ABSTRACT
The selective alkyl lithium-induced ring opening of 1,3-di-isopropylsilylenes is described. The reaction affords a differentially substituted 1,3-diol bearing a silane that resides at the oxygen in the more sterically demanding position. The reaction can be highly selective with a regiochemical preference up to >50:1 and likely proceeds via an alkoxy-silane intermediate. This intermediate can by trapped by methyl iodide to provide the corresponding silyl methyl ether, wherein the silane again resides at the oxygen in the more sterically demanding position.
Subject(s)
Alcohols/chemistry , Lithium/chemistry , Silanes/chemistry , Indicators and Reagents , Molecular Structure , StereoisomerismABSTRACT
Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymatic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry additional risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biologically relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.
Subject(s)
Enzyme Inhibitors/chemistry , Glutathione/chemistry , Drug Design , Glutathione/metabolism , Humans , Kinetics , Mass Spectrometry , Nuclear Magnetic Resonance, Biomolecular , Pharmaceutical Preparations/chemistryABSTRACT
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.
Subject(s)
Cross Infection/drug therapy , Drug Discovery , Drug Resistance, Multiple/drug effects , Gram-Negative Bacteria/drug effects , Polymyxins/chemistry , Polymyxins/pharmacology , beta-Alanine/analogs & derivatives , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Dogs , Female , Gram-Negative Bacteria/physiology , Humans , Male , Microbial Sensitivity Tests , Polymyxins/pharmacokinetics , Polymyxins/toxicity , Rats , beta-Alanine/chemistryABSTRACT
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Gram-Negative Bacteria/drug effects , Hydroxamic Acids/chemistry , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Hydroxamic Acids/chemical synthesis , Pyridones/chemical synthesis , Sulfonic Acids/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Protein Conformation , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonic Acids/pharmacokinetics , Sulfonic Acids/pharmacologyABSTRACT
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Phenyl Ethers/chemical synthesis , Pseudomonas Infections/drug therapy , Sulfides/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Catalytic Domain , Crystallography, X-Ray , Drug Resistance, Bacterial , Hydrogen Bonding , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Mice , Models, Molecular , Molecular Conformation , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Pseudomonas aeruginosa , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The use of the intramolecular vinylogous aldol reaction for the preparation of an advanced intermediate for the synthesis of peloruside A is described. The reaction was applied to compound 19 and proceeds in high yield and good levels of diastereoselectivity. Application of the Achmatowicz reaction to this intermediate provided the corresponding pyranone, a late stage intermediate well positioned for conversion to the natural product.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Lactones/chemical synthesis , Vinyl Compounds/chemistry , Aldehydes/chemistry , Cyclization , Molecular Structure , StereoisomerismABSTRACT
An efficient method was developed for the synthesis of 2-methylene-4-substituted ethyl butyrates via cyclopropyl opening followed by a Wittig reaction. The desired products were formed in a two-step, one-pot reaction sequence. Alternatively, the key intermediate ylide 2 was isolable and could be stored under oxygen-free conditions and subsequently utilized. A variety of nucleophiles were found to open the commercially available cyclopropane 1. The resulting ylide reacted with aldehydes to provide E-olefinic products.
Subject(s)
Borates/chemistry , Organophosphorus Compounds/chemistry , Aldehydes/chemistry , Cyclization , Molecular StructureABSTRACT
An intramolecular version of the Yamamoto vinylogous aldol reaction, a method that employs the bulky Lewis acid ATPH to control the site of aldolization, is described. This macrocyclization process is effective for the construction of 10-, 12-, and 14-membered macrolides. The yields are high (70-90%), and the reaction can proceed with excellent remote stereocontrol (dr > or = 20:1) with chiral substrates.
Subject(s)
Macrolides/chemical synthesis , Crystallography, X-Ray , Models, Molecular , Molecular StructureABSTRACT
A ferrocene derivative (2-[(methylsulfonyl)thio]ethylferrocene) (1) has been synthesized and incorporated into apo-azurin from Pseudomonas aeruginosa by covalent attachment to the highly conserved Cys112. The resulting artificial organometalloprotein (a protein containing organometallic compounds in the active site) has been characterized by UV-vis, electrospray mass spectrometry, and cyclic voltammetry (CV). Incorporation of 1 into azurin resulted in a higher solubility of the ferrocene group and improved stability of the ferrocenium species in aqueous solution, as shown by a more intense UV-vis absorption and a more reversible CV of the attached ferrocene group, respectively. The incorporation of 1 also increased the reduction potential of the complex from 402 to 579 mV (vs NHE), consistent with the ferrocene group being encapsulated inside the hydrophobic environment of the protein. Modulation of the reduction potential of ferrocene by residues near the secondary coordination sphere has also been demonstrated. Raising the pH from 4 to 9 resulted in a greater than 80 mV decrease in reduction potential of the protein-bound ferrocene (from 579 to 495 mV), while replacing Met121, an amino acid residue in close proximity to the ferrocene group with a positively charged Arg or negatively charged Glu, resulted in the predicted increase or decrease in reduction potential at all pH values. Similarly, substitution of Met121 with a more hydrophobic Leu raised the reduction potential. The increased solubility, stability, and tune-ability of this organometalloprotein make it an ideal choice for carrying out a number of biological reactions, such as long-range electron transfer or sensing. As an example of such applications, stoichiometric oxidation of ferrocytochrome c by the blue ferrocenium azurin was demonstrated.
Subject(s)
Azurin/chemistry , Ferrous Compounds/chemistry , Indicators and Reagents , Metallocenes , Metalloproteins/chemistry , Molecular Structure , Oxidation-Reduction , SolubilityABSTRACT
Introducing nonnative metal ions or metal-containing prosthetic groups into a protein can dramatically expand the repertoire of its functionalities and thus its range of applications. Particularly challenging is the control of substrate-binding and thus reaction selectivity such as enantioselectivity. To meet this challenge, both non-covalent and single-point attachments of metal complexes have been demonstrated previously. Since the protein template did not evolve to bind artificial metal complexes tightly in a single conformation, efforts to restrict conformational freedom by modifying the metal complexes and/or the protein are required to achieve high enantioselectivity using the above two strategies. Here we report a novel site-selective dual anchoring (two-point covalent attachment) strategy to introduce an achiral manganese salen complex (Mn(salen)), into apo sperm whale myoglobin (Mb) with bioconjugation yield close to 100%. The enantioselective excess increases from 0.3% for non-covalent, to 12.3% for single point, and to 51.3% for dual anchoring attachments. The dual anchoring method has the advantage of restricting the conformational freedom of the metal complex in the protein and can be generally applied to protein incorporation of other metal complexes with minimal structural modification to either the metal complex or the protein.
