Titia

We report and demonstrate the practical utility of an N-chloropeptide strategy for the rapid construction of ΔAA-containing peptides. The quinuclidine (ABCO)-catalyzed N-chlorination of peptide bonds and the subsequent β-elimination of N-chloroamide efficiently provides ΔAA-containing peptides in high yield. The strategy enables the late-stage installation of ΔAA motifs into already-constructed oligopeptides, including a macrocyclic peptide.

Abstract

Conventional methods for the construction of dehydroamino acids (ΔAAs), which are a unique class of non-proteinogenic amino acids, require the pre-installation of special amino acids. Herein, we report and demonstrate the practical utility of an N-chloropeptide strategy for the rapid construction of ΔAA-containing peptides. The electrophilic N-chlorination of peptide bonds is drastically accelerated by a catalytic amount of quinuclidine (ABCO), and the subsequent β-elimination of N-chloroamide efficiently provides ΔAA-containing peptides in high yield. The strategy enables, for the first time, the construction of a wide variety of ΔAA residues in peptides without any pre-functionalized side chains and facilitates the late-stage installation of ΔAA motifs into already-constructed oligopeptides, including a medicinally important macrocyclic peptide.

Continuous flow is a mainstay in the synthetic chemist's toolbox. It has also begun to see increasing application in biocatalysis. This manuscript discusses some of the challenges that continuous flow has contributed solutions to for the improvement of biocatalysis. It also poses how the future of continuous flow biocatalysis will change with new technologies such as automation, in-line analysis and AI.

Abstract

The use of flow reactors in biocatalysis has increased significantly in recent years. Chemists have begun to design flow systems that even allow new biocatalytic reactions to take place. This concept article will focus on the design of flow systems that have allowed enzymes to go beyond their limits in batch. The case is made for moving towards fully continuous systems. With flow chemistry increasingly seen as an enabling technology for automated synthesis, and with advancements in AI-assisted enzyme design, there is a real possibility to fully automate the development and implementation of a continuous biocatalytic processes. This will lead to significantly improved enzyme processes for synthesis.

Following a previously published proof-of-principle study on generating bipartite type S non-ribosomal peptide synthetases (NRPSs), the de novo generation of non-ribosomal peptide libraries with unprecedented simplicity was envisaged. By using synthetic zippers, NRPSs were split in up to three subunits to produce 49 peptides at titres up to 145 mg L⁻¹.

Abstract

Bacterial natural products in general, and non-ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatized as inefficient, time-, labour- and cost-intensive. Combinatorial chemistry, on the other hand, can produce new molecules in greater numbers, cheaper and in less time than traditional natural product discovery, but also fails to meet current medical needs due to the limited biologically relevant chemical space that can be addressed. Consequently, methods for the high throughput generation of new natural products would offer a new approach to identifying novel bioactive chemical entities for the hit to lead phase of drug discovery programs. As a follow-up to our previously published proof-of-principle study on generating bipartite type S non-ribosomal peptide synthetases (NRPSs), we now envisaged the de novo generation of non-ribosomal peptides (NRPs) on an unreached scale. Using synthetic zippers, we split NRPSs in up to three subunits and rapidly generated different bi- and tripartite NRPS libraries to produce 49 peptides, peptide derivatives, and de novo peptides at good titres up to 145 mg L⁻¹. A further advantage of type S NRPSs not only is the possibility to easily expand the created libraries by re-using previously created type S NRPS, but that functions of individual domains as well as domain-domain interactions can be studied and assigned rapidly.

Boronic acids. Hammett analysis of 2,6-diarylphenylboronic acids reveals that their Lewis acidity remains unchanged upon the introduction of EWG/EDG at the distant para position of the flanking aromatic rings. Structural and computational studies demonstrate that polar-π interactions and solvation effects contribute to the stabilization of boronic acids and boronate forms by aromatic rings, providing a valuable molecular insight into the rational design of novel catalysts and inhibitors.

Abstract

Boronic acids are Lewis acids that exist in equilibrium with boronate forms in aqueous solution. Here we experimentally and computationally investigated the Lewis acidity of 2,6-diarylphenylboronic acids; specially designed phenylboronic acids that possess two flanking aromatic rings with tunable aromatic character. Hammett analysis of 2,6-diarylphenylboronic acids reveals that their Lewis acidity remains unchanged upon the introduction of EWG/EDG at the distant para position of the flanking aromatic rings. Structural and computational studies demonstrate that polar-π interactions and solvation effects contribute to the stabilization of boronic acids and boronate forms by aromatic rings. Our physical-organic chemistry work highlights that boronic acids and boronates can be stabilized by aromatic systems, leading to an important molecular knowledge for rational design and development of boronic acid-based catalysts and inhibitors of biomedically important proteins.

Synlett
DOI: 10.1055/a-1741-9069

Capitalizing on the propensity of 1,2-amino group migration in γ-aminocyclopentenone with a suitable promoter, gem-diaryl-equipped systems unfolded an unprecedented avenue for the Lewis acid promoted displacement of γ-aniline group with nucleophiles such as indole. Such transformation, besides providing a means for direct γ-functionalization of cyclopentenones, presented innumerable scope for β,γ-annulation. Various tailored indolo bisnucleophiles were explored in the current study that rendered an array of indole alkaloid-like compounds in excellent yields and selectivity through one-pot operation. Analysis of collective experimental observation along with designed control experiments strongly suggested the possibility of a retro aza-Piancatelli rearrangement, which is hitherto unknown in the context. Such repertoire could find potential applications in the synthesis of complex assemblies from the Piancatelli rearrangement and related processes.1 Introduction2 Aza-Piancatelli Rearrangement and Related Domino Processes3 An Unprecedented Aza-Piancatelli-Templated Strategy for Polycyclic Assemblies4 Summary and Outlook
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Publication date: April 2022

Source: Current Opinion in Chemical Biology, Volume 67

Author(s): Regina E. Treviño, Hannah S. Shafaat

A reactive oxygen species (ROS)-activated smart theranostic prodrug system for efficient regional chemotherapy of metastatic cancers has been developed. The prodrug can selectively target cancer cells and be activated by highly expressed ROS, rapidly releasing drug with high efficiency. It shows significantly enhanced antitumor efficacy towards metastatic cancers (up to 99.9 %) with no obvious side effects.

Abstract

Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)-activated smart theranostic prodrug system based on an ROS active site linked with both a targeting group and an anticancer drug for efficient regional chemotherapy of metastatic cancers. The optimized prodrug (Bio-(8)-MB-CPT) with biotin as the targeting group displayed high sensitivity towards ROS and selectively targeting ability towards cervical cancer cells, showing highly efficient drug release (up to 92 %) in vitro. Bio-(8)-MB-CPT thus exerted strong toxicity towards cervical cancer cells, but unlike the parent drug (camptothecin), showed no toxicity towards normal cells. Moreover, the prodrug displayed significantly enhanced antitumor efficacy in vivo and eradicated the tumor with no obvious side effects (inhibition of the tumor reached up to 99.9 %).

Genetic encoded cyanopyridylalanines are presented as convenient and highly selective reactive groups for in vivo functionalization, cyclization and stapling of polypeptides. The non-toxic compounds can be genetically incorporated into proteins with high yields and their biocompatible reaction with amino-thiol moieties proceeds under physiological conditions to near completion without requiring a catalyst.

Abstract

Cyanopyridylalanines are non-canonical amino acids that react with aminothiol compounds under physiological conditions in a biocompatible manner without requiring added catalyst. Here we present newly developed aminoacyl-tRNA synthetases for genetic encoding of meta- and para-cyanopyridylalanine to enable the site-specific attachment of a wide range of different functionalities. The outstanding utility of the cyanopyridine moiety is demonstrated by examples of i) post-translational functionalization of proteins, ii) in-cell macrocyclization of peptides and proteins, and iii) protein stapling. The biocompatible nature of the protein ligation chemistry enabled by the cyanopyridylalanine amino acid opens a new path to specific in vivo protein modifications in complex biological environments.

A new multifunctional construct M1 combining a floxuridine (FUDR) with a protein phosphatase 2A (PP2A) inhibitor is presented. M1 targets the DNA damage response of cancer cells by inhibiting the PP2A activity and inducing mitochondrial and nucleus DNA damage-mediated apoptosis.

Abstract

We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.

Double feature: Functional AIEgen TA-Catechol with dual-mode detection capability towards series of boronic acids is presented. Photoluminescent properties of TA-Catechol are studied thoroughly both experimentally and theoretically. Detection performance is estimated for visual and quantitative mode while formation of tetra-coordinated boronic compound is confirmed to dominate the sensing procedure. Solid-state recognition and potential applications are discussed.

Abstract

Novel functional AIEgen based on three compact bound aryl skeletons is designed and synthesized. This tri-aryl type luminogen (TA-Catechol) embedded with catechol moiety responds rapidly to series of boronic acids. Real-time visual and quantitative dual-mode detection method is established for the first time with modest precision and low detection limit (8.0 μM). Detailed mechanistic discussion identifies tetra-coordinated boronic species as the key intermediate within sensing procedure. Wide range of organic boronic acids compatible with this strategy is displayed which is promising in high throughput screening technology. Furthermore, solid-state sensing capability of TA-Catechol is also demonstrated.

To improve the tumor selectivity of membrane lytic peptides, a self-assembly strategy based on rational design of peptide conjugates has been developed. A hydrophobic triphenylphosphonium (TPP) group for mitochondria targeting and a hydrophilic arginine-glycine-aspartic acid (RGD) sequence targeting the integrin receptor have been incorporated to pH-responsive lytic peptides. The self-assembled nanoparticles are endocytosed selectively into the cancer cells, followed by the disruption of lysosomal and mitochondrial membranes, and lead to apoptotic cell death in the micromolar range.

Abstract

Membrane lytic peptides (MLP) are widely explored as cellular delivery vehicles or antitumor/antibacterial agents. However, the poor selectivity between cancer and normal cells slims their prospects as potential anti-tumor drugs. Herein, we have developed a rationally designed self-assembly strategy to enhance tumor selectivity of MLP-based conjugates, incorporating a hydrophobic triphenylphosphonium (TPP) group for mitochondria targeting, and a hydrophilic arginine-glycine-aspartic acid (RGD) sequence targeting integrins. The self-assembly nanoparticles can enhance the stability of the peptides in vitro plasma and be endocytosed selectively into the cancer cells. The histidine-rich lytic peptide component assists the disruption of endosomal/lysosomal membranes and subsequent the mitochondria membrane, which leads to apoptosis. This rational design of MLP-based conjugates provides a practical strategy to increase the application prospects of lytic peptides in cancer treatment.

The utilization of inactivated alkyl sulfones as alkyl radical precursors in a base-mediated borylation reaction with B₂neop₂ is reported, allowing direct access to valuable alkyl boronate esters without further transesterification. This approach is scalable and is tolerant to a variety of functional groups and substrates including complex molecules.

Abstract

A practical and direct method was developed for the production of versatile alkyl boronate esters via transition metal-free borylation of primary and secondary alkyl sulfones. The key to the success of the strategy is the use of bis(neopentyl glycolato) diboron (B₂neop₂), with a stoichiometric amount of base as a promoter. The practicality and industrial potential of this protocol are highlighted by its wide functional group tolerance, the late-stage modification of complex compounds, no need for further transesterification, and operational simplicity. Radical clock, radical trap experiments, and EPR studies were conducted which show that the borylation process involves radical intermediates.

Glycosylated theranostic prodrugs have been developed, whereby the therapeutic component undergoes triggered release upon enzyme activation of the glycosidic bond through action of the specific glycosidase enzymes, resulting in selective delivery of the therapeutic cargo, a process observed through real-time bioimaging.

Abstract

Real-time tracking of prodrug uptake, delivery and activation in vivo represents a major challenge for prodrug development. Herein, we demonstrate the use of novel glycosylated theranostics of the cancer pharmacophore Amonafide in highly-selective, enzymatic triggered release. We show that the use of endogenous enzymes for activated release of the therapeutic component can be observed, in real time, and monitored using one and two-photon bioimaging, offering unique insight into the prodrug pharmacokinetic profile. Furthermore, we demonstrate that the potent cytotoxicity of Amonafide is preserved using this targeted approach.

Publication date: 15 February 2022

Source: European Journal of Medicinal Chemistry, Volume 230

Author(s): Lisa Tanzi, Marco Terreni, Yongmin Zhang