma cancer cell lines, ovarian cancer OVCAR-3, central nervous system cancer SF-295 and U251, non-small cell lung cancer NCI-H23, renal cancer SN12C, and colon cancer HCT-15 and HCT-116. The selected compounds exhibited moderate to weak anticancer activity to other cell lines.
Improved One-Pot Synthesis of C 3-Symmetric ClickPhos and Related Ligands: Structures of Unique T... more Improved One-Pot Synthesis of C 3-Symmetric ClickPhos and Related Ligands: Structures of Unique Triazole-Zinc Complexes.-Mono-, bis-, and tris(triazolyl)phosphanes are prepared by in three steps without isolation of the intermediates. The route involves the generation of an alkynylmagnesium bromide, the conversion into a triazolylmagnesium bromide by reaction with an azide, and the direct treatment of this salt with the chlorophosphanes. The method can be carried out on a gram scale.
Starting from salicylaldehydes and α,β-unsaturated aldehydes, a new coumarin synthesis in ionic l... more Starting from salicylaldehydes and α,β-unsaturated aldehydes, a new coumarin synthesis in ionic liquids is presented. The key feature is the generation of N-heterocyclic carbenes (NHC) and an Umpolung reaction. During the last decade, N-heterocyclic carbenes (NHCs) have been successfully introduced as ligands for transitionmetal catalysis [1] and recently NHCs have been effectively applied as organocatalysts [2] in a large number of chemical transformations, including transesterification/acylation, [3] benzoin [4] and Stetter [5] reactions. The generation of homoenolate equivalents, by NHC-catalyzed Umpolung of α,βunsaturated aldehydes, was independently described by Glorius [6] and Bode [7] in the synthesis of γ-butyrolactones. Subsequently, this methodology has been extended towards the synthesis of β-lactones, [8] spiro γ-butyrolactones, [9] γlactams [10] and to redox esterification of α,β-unsaturated al-Scheme 1. Reaction path a: synthesis of 2,2-dimethyl-2H-chromene-3-carbaldehydes 3 and 9-methyl-8,12-dioxatricyclo[7.3.1.0 2,7 ]trideca-2,4,6-trien-11-ols 4. [15] Reaction path b: preliminary synthesis of coumarin 6d-H.
The core structural unit of marmycins is prepared by vinylogous aldol—aza-Michael reaction of o-a... more The core structural unit of marmycins is prepared by vinylogous aldol—aza-Michael reaction of o-aminobenzaldehydes (I) with prenal (II).
Synthesis of Novel Spiro[indol-2,2'-pyrroles] Using Isocyanide-Based Multicomponent Reaction.-An ... more Synthesis of Novel Spiro[indol-2,2'-pyrroles] Using Isocyanide-Based Multicomponent Reaction.-An efficient and facile method for the synthesis of novel spiro[indole-2,2'-pyrroles] (IV) from N-methyl-3-isatin imines, alkyl isocyanide, and dialkyl acetylenedicarboxylate is achieved by [3 + 2] cycloaddition reaction. Structure of spiro compound (IVa) is elucidated by X-ray analysis. Isatin product (V) is retained by hydrolysis of (IVd) whereby, yield is not given.-(JALLI*, V.;
Metal-Free Radical Perfluoroalkylation of (Hetero)arenes.-Inexpensive and commercially available ... more Metal-Free Radical Perfluoroalkylation of (Hetero)arenes.-Inexpensive and commercially available perfluorocarboxylic anhydrides are used as source of perfluoroalkyl radicals for the perfluoroalkylation of various arenes, such as benzene derivatives, furans, thiophenes, and pyrroles.-(
Synthesis of Some New Heterocyclic Systems Bearing 2-Phenyl-6iodo-4(3H)-quinazolinon-3-yl Moiety ... more Synthesis of Some New Heterocyclic Systems Bearing 2-Phenyl-6iodo-4(3H)-quinazolinon-3-yl Moiety as Antibacterial Agents.-A variety of new quinazoline derivatives containing an additional heterocyclic moiety [cf. (IV), (VI), (VIII), (X), (XII), (XIV)] are synthesized starting from 3-amino-2-phenylquinazolinone (I). Some of the obtained heterocycles show
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