Function‐Oriented Synthesis of Liponucleoside Antibiotics

Tanino, Tetsuya; Yamaguchi, M; Matsuda, Akira; Ichikawa, Satoshi

doi:10.1002/ejoc.201400140

Cited by 11 publications

(16 citation statements)

References 37 publications

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“…The filtrate was concentrated in vacuo to give a crude aldehyde, which was used for the next step without further purification. 1 169.9, 163.3, 150.1, 142.4, 134.0, 120.2, 114.7, 105.3, 102.7 1-[5-O-(2,3-Di-O-acetyl-5-azido-5-deoxy-β-D-ribo-pentofuranosyl)-2,3-di-O-acetyl-6,7-dideoxy-α-L-talo-hept-6-enofranosyl]uracil (26). A solution of vinylmagnesium bromide in THF (1 M solution, 28.2 mL, 28.2 mmol) was added dropwise to the solution, and the whole mixture was stirred for further 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…16,17 , 18 which is a semisynthetic analogue of CPZs currently under preclinical study, 19 is the most promising derivative of the CPZs and has excellent antitubercular activity against not only drug-sensitive strains but also some multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis strains. [23][24][25][26][27] However, the diazepanone moiety serves as a scaffold to link these critical pharmacophore elements and could be replaced by a simpler scaffold. 20 CPZEN-45 possesses promising properties as a 10.1039/ c5ob01037c a drug candidate including higher resistance to biotransformation in mouse serum compared with CPZs, low toxicity and high in vivo efficacy.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and biological evaluation of 5′-C-piperidinyl-5′-O-aminoribosyluridines as potential antibacterial agents

2015

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The discovery of new antibiotics is critical because the emergence of drug-resistant bacteria has posed a serious public health problem. Caprazamycins, which are nucleoside antibiotics, are a promising lead with a novel mode of action, and we have designed simplified analogues containing a piperidine as a scaffold linking the crucial structural units of caprazamycins. These analogues were step-economically synthesized via a sequential aza-Prins-Ritter reaction. Among the tested compounds, the analogue 7 exhibited good MraY inhibitory activity, antibacterial activity against Gram-positive bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, and metabolic stability. The observed cytotoxicity of 7 against HepG2 cells was overcome by modulating the fatty acyl side chain. The knowledge obtained from our structure-activity relationship studies of the caprazamycins will provide further direction toward the design of potent MraY inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of 5′-C-piperidinyl-5′-O-aminoribosyluridines as potential antibacterial agents

2015

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“…Our group has been pursuing the medicinal chemistry of natural products utilizing the concept of FOS. This review describes our recent efforts on FOS of antibacterial nucleoside natural products 4–6…”

Section: Introductionmentioning

confidence: 99%

“…This review describes our recent efforts on FOS of antibacterial nucleoside natural products. [4][5][6]…”

Section: Introductionmentioning

confidence: 99%

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

Ichikawa

2016

The Chemical Record

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It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.

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“…Extensive use of these antibiotics has led to the development of drug-resistant bacterial pathogens including methicillin-resistant S. aureus (MRSA) and vancomycinresistant Enterococci (VRE). [11][12][13][14][15] We hypothesized that the diazepanone moiety that serves as a scaffold to link these critical pharmacophore elements could be replaced by a simpler scaffold. [1][2][3][4] Caprazamycin B (CPZ) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of isoxazolidine-containing uridine derivatives as caprazamycin analogues

2015

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Simplification of caprazamycins, which are promising antibacterial nucleoside natural products, was conducted by scaffold-hopping of the structurally complex diazepanone moiety to the isoxazolidine scaffold. The designed isoxazolidine-containing uridine derivatives were synthesized by an intramolecular 1,3-dipolar cycloaddition of alkenyl nitrone as a key step. The lactone-fused isoxazolidine intermediate was easily converted to the target compounds by sequential introduction of key substituents upon ring-opening the lactone moiety by nucleophilic substitution and electrophilic capping of the resulting primary alcohol. Several analogues exhibited good activity against H. influenzae ATCC 10211 (MIC 0.25-0.5 μg mL(-1)) and moderate activity against vancomycin-resistant E. faecalis SR7914 (MIC 4-8 μg mL(-1)).

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Function‐Oriented Synthesis of Liponucleoside Antibiotics

Cited by 11 publications

References 37 publications

Design, synthesis and biological evaluation of 5′-C-piperidinyl-5′-O-aminoribosyluridines as potential antibacterial agents

Design, synthesis and biological evaluation of 5′-C-piperidinyl-5′-O-aminoribosyluridines as potential antibacterial agents

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

Synthesis of isoxazolidine-containing uridine derivatives as caprazamycin analogues

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