75816-19-2Relevant articles and documents
METHODS FOR PRODUCING D-TRYPTOPHAN AND SUBSTITUTED D-TRYPTOPHANS
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Page/Page column 17, (2021/04/01)
Single-module nonribosomal peptide synthetases (NRPSs) and NRPS-like enzymes activate and transform carboxylic acids in both primary and secondary metabolism; and are of great interest due to their biocatalytic potentials. The single-module NRPS IvoA is essential for fungal pigment biosynthesis. As disclosed herein, we show that IvoA catalyzes ATP-dependent unidirectional stereoinversion of L-tryptophan to D-tryptophan with complete conversion. While the stereoinversion is catalyzed by the epimerization (E) domain, the terminal condensation (C) domain stereoselectively hydrolyzes D-tryptophanyl-S-phosphopantetheine thioester and thus represents a noncanonical C domain function. Using IvoA, we demonstrate a biocatalytic stereoinversion/deracemization route to access a variety of substituted D-tryptophan analogs in high enantiomeric excess.
Novel Arylindigoids by Late-Stage Derivatization of Biocatalytically Synthesized Dibromoindigo
Schnepel, Christian,Dodero, Veronica I.,Sewald, Norbert
supporting information, p. 5404 - 5411 (2021/03/03)
Indigoids represent natural product-based compounds applicable as organic semiconductors and photoresponsive materials. Yet modified indigo derivatives are difficult to access by chemical synthesis. A biocatalytic approach applying several consecutive selective C?H functionalizations was developed that selectively provides access to various indigoids: Enzymatic halogenation of l-tryptophan followed by indole generation with tryptophanase yields 5-, 6- and 7-bromoindoles. Subsequent hydroxylation using a flavin monooxygenase furnishes dibromoindigo that is derivatized by acylation. This four-step one-pot cascade gives dibromoindigo in good isolated yields. Moreover, the halogen substituent allows for late-stage diversification by cross-coupling directly performed in the crude mixture, thus enabling synthesis of a small set of 6,6’-diarylindigo derivatives. This chemoenzymatic approach provides a modular platform towards novel indigoids with attractive spectral properties.
Cyclization of RGD Peptides by Suzuki-Miyaura Cross-Coupling
Kemker, Isabell,Schnepel, Christian,Schr?der, David C.,Marion, Antoine,Sewald, Norbert
, p. 7417 - 7430 (2019/08/26)
Halogenated l- or d-tryptophan obtained by biocatalytic halogenation was incorporated into RGD peptides together with a variety of alkyl or aryl boronic acids. Suzuki-Miyaura cross-coupling either in solution or on-resin results in side chain-to-tail-cyclized RGD peptides, for example, with biaryl moieties, providing a new dimension of structure-activity relationships. An array of RGD peptides differing in macrocycle size, the presence of d-amino acid, N-methylation, or connectivity between the indole moiety and the boronic acid showed that, in particular, connectivity exhibits a major impact on affinities toward integrins, for example, αVβ3. Structure-activity relationship studies yielded peptides with affinities toward αVβ3 in the low nanomolar range, good selectivity, and high plasma stability. Structural characteristics of representative molecules have been investigated by molecular dynamics simulations, which allowed understanding the observed activity differences.
