Construction Of Side Chain Research Articles

Sidechains With Fast Cross-Chain Transfers

With the rapid evolution of the blockchain technologies, the interoperability of different blockchain systems is emerging as one of the essential features of blockchains. Sidechains, a mechanism providing communications between different blockchains, have been heralded as the crucial factor of blockchain interoperability. However, there are still issues that need to be addressed in terms of security and feasibility. In this article, for proof-of-stake (PoS) and proof-of-work (PoW) blockchains, we propose efficient sidechain constructions with fast cross-chain transfers and small proof size by novel cross-chain certificate generation process and committee selection methods. Moreover, we also provide an extra functionality of supporting instant cross-chain transfers, such that emergent cross-chain transactions can be processed immediately. Compared to prior sidechains, our PoS sidechain construction can achieve faster cross-chain transfers, which improves the promptness of cross-chain transfers. While our PoW sidechain construction is more efficient with smaller proof size, reducing the storage and bandwidth overhead. Furthermore, we formally prove our sidechain constructions satisfying the properties of atomicity and timeliness. Finally, we develop a proof-of-concept implementation of our sidechains, and the experimental results show our constructions is not only faster, but also efficient with low storage and bandwidth overhead.

Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis.

Carbapenems are antibiotics of last resort in the clinic. Owing to their potency and broad-spectrum activity, they are an important part of the antibiotic arsenal. The vital role of carbapenems is exemplified by the approval acquired by Merck from the US Food and Drug Administration (FDA) for the use of an imipenem combination therapy to treat the increased levels of hospital-acquired and ventilator-associated bacterial pneumonia that have occurred during the COVID-19 pandemic1. The C6 hydroxyethyl side chain distinguishes the clinically used carbapenems from the other classes of β-lactam antibiotics and is responsible for their low susceptibility to inactivation by occluding water from the β-lactamase active site2. The construction of the C6 hydroxyethyl side chain is mediated by cobalamin- or B12-dependent radical S-adenosylmethionine (SAM) enzymes3. These radical SAM methylases (RSMTs) assemble the alkyl backbone by sequential methylation reactions, and thereby underlie the therapeutic usefulness of clinically used carbapenems. Here we present X-ray crystal structures of TokK, a B12-dependent RSMT that catalyses three-sequential methylations during the biosynthesis of asparenomycin A. These structures, which contain the two metallocofactors of the enzyme and were determined in the presence and absence of a carbapenam substrate, provide a visualization of a B12-dependent RSMT that uses the radical mechanism that is shared by most of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggest that substrate positioning governs the rate of each methylation event.

A Novel Scheme for the Synthesis of 21-Acetoxypregna-1,4,9(11)-triene- 17α,21-diol-3,20-dione from 9α-Hydroxyandrostenedione

Background: Vietnam currently imports up to 90% of the pharmaceuticals it consumes and 100% of the steroid-based pharmaceuticals. The ability for efficient chemical synthesis of the steroids could create commercial opportunities to address this issue. Synthesis of 21-acetoxypregna-1,4,9(11)- triene-17α,21-diol-3,20-dione is considered a key intermediate in the scheme of steroidal drug synthesis. Previous synthesis attempts of such steroids (corticoids) introduce a double bond at C-1(2) in the final stage of synthesis, which delivers a poor yield and reduces the economic efficiency of the process. Objective: To study and develop a novel and effective method for the synthesis of 21-acetoxypregna- 1,4,9(11)-triene-17α,21-diol-3,20-dione. Methods: Using 9α-hydroxyandrostenedione as a substrate chemical synthesis was performed as follows: pregnane side chain construction at C-17 (acetylene method), introduction of C-1(2) double bond (using SeO2), epimerization of C-17 (via 17-ONO2 ester) and Stork’s iodination. Results: 21-acetoxypregna-1,4,9(11)-triene-17α,21-diol-3,20-dione was prepared from 9α- hydroxyandrostenedione with an improved yield compared to previous attempts. Conclusion: Here, 21-acetoxypregna-1,4,9(11)-triene-17α,21-diol-3,20-dione has been synthesized from 9α-hydroxyandrostenedione based on a novel, effective and commercially feasible scheme. The introduction of the C-1(2) double bond at an earlier stage of the synthesis has increased the economic efficiency of the entire process. For the first time, the indirect epimerization mechanism has been clarified along with the configuration of the C-17 stereo-center which has been confirmed using NOESY data.

Conservation and Divergence in the Candida Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control.

ABSTRACTCandida biofilms resist the effects of available antifungal therapies. Prior studies with Candida albicans biofilms show that an extracellular matrix mannan-glucan complex (MGCx) contributes to antifungal sequestration, leading to drug resistance. Here we implement biochemical, pharmacological, and genetic approaches to explore a similar mechanism of resistance for the three most common clinically encountered non-albicans Candida species (NAC). Our findings reveal that each Candida species biofilm synthesizes a mannan-glucan complex and that the antifungal-protective function of this complex is conserved. Structural similarities extended primarily to the polysaccharide backbone (α-1,6-mannan and β-1,6-glucan). Surprisingly, biochemical analysis uncovered stark differences in the branching side chains of the MGCx among the species. Consistent with the structural analysis, similarities in the genetic control of MGCx production for each Candida species also appeared limited to the synthesis of the polysaccharide backbone. Each species appears to employ a unique subset of modification enzymes for MGCx synthesis, likely accounting for the observed side chain diversity. Our results argue for the conservation of matrix function among Candida spp. While biogenesis is preserved at the level of the mannan-glucan complex backbone, divergence emerges for construction of branching side chains. Thus, the MGCx backbone represents an ideal drug target for effective pan-Candida species biofilm therapy.

Construction of Topological Macromolecular Side Chains Packing Model: Study Unique Relationship and Differences in LC-Microstructures and Properties of Two Analogous Architectures with Well-Designed Side Attachment Density

A new series of linear–comb and 4-arm star–comb side chain liquid crystalline polymers (Lc-/Sc-SCLCPs) have been synthesized and characterized. The treatment of hydride siloxane-containing terminated liquid crystalline and high 1,2-/1,4- (high vinyl, hv/low vinyl, lv) linear or 4-arm star polybutadienes (L-/S-PBs) was conducted via the methods in combination of living anionic polymerization and “reverse” hydrosilylation to obtain SCLCPs with wide mesomorphic temperature range (ΔT) and narrow polydispersity index (PDI). The possible molecular arrangement model of two analogous hv-/lv-architectures was constructed, that was used to systematically investigate the effects of Lc- and Sc- topological morphology on liquid crystalline (LC) properties and molecular microstructures. SCLCPs exhibited the same smectic A phase around room temperature, but thermal properties were significantly different due to differences of interaction force resulting from different macromolecular side chains packing. Surprisingly, th...

The development and use of a general route to brassinolide, its biosynthetic precursors, metabolites and analogues.

A new method for the construction of steroid side chains through the addition of lithium salts of dithianes to a C-22 aldehyde was developed. An efficient one-pot procedure for the preparation of a suitable C-22 aldehyde from commercial epibrassinolide in three steps in 86% isolated yield was described. Enantioselective hydroxymethylation of isovaleraldehyde and Kulinkovich cyclopropanation of silylated Roche esters were used as key steps for the dithiane syntheses. The method was applied for the preparation of brassinolide, its biosynthetic precursors and metabolites. In addition, a number of brassinosteroids with a double bond in the side chain were prepared as precursors for tritiated derivatives for biosynthetic studies.

A three dimensional visualisation approach to protein heavy-atom structure reconstruction.

BackgroundA commonly recurring problem in structural protein studies, is the determination of all heavy atom positions from the knowledge of the central α-carbon coordinates.ResultsWe employ advances in virtual reality to address the problem. The outcome is a 3D visualisation based technique where all the heavy backbone and side chain atoms are treated on equal footing, in terms of the Cα coordinates. Each heavy atom is visualised on the surfaces of a different two-sphere, that is centered at another heavy backbone and side chain atoms. In particular, the rotamers are visible as clusters, that display a clear and strong dependence on the underlying backbone secondary structure.ConclusionsWe demonstrate that there is a clear interdependence between rotameric states and secondary structure. Our method easily detects those atoms in a crystallographic protein structure which are either outliers or have been likely misplaced, possibly due to radiation damage. Our approach forms a basis for the development of a new generation, visualization based side chain construction, validation and refinement tools. The heavy atom positions are identified in a manner which accounts for the secondary structure environment, leading to improved accuracy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-014-0027-8) contains supplementary material, which is available to authorized users.

The metathesis reaction for side chain construction in carbocyclic sinefungin analogue synthesis

The naturally occurring nucleoside sinefungin has found considerable use in biological investigations. More extensive sinefungin studies have been limited because few analogues have been reported due to the synthetic challenges associated with such studies. Reported herein are preparative ways to two carbocyclic sinefungin analogues: 6′-deaminocarbocyclic sinefungin and (S)-6′-hydroxy-6′-deaminocarbocyclic sinefungin. The synthetic routes were made efficient and practical by the application of two metathesis reactions employing second generation Grubbs catalyst.

Residual dipolar couplings measured in unfolded proteins are sensitive to amino-acid-specific geometries as well as local conformational sampling

Many functional proteins do not have well defined folded structures. In recent years, both experimental and computational approaches have been developed to study the conformational behaviour of this type of protein. It has been shown previously that experimental RDCs (residual dipolar couplings) can be used to study the backbone sampling of disordered proteins in some detail. In these studies, the backbone structure was modelled using a common geometry for all amino acids. In the present paper, we demonstrate that experimental RDCs are also sensitive to the specific geometry of each amino acid as defined by energy-minimized internal co-ordinates. We have modified the FM (flexible-Meccano) algorithm that constructs conformational ensembles on the basis of a statistical coil model, to account for these differences. The modified algorithm inherits the advantages of the FM algorithm to efficiently sample the potential energy landscape for coil conformations. The specific geometries incorporated in the new algorithm result in a better reproduction of experimental RDCs and are generally applicable for further studies to characterize the conformational properties of intrinsically disordered proteins. In addition, the internal-co-ordinate-based algorithm is an order of magnitude more efficient, and facilitates side-chain construction, surface osmolyte simulation, spin-label distribution sampling and proline cis/trans isomer simulation.

Total synthesis and structural confirmation of (±)-cuevaene A

The total synthesis and structural reassignment of cuevaene A have been completed. The key synthetic steps in the total synthesis included a base-promoted double conjugate addition and further elaboration to generate the tricyclic core structure, followed by construction of the trienoic acid side chain. Detailed comparison of proton and carbon NMR data with published values enabled the connectivity of the natural product, which had been debated in earlier publications, to be confirmed.

Eleuthesides and their analogs: II. Side chain construction in the A ring. Specific action of Red-Al

Side chains were constructed in the modified A ring of eleutheside analog. The structure of the transformation product of 6-oxiranylcyclohex-3-ene-1-carbonitrile by the action of Red-Al, (1S,2R,6R,7S)-7-[(1S,2S)-1,2-isopropylidenedioxy-2-methylbut-3-yn-1-yl]-2-methylbicyclo[4.1.0]hept-3-ene-1-carbaldehyde, was determined by X-ray analysis.

Total Synthesis of a CD-Ring: Side-Chain Building Block for Preparing 17-epi-Calcitriol Derivatives from the Hajos–Parrish Dione

An efficient synthesis of the key building block for 17-epi-calctriol from the Hajos-Parrish dione involving a sequence of diastereoselective transformation of the azulene core and the side-chain construction is presented.

ChemInform Abstract: Methods for the Stereoselective Construction of Steroid Side Chains

ChemInform Abstract: Methods for the Stereoselective Construction of Steroid Side Chains

Stereoselective Construction of Steroidal Side Chain from 16-Dehydropregnenolone Acetate

Stereoselective construction of steroidal side chain at C-20 having ‘natural’ configuration using 16-dehydropregnalone acetate (16-DPA) as a starting material has been carried out. Palladium-catalyzed carbon-carbon bond-forming Heck reaction between C-20 vinyl iodide with methyl acrylate and transfer hydrogenation with triethylsilane and Pd/C are the key steps for stereoselective side-chain synthesis.

6,6-スピロケタール天然物reveromycin A,Bおよびspirofungin A,Bの合成と活性

The first asymmetric total synthesis of reveromycin A (1), a potent inhibitor of isoleucyl tRNA synthetase, has been accomplished based on the stereocontrolled construction of the 6,6-spiroketal system, efficient succinylation of the tert-alcohol under high pressure as a key step. The stereocontrolled total synthesis of (−)-spirofungin A (5) and (+)-spirofungin B (6a), polyketide-type antibiotics having various antifungal activities, has been achieved employing the Weinreb amide, the alkyne and the vinyl boronate readily available from the common intermediate employing Horner-Emmons reaction and Suzuki coupling reaction for the construction of the both side chains. The succinates of the tertiary hydroxyl group having the formyl group in the structures were conveniently synthesized by oxidative cleavage of the dihydropyrans prepared from the lactone via coupling of the ketene acetal triflates and zinc homoenolate. Various derivatives of 1, 5 and 6a were synthesized and their inhibitory effects on both the isoleucyl-tRNA synthetase activity and the survival of osteoclasts, and activities on the morphological reversion of srcts-NRK cells were examined.

A New Type of Modified Brassinosteroids for Enzyme-linked Immunosorbent Assay

New modified brassinosteroids (BS) with a full set of specific functional groups and with an additional one at C-26 have been synthesized and used as haptens for enzyme-linked immunosorbent assay. The haptens were conjugated to bovine serum albumin (BSA) and the obtained immunoconjugates were applied for production of polyclonal antibodies. A conjugation of the haptens to horseradish peroxidase (HRP) gave the corresponding enzyme-labeled BS – another principal component for immuno-competitive analysis. The steroids were linked to proteins through spacers at the terminal side chain carbon atom (C-26) that made both the cyclic part and the side chain exposed for recognition by antibodies. It allowed maximization of their sensitivity and for the first time made possible immunochemical distinguishing of the most important group of natural BS, B-lactones, from B-ketones and 6-deoxo derivatives. The synthesis of haptens based on a sequence of transformations starting from stigmasterol included Claisen rearrangement of 22-allylic ethers as a key reaction in the side chain construction.

Synthetic Studies on Maitotoxin. 1. Stereoselective Synthesis of the C′D′E′F′-Ring System Having a Side Chain

The stereoselective synthesis of the maitotoxin C'D'E'F'-ring system having a side chain has been accomplished through a convergent strategy. The key reactions include Horner-Wadsworth-Emmons coupling of the C'D'E'-ring and the side chain and subsequent construction of the F'-ring by silane reduction of dihydropyran.

Application of the solid-phase Julia-Lythgoe olefination in vitamin D side-chain construction.

An example of the Julia-Lythgoe attachment of the vitamin D side chain to a solid-phase linked Inhoffen-Lythgoe diol derived CD-ring fragment is reported.

Total Synthesis of the Proposed Structure of Brevenal

Total synthesis of the proposed structure of brevenal, a natural marine polycyclic ether product, has been accomplished. The synthesis features (i) convergent synthesis of the pentacyclic polyether skeleton using our developed Suzuki-Miyaura coupling strategy and (ii) construction of the multi-substituted dienal side chain by CuTC-mediated Stille reaction. Comparison of the NMR data of the synthetic compound with those reported for the natural product revealed that the proposed structure of brevenal needs to be revised.

New Synthesis of Naratriptan

A new synthesis of N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide (naratriptan, la) has been elaborated starting from 1-benzyl-1H-indole-5-carbaldehyde (14b). The 1-benzyl group proved to be an advantageous protecting group in the course of the construction of the ethanesulfonamide and methylpipieridinyl side-chains and it was removed in the last step of the synthesis.