Sequence-specific inhibition of a designed metallopeptide catalyst

Rhodium metallopeptides catalyze proximity-driven modification of peptide and protein substrates with enzyme-like selectivity. In this communication, we demonstrate that designed metallopeptide catalysts can be inhibited in a sequence-specific manner, mimicking the inhibition and regulation of natural enzymes. We demonstrate sub-micromolar inhibition by a histidine-containing inhibitor peptide, taking advantage of cooperative supramolecular assembly and inorganic coordination.     

Rhodium(II) Metallopeptide Catalyst Design Enables Fine Control in Selective Functionalization of Natural SH3 Domains

Chemically modified proteins are increasingly important for use in fundamental biophysical studies, chemical biology, therapeutic protein development, and biomaterials. However, chemical methods typically produce heterogeneous labeling and cannot approach the exquisite selectivity of enzymatic reactions. While bioengineered methods are sometimes an option, selective reactions of natural proteins remain an unsolved problem. Here we show that rhodium(II) metallopeptides combine molecular recognition with promiscuous catalytic activity to allow covalent decoration of natural SH3 domains, depending on choice of catalyst but independent of the specific residue present. A metallopeptide catalyst succeeds in modifying a single SH3‐containing kinase at endogenous concentrations in prostate cancer (PC‐3) cell lysate.     

A Cysteine-Directed Proximity-Driven Crosslinking Method for Native Peptide Bicyclization

Efficient and site-specific modification of native peptides and proteins is desirable for synthesizing antibody-drug conjugates as well as for constructing chemically modified peptide libraries using genetically encoded platforms such as phage display. In particular, there is much interest in efficient multicyclization of native peptides due to the appeals of multicyclic peptides as therapeutics. However, conventional approaches for multicyclic peptide synthesis require orthogonal protecting groups or non-proteinogenic clickable handles. Herein, we report a cysteine-directed proximity-driven strategy for the constructing bicyclic peptides from simple natural peptide precursors. This linear to bicycle transformation initiates with rapid cysteine labeling, which then triggers proximity-driven amine-selective cyclization. This bicyclization proceeds rapidly under physiologic conditions, yielding bicyclic peptides with a Cys-Lys-Cys, Lys-Cys-Lys or N-terminus-Cys-Cys stapling pattern. We demonstrate the utility and power of this strategy by constructing bicyclic peptides fused to proteins as well as to the M13 phage, paving the way to phage display of novel bicyclic peptide libraries.     

Supramolecular bidentate ligands by metal-directed in situ formation of antiparallel beta-sheet structures and application in asymmetric catalysis

The principles of protein structure design, molecular recognition, and supramolecular and combinatorial chemistry have been applied to develop a convergent metal-ion-assisted self-assembly approach that is a very simple and effective method for the de novo design and the construction of topologically predetermined antiparallel beta-sheet structures and self-assembled catalysts. A new concept of in situ generation of bidentate P-ligands for transition-metal catalysis, in which two complementary, monodentate, peptide-based ligands are brought together by employing peptide secondary structure motif as constructing tool to direct the self-assembly process, is achieved through formation of stable beta-sheet motifs and subsequent control of selectivity. The supramolecular structures were studied by (1)H, (31)P, and (13)C NMR spectroscopy, ESI mass spectrometry, X-ray structure analysis, and theoretical calculations. Our initial catalysis results confirm the close relationship between the self-assembled sheet conformations and the catalytic activity of these metallopeptides in the asymmetric rhodium-catalyzed hydroformylation. Good catalyst activity and moderate enantioselectivity were observed for the selected combination of catalyst and substrate, but most importantly the concept of this new methodology was successfully proven. This work presents a perspective interface between protein design and supramolecular catalysis for the design of beta-sheet mimetics and screening of libraries of self-organizing supramolecular catalysts.     

"Cofactor"-controlled enantioselective catalysis

We report an achiral bisphosphine rhodium complex equipped with a binding site for the recognition of chiral anion guests. Upon binding small chiral guests--cofactors--the rhodium complex becomes chiral and can thus be used for asymmetric catalysis. Screening of a library of cofactors revealed that the best cofactors lead to hydrogenation catalysts that form the products with high enantioselectivity (ee's up to 99%). Interestingly, a competition experiment shows that even in a mixture of 12 cofactors high ee is obtained, indicating that the complex based on the best cofactor dominates the catalysis.     

含半夹心铱/铑/钌结构基元的离散型金属环状化合物的研究进展

由于离散型金属环状化合物在主客体化学、气体吸附、分子识别及催化等领域被广泛应用,因此,构筑新型金属环状化合物并研究它们的物理化学性质及应用成为无机化学、有机化学和超分子化学中热门研究方向之一.具有半夹心结构的钌、铱和铑有机金属单元在形成金属环状化合物时具有以下的优势:增强了化合物的溶解性,屏蔽住金属的一半以减少反应的复杂性,易于修饰得到不同结构的产物.综述了近年来以半夹心结构的钌、铱和铑结构基元的离散型金属框架化合物的组装合成和应用.     

New supramolecular transition metal catalysts

The covalent connection of a catalytically active transition metal center with a water-soluble receptor (host molecule) generates a new type of supramolecular catalyst in which the features of molecular recognition, phase transfer catalysis and transition metal catalysis are combined in a single system. The first examples of this principle make use of commercially available β-cyclodextrin (β-CD) as the receptor and rhodium complexes of diphosphanes as the catalytically active center, these being covalently connected to one another via a spacer. In competitive hydrogenation of certain olefins, unusual degrees of substrate selectivity based on molecular recognition are observed, not possible by conventional transition metal catalysts. The two-phase (water/organic) hydrogenation of nitro-aromatics also is a smooth process catalyzed by these supramolecular complexes. They also constitute an unusually active catalyst system for the selective hydroformylation of higher olefins such as 1-octene in a two-phase system. Dendrimers having diphosphane moieties on the surface provide ligands for transition metals, the corresponding metal complexes (e.g., Pd) functioning as efficient catalysts which can be recycled due to their nanoscopic properties.     

Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity

Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. The rate of the ligation between trans-cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine is very rapid (k2 2000 M-1 s-1). This fast reactivity enables protein modification at low concentration.     

Multi-component syntheses of heterocycles by transition-metal catalysis

For a long time multi-component syntheses of heterocycles have undeniably been a domain of classical carbonyl condensation chemistry. However, the advent of transition-metal catalysis not only has fertilized strategies in heterocyclic synthesis by uni- and bimolecular transformations but the past decade has also witnessed a rapid development of transition-metal catalysis in new multi-component reactions (MCR). Expectedly, palladium catalyzed processes have received a dominant position, yet, other transition-metal complexes are catching up implying organometallic elementary steps that reach even further than cross-coupling and carbometallation. Besides domino MCRs that are purely based upon organometallic catalysis the sequential and consecutive combination with condensation, addition and cycloaddition steps opens a vast playground for the invention of new sequences in heterocyclic synthesis. This tutorial review outlines the underlying reaction based principles of transition-metal catalysis in multi-component syntheses of heterocycles, summarizes recent developments of palladium catalyzed MCR, and highlights the more recent contributions to MCR based heterocyclic synthesis by virtue of rhodium, ruthenium, and copper catalysis.     

Synthesis and evaluation of bioorthogonal pantetheine analogues for in vivo protein modification

In vivo carrier protein tagging has recently become an attractive target for the site-specific modification of fusion systems and new approaches to natural product proteomics. A detailed study of pantetheine analogues was performed in order to identify suitable partners for covalent protein labeling inside living cells. A rapid synthesis of pantothenamide analogues was developed and used to produce a panel which was evaluated for in vitro and in vivo protein labeling. Kinetic comparisons allowed the construction of a structure-activity relationship to pinpoint the linker, dye, and bioorthogonal reporter of choice for carrier protein labeling. Finally bioorthogonal pantetheine analogues were shown to target carrier proteins with high specificity in vivo and undergo chemoselective ligation to reporters in crude cell lysate. The methods demonstrated here allow carrier proteins to be visualized and isolated for the first time without the need for antibody techniques and set the stage for the future use of carrier protein fusions in chemical biology.     

Metal‐Mediated Functionalization of Natural Peptides and Proteins: Panning for Bioconjugation Gold

Selective modification of natural proteins is a daunting methodological challenge and a stringent test of selectivity and reaction scope. There is a continued need for new reactivity and new selectivity concepts. Transition metals exhibit a wealth of unique reactivity that is orthogonal to biological reactions and processes. As such, metal‐based methods play an increasingly important role in bioconjugation. This Review examines metal‐based methods as well as their reactivity and selectivity for the functionalization of natural proteins and peptides.     

A bioorthogonal quadricyclane ligation

New additions to the bioorthogonal chemistry compendium can advance biological research by enabling multiplexed analysis of biomolecules in complex systems. Here we introduce the quadricyclane ligation, a new bioorthogonal reaction between the highly strained hydrocarbon quadricyclane and Ni bis(dithiolene) reagents. This reaction has a second-order rate constant of 0.25 M(-1) s(-1), on par with fast bioorthogonal reactions of azides, and proceeds readily in aqueous environments. Ni bis(dithiolene) probes selectively labeled quadricyclane-modified bovine serum albumin, even in the presence of cell lysate. We have demonstrated that the quadricyclane ligation is compatible with, and orthogonal to, strain-promoted azide-alkyne cycloaddition and oxime ligation chemistries by performing all three reactions in one pot on differentially functionalized protein substrates. The quadricyclane ligation joins a small but growing list of tools for the selective covalent modification of biomolecules.     

Concise synthesis of the Erythrina alkaloid 3-demethoxyerythratidinone via combined rhodium catalysis

The total synthesis of the erythrina alkaloid 3-demethoxyerythratidinone has been achieved via a strategy based on combined rhodium catalysis. The catalytic tandem cyclization effected by the interplay of alkynyl and vinylidene rhodium species allows for efficient access to the A and B rings of the tetracyclic erythrinane skeleton in a single step. The synthesis also features rapid preparation of the requisite precursor for the double ring closure and thus has been completed in only 7 total steps in 41% overall yield.     

Rhodium Enalcarbenoids: Direct Synthesis of Indoles by Rhodium(II)‐Catalyzed [4+2] Benzannulation of Pyrroles

Disclosed herein is the design of an unprecedented electrophilic rhodium enalcarbenoid which results from rhodium(II)‐catalyzed decomposition of a new class of enaldiazo compounds. The synthetic utility of these enalcarbenoids has been successfully demonstrated in the first transition‐metal‐catalyzed [4+2] benzannulation of pyrroles, thus leading to substituted indoles. The new benzannulation has been applied to the efficient synthesis of the natural product leiocarpone as well as a potent adipocyte fatty‐acid binding protein inhibitor.     

The interaction of rhodium carbenoids with carbonyl compounds as a method for the synthesis of tetrahydrofurans

The transition metal catalyzed reaction of α-diazo carbonyl compounds has found numerous applications in organic synthesis, and its use in either heterocyclic or carbocyclic ring formation is well precedented. In contrast to other catalysts that are suitable for carbenoid reactions of diazo compounds, those constructed with the dirhodium(II) framework are most amenable to ligand modification that, in turn, can influence reaction selectivity. The reaction of rhodium carbenoids with carbonyl groups represents a very efficient method for generating carbonyl ylide dipoles. Rhodium-mediated carbenoid–carbonyl cyclization reactions have been extensively utilized as a powerful method for the construction of a variety of novel polycyclic ring systems. This article will emphasize some of the more recent synthetic applications of the tandem rhodium carbenoid cyclization/cycloaddition cascade for natural product synthesis. Discussion centers on the chemical behavior of the rhodium metal carbenoid complex that is often affected by the nature of the ligand groups attached to the metal center.     

Tuning the Reactivity of a Substrate for SNAP-Tag Expands Its Application for Recognition-Driven DNA-Protein Conjugation

Recognition-driven modification has been emerging as a novel approach to modifying biomolecular targets of interest site-specifically and efficiently. To this end, protein modular adaptors (MAs) are the ideal reaction model for recognition-driven modification of DNA as they consist of both a sequence-specific DNA-binding domain (DBD) and a self-ligating protein-tag. Coupling DNA recognition by DBD and the chemoselective reaction of the protein tag could provide a highly efficient sequence-specific reaction. However, combining an MA consisting of a reactive protein-tag and its substrate, for example, SNAP-tag and benzyl guanine (BG), revealed rather nonselective reaction with DNA. Therefore new substrates of SNAP-tag have been designed to realize sequence-selective rapid crosslinking reactions of MAs with SNAP-tag. The reactions of substrates with SNAP-tag were verified by kinetic analyses to enable the sequence-selective crosslinking reaction of MA. The new substrate enables the distinctive orthogonality of SNAP-tag against CLIP-tag to achieve orthogonal DNA-protein crosslinking by six unique MAs.     

Rhodium(III)‐Catalyzed Selective ortho‐Olefinations of N‐Acyl and N‐Aroyl Sulfoximines by CH Bond Activation

Two new rhodium‐catalyzed oxidative couplings between sulfoximine derivatives and alkenes by regioselective C?H activation, affording ortho‐olefinated (Heck‐type) products, are reported. A synthetic application of the ortho‐alkenylated products into the corresponding cyclic derivatives has been demonstrated, and a mechanistic rational for the rhodium catalysis is presented.     

Enzyme mimics

Chemists are trying to create synthetic molecules which mimic the recognition and catalytic properties of real enzymes. One target of interest is catalysis of reactions for which there are no known natural enzymes. Inspired by the examples of nature, approaches to the design of enzyme mimics for catalysis of Diels-Alder reaction are described. The design is based on porphyrin molecular boxes and zinc co-ordination. The potential of design of enzyme mimics employing cholic acid and other systems is also discussed.     

Rhodium chemzymes: Michaelis-Menten kinetics in dirhodium(II) carboxylate-catalyzed carbenoid reactions

Rhodium carboxylate-mediated reactions of diazoketones involving cyclopropanation, C-H insertion, and aromatic C-C double bond addition/electrocyclic ring opening obey saturation (Michaelis-Menten) kinetics. Axial ligands for rhodium, including aromatic hydrocarbons and Lewis bases such as nitriles, ethers, and ketones, inhibit these reactions by a mixed kinetic inhibition mechanism, meaning that they can bind both to the free catalyst and to the catalyst-substrate complex. Substrate inhibition can also be exhibited by diazocompounds bearing these groupings in addition to the diazo group. The analysis of inhibition shows that the active catalyst uses only one of its two coordination sites at a time for catalysis. Some ketones exhibit the interesting property that they selectively bind to the catalyst-substrate complex. The similarity of the kinetic constants from different types of reactions with similar diazoketones, regardless of the linking unit or the environment of the reacting alkene, suggests that the rate-determining step is the generation of the rhodium carbenoid. A very useful rhodium carboxylate catalyst for asymmetric synthesis, Rh(2)(DOSP)(4), shows slightly slower kinetic parameters than the achiral catalysts, implying that enantioselectivity of this catalyst is based on slowing reactions from one of the enantiotopic faces of the reactant, rather than any type of ligand-accelerated catalysis. A series of rhodium catalysts derived from acids with pK(a)s spanning 4 orders of magnitude give very similar kinetic constants.     

Signal amplification by allosteric catalysis

In this article we unify a series of recent studies on bio- and chemosensors under a single signaling strategy: signal amplification by allosteric catalysis (SAAC). The SAAC strategy mimics biological signal transduction processes, where molecular recognition between an external signal and a protein receptor is allosterically transduced into catalytically amplified chemical information (usually second messengers). Several recent biosensing and chemosensing studies apply this nature-inspired strategy by using engineered allosteric enzymes, ribozymes, or regulatable organic catalysts. The factors pertinent to achieving high sensitivity and specificity in SAAC strategies are analyzed. The authors believe that these early studies from a variety of research groups have opened up a new venue for the development of sensing technologies where molecular recognition and catalysis can be coupled for practical purposes.