Optimization of a biomimetic transamination reaction

For a range of protein substrates, N-terminal transamination offers a convenient way to install a reactive ketone or aldehyde functional group at a single location. We report herein the effects of the identity of N-terminal residues on the product distribution generated upon reaction with pyridoxal 5'-phosphate (PLP). This study was accomplished through the combination of solid-phase peptide synthesis with detailed liquid chromatography-mass spectrometry analysis. Many N-terminal amino acids provided high yields of the desired transaminated products, but some residues (His, Trp, Lys, and Pro) generated adducts with PLP itself. N-terminal Cys and Ser residues were observed to undergo beta-elimination in addition to transamination, and the transamination product of N-terminal Gln was resistant to subsequent oxime formation attempts. The information generated through the screening of peptide substrates was successfully applied to a protein target, changing an initially unreactive terminus into one that could be modified in high (70%) yield. Thus, these studies have increased our predictive power for the reaction, both in terms of improving conversion and suppressing reaction byproducts. An initial set of guidelines that may be used to increase the applicability of this reaction to specific proteins of interest is provided.     

Synthesis of (+)-sch 642305 by a biomimetic transannular Michael reaction

[reaction: see text] The synthesis of (+)-Sch 642305 (1) has been completed in 17 steps in 1.6% overall yield. Transannular Michael reaction of 2b with NaH in THF provided cyclohexenone 23 stereospecifically. Heating 23 in TFA/CDCl(3) provided a 3:1 equilibrium mixture of 23 and 25, which was hydrolyzed to give (+)-6-epi-Sch 642305 (24) and (+)-Sch 642305 (1), respectively.     

Electron transfer driven by proton fluctuations in a hydrogen-bonded donor-acceptor assembly

The temperature-isotope dependence of proton-coupled electron transfer (PCET) for a noncovalent molecular dyad is reported. The system consists of an excited-state Zn(II) porphyrin that transfers an electron to a naphthalene diimide acceptor through an amidinium-carboxylate interface. Two different isotope effects are observed for variant temperature regimes. A reverse isotope effect (i.e., kH/kD < 1) is observed as T approaches 120 K (kH/kD = 0.9, 120 K), whereas a normal isotope effect (i.e., kH/kD > 1) is recovered as the temperature is increased (kH/kD = 1.2, 300 K). The transition between these limits is smooth, with a crossover temperature of T approximately 160 K. These observations are in accordance with charge-transfer dynamics that are susceptible to bath-induced fluctuations in the proton coordinate.     

Hydrogen-bond driven assembly of a molecular capsule facilitated by supramolecular chelation

Resorcinarene-based cavitands functionalized with acetamido groups capable of self-complementary hydrogen-bond interactions, were synthesized in order to construct supramolecular capsules. The 1,3-bifunctionalized cavitand produced a polymeric assembly, whereas the tetra-functionalized analogue yielded a discrete capsule held together via N-H···O hydrogen bonds. The ethynyl species attached to the rim of these host molecules deepen each cavitand and expands the volume of the resulting capsule.     

仿生微胶囊的组装及其应用

在生物物理和生物医药研究领域中,在分子水平上组装功能化的仿生微胶囊具有重要的理论和应用价值.在现有制备微胶囊的技术手段中,层层组装技术以其能够控制胶囊的尺寸、形状、囊壁的厚度和组成以及易于实现功能化等特点,引起了人们越来越多的研究兴趣.本文将着重介绍如何利用层层组装技术,以磷脂、蛋白质和其他生物大分子为组装基元构筑仿生微胶囊、以及如何将微胶囊进行生物界面化的修饰.此外,以仿生微胶囊为药物载体,探讨其在光动力治疗方面的应用也作简单介绍.     

Synchronized assembly of gold nanoparticles driven by a dynamic DNA-fueled molecular machine

A strategy for gold nanoparticle (AuNP) assembly driven by a dynamic DNA-fueled molecular machine is revealed here. In this machine, the aggregation of DNA-functionalized AuNPs is regulated by a series of toehold-mediated strand displacement reactions of DNA. The aggregation rate of the AuNPs can be regulated by controlling the amount of oligonucleotide catalyst. The versatility of the dynamic DNA-fueled molecular machine in the construction of two-component "OR" and "AND" logic gates has been demonstrated. This newly established strategy may find broad potential applications in terms of building up an "interface" that allows the combination of the strand displacement-based characteristic of DNA with the distinct assembly properties of inorganic nanoparticles, ultimately leading to the fabrication of a wide range of complex multicomponent devices and architectures.     

Membrane activity of biomimetic facially amphiphilic antibiotics

Membranes are a central feature of all biological systems, and their ability to control many cellular processes is critically important. As a result, a better understanding of how molecules bind to and select between biological membranes is an active area of research. Antimicrobial host defense peptides are known to be membrane-active and, in many cases, exhibit discrimination between prokaryotic and eukaryotic cells. The design of synthetic molecules that capture the biological activity of these natural peptides has been shown. In this report, the interaction between our biomimetic structures and different biological membranes is reported using both model vesicle and in vitro bacterial cell experiments. Compound 1 induces 12% leakage at 20 microg/mL against phosphatidylglycerol (PG)-phosphatidylethanolamine (PE) vesicles vs only 3% leakage at 200 microg/mL against phosphatidyl-L-serine (PS)-phosphatidylcholine (PC) vesicles. Similarly, a 40% reduction in fluorescence is measured in lipid movement experiments for PG-PE compared to 10% for PS-PC at 600 s. A 30 degrees C increase in the phase transition of stearoyl-oleoyl-phosphatidylserine is observed in the presence of 1. These results show that lipid composition is more important for selectivity than overall net charge. Additionally, the overall concentration of a given lipid is another important factor. An effort is made to connect model vesicle studies with in vitro data and naturally occurring lipid compositions.     

Stereoselective synthesis of olefins by a reductive coupling reaction

Ketones and aldehydes are converted to symmetrical and (E)-olefins (1-15) by reaction with 2,4-bis(phenyl)-1,3-diselenadiphosphetane-2,4-diselenide (PhPSe(2))(2), Woollins' reagent, in refluxing toluene; use of diketones was demonstrated by the reaction of PhC(O)CH(2)C(O)Ph which gives 1,2,4,5-tetraphenylbenzene (16) in 83% yield.     

Topochemical transketalization reaction driven by hydrogen bonding

An unusual thermal isomerization of 1,2;3,4-di-O-isopropylidene-myo-inositol to 1,2;5,6-di-O-isopropylidene-myo-inositol was observed in the solid state. A detailed study revealed that this ketal migration is a topochemically driven one. X-ray structure revealed that strong intermolecular hydrogen bonding in the crystal preorganizes the hydroxyl and ketal carbon in a transition-state-like arrangement favorable for the reaction. The 5-OH of each molecule faces the trans ketal carbon of a neighboring molecule at a close distance and an angle of approach near to linearity, making a trigonal-bipyramidal-like arrangement in the crystal, which could facilitate the reaction. This is the first report of a topochemical transketalization reaction.     

Oxidative coupling as a biomimetic approach to the synthesis of scytonemin

The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations in its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated in a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin.     

How the biomimetic assembly of membrane receptors into multivalent domains is regulated by a small ligand

In living cells, communication requires the action of membrane receptors that are activated following very small environmental changes. A binary all-or-nothing behavior follows, making the organism extremely efficient at responding to specific stimuli. Using a minimal system composed of lipid vesicles, chemical models of a membrane receptor and their ligands, we show that bio-mimetic ON/OFF assembly of high avidity, multivalent domains is triggered by small temperature changes. Moreover, the intensity of the ON signal at the onset of the switch is modulated by the presence of small, weakly binding divalent ligands, reminiscent of the action of primary messengers in biological systems. Based on the analysis of spectroscopic data, we develop a mathematical model that rigorously describes the temperature-dependent switching of the membrane receptor assembly and ligand binding. From this we derive an equation that predicts the intensity of the modulation of the ON signal by the ligand-messenger as a function of the pairwise binding parameters, the number of binding sites that it features and the concentration. The behavior of our system, and the model derived, highlight the usefulness of weakly binding ligands in the regulation of membrane receptors and the pitfalls inherent to their binding promiscuity, such as non-specific binding to the membrane. Our model, and the equations derived from it, offer a valuable tool for the study of membrane receptors in both biological and biomimetic settings. The latter can be exploited to program membrane receptor avidity on sensing vesicles, create hierarchical protocell tissues or develop highly specific drug delivery vehicles.

In lipid vesicles near their membrane phase-transition temperature, the presence of a small, weakly binding ligand tips the balance for the assembly of multivalent receptor domains. We recapitulate this behaviour using a global binding-clustering model.     

Subtractive assembly of DNA nanoarchitectures driven by fuel strand displacement

Herein we demonstrate that flexible DNA architectures with larger cavities can be efficiently constructed by first assembling a relatively more rigid DNA tile architecture and subsequently subtracting a center tile through fuel strand displacement; such structures are otherwise difficult to obtain if the center tile is missing in the beginning, proving a new strategy for DNA self-assembly.     

Synthesis of polycarbonates by a silicon-assisted alkoxy/carbonylimidazolide coupling reaction

The investigation of a silicon-mediated coupling reaction between hydroxyl and carbonylimidazolide functional groups in the preparation of carbonate linkages is described. Application of this reaction to the formation of aliphatic polycarbonates was accomplished by the polymerization of an AB monomer unit, which was composed of 1,4-cyclohexanediol, where one of the hydroxyl groups was protected as a dimethylphenylsilyl ether and the other carried the carbonylimidazolide functionality. Reaction of this monomer with cesium fluoride removed the silicon protecting group and the resulting alkoxy anion promoted polymerization. Poly(1,4-cyclohexanecarbonate)s with typical molecular weights of M_w = 20,000 and M_n = 7300 a.m.u. (from GPC based upon polystyrene standards) were prepared in ca. 65% yield. The polymer showed a glass transition temperature at 138°C by DSC. TGA gave 85% mass loss between 275 and 350°C. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 1133–1137, 1997.     

Macrocycles from simple building blocks by a multifold Heck-type coupling reaction

Diiodobenzenes and bisallylic alcohols—two equivalents of each—were coupled under palladium catalysis to give oxofunctionalized macrocycles as 2:2 products. The 1:1 products as medium sized rings were disfavoured and not observed.     

Novel assembly of cyclic ethers by coupling alpha-chlorosulfides and alcohols

A novel protocol for assembling polycyclic ethers was developed and successfully applied to the synthesis of the EFGH ring system of ciguatoxin CTX3C. A key transformation involves construction of an O,S-acetal through coupling of alpha-chlorosulfide and a secondary alcohol under mild conditions. The method is highly applicable to use with sensitive substrates and will enable the synthesis of various natural and artificial polycyclic ethers. [reaction: see text]