Structure-activity relationship studies of the two-component lantibiotic haloduracin

The lantibiotic haloduracin consists of two posttranslationally processed peptides, Halalpha and Halbeta, which act in synergy to provide bactericidal activity. An in vitro haloduracin production system was used to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Halalpha B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin's predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine completely abolished antibacterial activity. This study also established that Halalpha-Ser26 and Halbeta-Ser22 escape dehydration, requiring revision of the Halbeta structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Halalpha cystine that is dispensable for bioactivity protects Halalpha from further proteolytic degradation.     

Structure-activity relationship studies of illudins: analogues possessing a spiro-cyclobutane ring

Bicyclic and tricyclic analogues of anticancer sesquiterpene illudin S have been synthesized. These contain a spiro-cyclobutane instead of spiro-cyclopropane structure. The cytotoxicity of the former is less than that of the corresponding cyclopropane-containing compounds.     

Structure-activity relationship studies on CXCR4 antagonists having cyclic pentapeptide scaffolds

Structure-activity relationship studies on CXCR4 antagonists, which were previously found by using cyclic pentapeptide libraries, were performed to optimize side-chain functional groups, involving conformationally constrained analogues. In addition, a new lead of cyclic pentapeptides with the introduction of a novel pharmacophore was developed.     

Total synthesis of gymnocin-A

A highly convergent total synthesis of gymnocin-A, a cyctotoxic polyether marine natural product, has been achieved. The synthesis features Suzuki-Miyaura coupling of the ABCD and FGHIJKLMN rings, stereoselective introduction of the C17 hydroxyl group, ring-closure of the F ring, and a late-stage incorporation of a 2-methyl-2-butenal side chain.     

Structure-activity relationship studies: methods and ligand design for G-protein coupled peptide receptors

The exchange of information between cells represents an important regulatory mechanism for cellular activities. Such regulation processes mainly occur by hydrophilic compounds, unable to penetrate the cell membrane. Accordingly such signals have to be transmitted into the cell that is performed by transmembrane receptors. The widespread group of G-protein coupled receptors plays a decisive role in extracellular signal recognition and transition into cellular response. The importance of this interaction is evidently shown by the severe diseases that correlate with dysfunction of the interaction between ligand and G-protein coupled receptor. The development of drugs against these diseases needs the comprehension of signal recognition and transition as well as the understanding of intracellular signal pathways. In this review, we describe concepts and methods to identify the structure-activity relationships of G-protein coupled peptide receptors and their successful application. Furthermore we provide an insight into peptide based drug design. Examples are taken from the field of CGRP, orexin and growth hormone secretagogue receptor ligands.     

Structure-activity relationship of defective electrocatalysts for nitrogen fixation

Ammonia (NH₃), as an important chemical substance and clean energy carrier, plays an indispensable role in industrial and agricultural production. The electrocatalytic synthesis of NH₃ under mild conditions has attracted worldwide attention in the energy field due to its environmental friendliness and cost efficiency, but unsatisfactory NH₃ yields and Faradaic efficiencies are restricting its development. The introduction of defect has been demonstrated as a feasible way to overcome the disadvantages of electrochemistry, as it can regulate the electronic structure and modulate coordination environment of electrocatalysts, which further create active sites and enhance nitrogen adsorption. In this regard, it is necessary to understand the effects of various types of defects on electrocatalysts based on the latest progress in the defect engineering for nitrogen reduction reaction (NRR). In this review, the concept, classifications, and characterization of defects as well as the approaches to create them in electrocatalysts are firstly discussed. Then, certain types of defects (vacancy, dopant, amorphism, edge/corner, and porousness) affecting the performances of various electrocatalysts are further described. Finally, the summary and challenges of electrocatalytic ammonia synthesis are proposed to design advanced electrocatalysts with high efficiency.     

Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency

Antimicrobial alpha-helical alpha-peptides are part of the host-defense mechanism of multicellular organisms and could find therapeutic use against bacteria that are resistant to conventional antibiotics. Recent work from Hamuro et al. has shown that oligomers of beta-amino acids ("beta-peptides") that can adopt an amphiphilic helix defined by 14-membered ring hydrogen bonds ("14-helix") are active against Escherichia coli [Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200-12201]. We have created two series of cationic 9- and 10-residue amphiphilic beta-peptides to probe the effect of 14-helix stability on antimicrobial and hemolytic activity. 14-Helix stability within these series is modulated by varying the proportions of rigid trans-2-aminocyclohexanecarboxylic acid (ACHC) residues and flexible acyclic residues. We have previously shown that a high proportion of ACHC residues in short beta-peptides encourages 14-helical structure in aqueous solution [Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309-2310]. Circular dichroism of the beta-peptides described here reveals a broad range of 14-helix population in aqueous buffer, but this variation in helical propensity does not lead to significant changes in antibiotic activity against a set of four bacteria. Several of the 9-mers display antibiotic activity comparable to that of a synthetic magainin derivative. Among these 9-mers, hemolytic activity increases slightly with increasing 14-helical propensity, but all of the 9-mers are less hemolytic than the magainin derivative. Previous studies with conventional peptides (alpha-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because alpha-helix stability can be varied to only a limited extent among linear alpha-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with beta-peptides. For example, it is very rare for a linear alpha-peptide to display significant alpha-helix formation in aqueous solution and manifest antibacterial activity, while the linear beta-peptides described here range from fully unfolded to very highly folded in aqueous solution. This study shows that beta-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.     

Convergent total synthesis of gymnocin-A and evaluation of synthetic analogues

The first total synthesis of gymnocin-A (1), a cytotoxic polycyclic ether isolated from a notorious red tide dinoflagellate, Karenia mikimotoi, has been accomplished. The synthesis relies heavily on the Suzuki-Miyaura cross-coupling-based methodology to assemble the tetradecacyclic polyether skeleton. Convergent union of the GHI (5) and KLMN (6) rings, both of which were prepared from a common intermediate 7, and the subsequent ring closure of the J ring delivered the GHIJKLMN ring. The crucial coupling between the ABCD and FGHIJKLMN ring fragments (3 and 4, respectively) and stereoselective installation of the C17 hydroxyl group, followed by cyclization of the E ring gave rise to the tetradecacyclic polyether skeleton 2. Finally, incorporation of the 2-methyl-2-butenal side chain completed the total synthesis of gymnocin-A. The convergent nature of the synthesis, which employs three fragments of comparable complexity, is well-suited for preparation of various structural analogues of gymnocin-A to explore the structure-activity relationship. The results of preliminary structure-activity relationship studies of several synthetic analogues are also provided.     

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 1. Conversion of 5-substituent on oxazolidinone

A structure-activity relationship (SAR) study on 5-substituted oxazolidinones as an antibacterial agent is described. The oxazolidinones, of which 5-acetylaminomethyl moiety was converted into other functions, were prepared and evaluated for antibacterial activity. Elongation of the methylene chain (8) and conversion of the acetamido moiety into guanidino moiety (12) decreased the antibacterial activity. The replacement of carbonyl oxygen (=O) by thiocarbonyl sulfur (=S) enhanced in vitro antibacterial activity. Especially, compound 16, which had the 5-thiourea group, showed 4-8 stronger in vitro activity than linezolid. Our SAR study revealed that the antibacterial activity was greatly affected by the conversion of 5-substituent.     

Synthetic study of gymnocin-A: synthesis of the ABC ring fragment

The synthesis of the ABC ring fragment of gymnocin-A is described. The key feature of this approach was the convergent BC ring formation using an oxiranyl anion coupling, which was followed by intramolecular Williamson ether synthesis and the reductive etherification of an α-acetoxy acetal. The five-membered A ring was then constructed on the seven-membered B ring by radical cyclization of a β-alkoxy acrylate derivative.     

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 3. Synthesis and evaluation of 5-thiocarbamate oxazolidinones

A series of 5-thiocarbamate oxazolidinones was prepared and tested for in vitro and in vivo antibacterial activities. The results of in vitro antibacterial activity indicated that the 5-thiocarbamate group was a suitable substituent for the activity by the 5-moderate hydrophilicity. The compounds within a favorable logP value range were found to have potent in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Compounds 3a and 4h were superior to linezolid in both in vitro and in vivo potency and were considered to be hopeful compounds. We also discuss the pharmacokinetic properties of several compounds in mice.     

Pd/CeO2甲烷氧化催化剂的构效关系

钯基催化剂是甲烷氧化活最具活性的催化剂.在宏观和纳米尺度上,它们的组成、结构和形态的调整可以显著改变其催化行为和稳定性,对催化剂的整体性能有很大的影响.在已经应用的几种载体和促进剂组合中, Pd/CeO2由于其活性和耐用性以及Pd/Pd O载体之间较强的相互作用而引起了人们的极大关注.这使得人们可在纳米尺度上创建特定的结构,从而对甲烷活化特性产生重大的影响.本文综述了该领域的最新发现,特别是设想如何在纳米尺度上尽可能控制Pd-CeO2相互作用,从而有助于设计更强劲的甲烷氧化催化剂.     

Structure-activity relationship study of flowering-inducer FN against Lemna paucicostata

FN1 (1) and FN2 (2), cycloadducts of α-ketol octadecadienoic acid (3) with norepinephrine (NE), induce flowering in Lemna paucicostata. In order to broaden our understanding of structural requirements of FN for flower induction, nine analogs of 3 (4-12) were synthesized and reacted with NE under basic conditions. These analogs, except for 8, 10, and 12, exhibited significant activity regarding to floral induction in L. paucicostata. Similar experiments were carried out by using 3 and epinephrine, and it was demonstrated that these products also possessed biological activity.