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Rizzo S.,Max Planck Institute For Molekulare Physiologie | Waldmann H.,Max Planck Institute For Molekulare Physiologie | Waldmann H.,TU Dortmund
Chemical Reviews | Year: 2014

Examples of some of the most used techniques for producing libraries of natural products (NPs) or NP-inspired compounds are reviewed. Natural-product-derived libraries are generated around a scaffold that is identical to that of the leading NP and which is obtained by means of chemical modification or degradation. The library members are then synthesized from the scaffold using a step-by-step derivatization. The scaffolds of compound collections inspired by NPs usually are closely related to the guiding NP. Multistep sequences are used to build up the scaffold from preassembled functionalized building blocks. This strategy allows variation of substitution pattern and stereochemistry, which can be different from the inspiring NP. Solid-support-based synthesis techniques allow one to easily remove surplus reagents typically used to ensure high conversion. Transition-metal-catalyzed transformations on solid support have offered novel opportunities for NP-inspired library synthesis.


Antonchick A.P.,Max Planck Institute For Molekulare Physiologie | Burgmann L.,Max Planck Institute For Molekulare Physiologie | Burgmann L.,TU Dortmund
Angewandte Chemie - International Edition | Year: 2013

A dream reaction: An efficient and practical method for the oxidative cross-coupling of heteroaromatic compounds and simple alkanes has been developed. The desired products are smoothly and regioselectively formed under mild reaction conditions at ambient temperature in a hypervalent-iodine-mediated transformation. The method allows for preferential transformation of stronger C sp 3-H bonds in the presence of weaker C sp 3-H bonds under metal-free conditions. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Matcha K.,Max Planck Institute For Molekulare Physiologie | Narayan R.,Max Planck Institute For Molekulare Physiologie | Antonchick A.P.,Max Planck Institute For Molekulare Physiologie
Angewandte Chemie - International Edition | Year: 2013

A novel method for the oxidative radical azidation of alkenes relies on an azide in combination with a hypervalent iodine reagent. A cascade of C-N and C-C bond-forming reactions yields 2-oxindoles under metal-free conditions with high reaction rates at ambient temperature and provides access to complex products (see scheme; TMS=trimethylsilyl). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Prinz H.,Max Planck Institute For Molekulare Physiologie
Journal of Chemical Biology | Year: 2010

Hill coefficients (n H) derived from four parameter logistic fits to dose-response curves were compared to calculated realistic reaction schemes and related to experimental data: (1) Hill coefficients may give information on the number of interacting sites but cannot distinguish between competitive, non-competitive or ortho-, iso-, or allosteric mechanisms. (2) For enzymatic dose-inhibition curves, Hill coefficients smaller than one do not indicate anticooperative binding but show that at least one ternary complex has enzymatic activity. (3) Hill coefficients different from one are proof for multiple ligand binding. The large variations of reported Hill coefficients corresponds to multiple allosteric binding, where induced conformational changes cause loss of the active conformation. Such a denaturation mechanism is in stark contrast to the desired specificity of drugs. The discussion is open. © 2009 Springer-Verlag.


Ismail S.A.,Max Planck Institute For Molekulare Physiologie | Vetter I.R.,Max Planck Institute For Molekulare Physiologie | Sot B.,Max Planck Institute For Molekulare Physiologie | Wittinghofer A.,Max Planck Institute For Molekulare Physiologie
Cell | Year: 2010

Arfs are small G proteins that have a key role in vesicle trafficking and cytoskeletal remodeling. ArfGAP proteins stimulate Arf intrinsic GTP hydrolysis by a mechanism that is still unresolved. Using a fusion construct we solved the structure of the ArfGAP ASAP3 in complex with Arf6 in the transition state. This structure clarifies the ArfGAP catalytic mechanism and shows a glutamine(Arf6) and an arginine finger(ASAP3) as the important catalytic residues. Unexpectedly the structure shows a calcium ion, liganded by both proteins in the complex interface, stabilizing the interaction and orienting the catalytic machinery. Calcium stimulates the GAP activity of ASAPs, but not other members of the ArfGAP family. This type of regulation is unique for GAPs and any other calcium-regulated processes and hints at a crosstalk between Ca2+ and Arf signaling. © 2010 Elsevier Inc.


Schonichen A.,Max Planck Institute For Molekulare Physiologie | Geyer M.,Max Planck Institute For Molekulare Physiologie
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2010

The regulation of the actin cytoskeleton is a key process for the stability and motility of eukaryotic cells. Besides the Arp2/3 complex and its nucleation promoting factors, WH2 domain-containing proteins and a diverse family of formin proteins have recently been recognized as actin nucleators and potent polymerization factors of actin filaments. Formins are defined by the presence of a catalytic formin homology 2 (FH2) domain, yet, the modular domain architecture appears significantly different for the eight formin families identified in humans. A diverse picture of protein localization, interaction partners and cell specific regulation emerged, suggesting various functions of formins in the building and maintenance of actin filaments. This review focuses on the domain architecture of human formins, the regulation mechanisms of their activation and the diversity in formin cellular functions. © 2010 Elsevier B.V. All rights reserved.


Matcha K.,Max Planck Institute For Molekulare Physiologie | Antonchick A.P.,Max Planck Institute For Molekulare Physiologie
Angewandte Chemie - International Edition | Year: 2013

A range of heterocyclic compounds were synthesized by a novel, metal-free cross-dehydrogenative coupling between heterocycles and aldehydes under mild reaction conditions that are not sensitive to moisture. The products are formed smoothly and regioselectively at room temperature by a hypervalent iodine mediated transformation. This method has a broad substrate scope and was used in the highly efficient, one-step synthesis of natural products. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Samanta R.,Max Planck Institute For Molekulare Physiologie | Antonchick A.P.,Max Planck Institute For Molekulare Physiologie
Angewandte Chemie - International Edition | Year: 2011

S=O shows where to go: A novel double C-H activation of aromatic compounds with a sulfoxide as a directing group results in the highly regioselective synthesis of polysubstituted dibenzothiophenes (see scheme). The reaction cascade consists of palladium-catalyzed double C-H activation and a Pummerer rearrangement followed by palladium-catalyzed C-S bond formation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Braunshausen A.,Max Planck Institute For Molekulare Physiologie | Seebeck F.P.,Max Planck Institute For Molekulare Physiologie
Journal of the American Chemical Society | Year: 2011

Ovothiols are histidine-derived thiols that were first isolated from marine invertebrates. We have identified a 5-histidylcysteine sulfoxide synthase (OvoA) as the first ovothiol biosynthetic enzyme and characterized OvoAs from Erwinia tasmaniensis and Trypanosoma cruzi. Homologous enzymes are encoded in more than 80 genomes ranging from proteobacteria to animalia. © 2011 American Chemical Society.


Seebeck F.P.,Max Planck Institute For Molekulare Physiologie
Journal of the American Chemical Society | Year: 2010

Ergothioneine is a histidine-derived thiol of bacterial and fungal origin that has also been isolated from animal and human tissue. Recent findings point to critical functions of ergothioneine in human physiology, but its role in microbial life is poorly understood. This report describes the identification of the ergothioneine biosynthetic gene cluster from mycobacteria and in vitro reconstitution of this process using recombinant proteins from Mycobacterium smegmatis. The key reactions are catalyzed by a methyltransferase that transfers three methyl groups to the α-amino moiety of histidine and an iron(II)-dependent enzyme that catalyzes oxidative sulfurization of trimethylhistidine. A search for homologous genes indicated that ergothioneine production is a frequent trait among fungi, actinobacteria, and cyanobacteria but also occurs in numerous bacteroidetes and proteobacteria. © 2010 American Chemical Society.

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