A bis-macrocycle containing two back-to-back connected 1,10-phenanthroline chelates has been prepared. The synthetic strategy involves the preparation of a monocyclic precursor consisting of a 1,10-phenanthroline-5,6-dione fragment incorporated in a 30-membered ring. This important intermediate has been prepared via two distinct routes, both strategies relying on the use of a ketal as a 1,2-dione protective group. A four-component condensation reaction between two molecules of the macrocyclic dione and two equivalents of ammonia (used in large excess) in the presence of a reducing agent (Na(2)S(2)O(4)) leads to the desired bis-ring in good yield. The most direct synthetic route allows preparation of the bis-macrocycle in seven steps from 1,10-phenanthroline in an overall yield of 14 %. Using the now well-established "gathering and threading" effect of copper(I), a doubly threaded species could be obtained in quantitative yield, in which each ring of the bis-macrocycle is threaded by a "molecular string". These fragments bear terminal allylic groups, which are used to prepare the final catenane by performing a double ring-closing metathesis reaction. This final cyclisation reaction is high yielding and affords the desired catenane consisting of a bis-macrocycle of which the two cyclic units are threaded by a large ring. The compound has been fully characterised by classical techniques. Electronic spectroscopy and electrochemical measurements suggest that the two copper complex subunits do not interact electronically, in spite of the aromatic nature of the bridging ligand between the two metal centres.
Chemically modified nucleoside triphosphates (NTPs) are widely exploited as unnatural metabolites in chemical biology and medicinal chemistry. Because anionic NTPs do not permeate cell membranes, their corresponding neutral precursors are employed in cell-based assays. These precursors become active metabolites after enzymatic conversion, which often proceeds insufficiently. Here we show that metabolically-active NTPs can be directly transported into eukaryotic cells and bacteria by the action of designed synthetic nucleoside triphosphate transporters (SNTTs). The transporter is composed of a receptor, which forms a non-covalent complex with a triphosphate anion, and a cell-penetrating agent, which translocates the complex across the plasma membrane. NTP is then released from the complex in the intracellular milieu and accumulates in nuclei and nucleoli in high concentration. The transport of NTPs proceeds rapidly (seconds to minutes) and selectively even in the presence of other organic anions. We demonstrate that this operationally simple and efficient means of transport of fluorescently labelled NTPs into cells can be used for metabolic labeling of DNA in live cells.
Apart from its role in insulin receptor (IR) activation, the C terminus of the B-chain of insulin is also responsible for the formation of insulin dimers. The dimerization of insulin plays an important role in the endogenous delivery of the hormone and in the administration of insulin to patients. Here, we investigated insulin analogues with selective N-methylations of peptide bond amides at positions B24, B25, or B26 to delineate their structural and functional contribution to the dimer interface. All N-methylated analogues showed impaired binding affinities to IR, which suggests a direct IR-interacting role for the respective amide hydrogens. The dimerization capabilities of analogues were investigated by isothermal microcalorimetry. Insulin is an important polypeptide hormone that controls a wide range of cellular processes such as the regulation of blood glucose uptake and has a large impact on protein and lipid metabolism. However, despite decades of intensive research, many questions about the structure of insulin and its mechanism of action remain. The solid state-based structural insight into the insulin molecule is limited to inactive dimeric or hexameric storage forms (1-3), whereas the insulin monomer represents the active form of the hormone when binding to the insulin receptor (IR).3 It is also widely accepted that insulin undergoes a profound structural change during this process (4 -6), a hypothesis supported by a plethora of highly dynamic hormone conformers identified by NMR studies (7-13). Attempts to determine the structure of the insulin-IR complex have been unsuccessful so far. However, the regions of the insulin molecule responsible for the interaction with the IR (3, 14) or for its dimerization and hexamerization (15, 16) have been functionally and structurally identified in a number of insulin analogues.The insulin molecule consists of two peptide chains, a 21-amino acid A-chain and a 30-amino acid B-chain, interconnected by two interchain and one intrachain disulfide bridges. The C terminus of the B-chain of insulin, particularly residues B24 -B26, plays a substantial role in the initial contact with the receptor. It is believed that the C terminus of the B-chain of insulin must be detached away from the central B-chain ␣-helix of insulin (2, 6). One of the main signatures of this so-called "active form" of insulin should be the exposure of the previously hidden amino acids Gly-A1, Ile-A2, and Val-A3, which are important for the interaction with IR (3). Recently, we described crystal structures of several shortened and full-length insulin analogues with modifications at the B26 position (17). The structural convergence of some of these highly active analogues (200 -400%) enabled us to postulate that the active form of human insulin is characterized by a formation of a new type II -turn at positions B24 -B26.Besides its role in IR activation and IR negative cooperativity (18,19), the C terminus of the B-chain is also responsible for the formation and stabilization of the insulin dimers t...
β-Cyclodextrin-flavin conjugates are highly efficient catalysts for the sulfoxidation of methyl phenyl sulfides with hydrogen peroxide in neat aqueous media operating at loadings down to 0.2 mol% and allowing for enantioselectivities up to 80% ee.
The rigid duplex cyclodextrin 6 composed of two α-cyclodextrin macrocycles connected with two disulfide bonds in “transannular” (C6I, C6IV) positions was prepared from partially debenzylated α-cyclodextrin 1 in four steps in 73% overall yield. In the last key step involving oxidative coupling of the thiol 5, predominance of the target duplex 6 can be attained under conditions of thermodynamic control. The structure of duplex cyclodextrin was established by MS as well as 2-D NMR methods and confirmed by a single-crystal X-ray analysis. The ability of the duplex cyclodextrin 6 to bind α,ω-alkanediols (C9−C14) and 1-alkanols (C9 and C10) was studied by isothermal titration calorimetry in aqueous solutions. The stability constants of the complexes gradually increase with the alkyl chain length and reach an unprecedently high value of K = 8.6 × 109 M−1 for 1,14-tetradecanediol. It was found that the doubly bridged dimer 6 exhibits higher binding affinity toward the series of α,ω-alkanediols than the singly bridged analogue 10 by about 2 orders of magnitude in K (M−1) or 3.1−3.3 kcal/mol in ΔG°, the enhancement being due to enthalpic factors. Theoretical calculations using DFT-D methods suggest that the enthalpic contribution stems from dispersion interactions.
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