Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics

Ichikawa, Satoshi; Yamaguchi, M; Hsuan, Lee Shang; Kato, Yuta; Matsuda, Akira

doi:10.1021/id5000376

Cited by 34 publications

(39 citation statements)

References 44 publications

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“…To date, several derivatives of uridylpeptide natural products have been generated through engineering of the organisms that produce the natural products or through semi-synthetic approaches and, as such, feature limited structural variation171819202122232425. A number of synthetic studies have also been reported on uridylpeptide natural products and analogues2627282930313233, some of which have been shown to possess antimicrobial activity78. The focus of the present study was to develop a rapid and divergent synthetic strategy to access a diverse library of sansanmycin analogues that would enable the determination of key structure-activity relationships specifically against Mtb.…”

Section: Resultsmentioning

confidence: 99%

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

et al. 2017

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Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

et al. 2017

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“…[102] As the oxazolidine analogues were revealed to be weak MraY inhibitors (IC 50 = 920-1200 mm), Ichikawa et al recently reported the carbacaprazamycin analogues,w ith MIC values of 4-16 mgmL À1 and MraY inhibition with IC 50 values of 2.6-6.9 nmol L À1 . [108] However,t he morphological changes observed in S. aureus indicated am ode of action that may be completely different from existing peptidoglycan inhibitors.…”

Section: Angewandte Chemiementioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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“…Assignment was based on 1 H-1 H COSY, HMBC and HMQC NMR spectra. 1 (22). 1-(6,7-Dideoxy-2,3-O-isopropylidene-β-D-allo-hept-6-enofranosyl)uracil (17).…”

Section: Methodsmentioning

confidence: 99%

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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Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics

Cited by 34 publications

References 44 publications

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

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

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