Short Synthesis of (+)‐Actinobolin: Simple Entry to Complex Small‐Molecule Inhibitors of Protein Synthesis

Tharra, Prabhakara R.; Mikhaylov, Andrey А.; Švejkar, Jiří; Gysin, Marina; Hobbie, Sven N.; Švenda, Jakub

doi:10.1002/anie.202116520

Cited by 6 publications

(1 citation statement)

References 48 publications

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“…Mycobacterial cell-free translation inhibition assays were performed as described previously [24]. In brief, M. smegmatis strain SZ380 bacterial cells were disrupted and emulsified with a microfluidizer processor (Microfluidics, Westwood, MA, USA) at 25,000 lb/in 2 .…”

Section: Ribosomal Inhibition Assaysmentioning

confidence: 99%

Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

Dharuman,

Phelps,

Dunn

et al. 2024

J Antibiot

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Spectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6’-position to produce trospectomycin and to the 3’-position to produce spectinamides and aminomethyl spectinomycins. This study focused on the design, synthesis, and evaluation of three 3’,6’-disubstituted spectinomycin analogs: trospectinamide, N-benzyl linked aminomethyl, and N-ethylene linked aminomethyl trospectomycins. Computational experiments predicted that these disubstituted analogs would be capable of binding within the SPC ribosomal binding site. The new analogs were synthesized from trospectomycin, adapting the previously established routes for the spectinamide and aminomethyl spectinomycin series. In a cell-free translation assay, the disubstituted analogs showed ribosomal inhibition similar to spectinomycin or trospectomycin. These disubstituted analogs demonstrated inhibitory MIC activity against various bacterial species with the 3’-modification dictating spectrum of activity, leading to improved activity against mycobacterium species. Notably, N-ethylene linked aminomethyl trospectomycins exhibited increased potency against Mycobacterium abscessus and trospectinamide displayed robust activity against M. tuberculosis, aligning with the selective efficacy of spectinamides. The study also found that trospectomycin is susceptible to efflux in M. tuberculosis and M. abscessus. These findings contribute to the understanding of the structure-activity relationship of spectinomycin analogs and can guide the design and synthesis of more effective spectinomycin compounds.

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Section: Ribosomal Inhibition Assaysmentioning

confidence: 99%

Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

Dharuman,

Phelps,

Dunn

et al. 2024

J Antibiot

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Asymmetric transfer hydrogenation of fluorinated ketone and imine derivatives: An efficient access to valuable building blocks

Bacheley,

Guillamot,

Phansavath

et al. 2024

Tetrahedron

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Enantioselective Transfer Hydrogenation of α-Methoxyimino-β-keto Esters

Tharra,

Švejkar,

Jadhav

et al. 2024

J. Org. Chem.

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α-Methoxyimino-β-keto esters are reported to undergo highly enantioselective catalytic transfer hydrogenation using the Noyori−Ikariya complex RuCl(p-cymene)[(S,S)-Ts-DPEN] in a mixture of formic acid−triethylamine and dimethylformamide at 25 °C. The experimental study performed on over 25 substrates combined with computational analysis revealed that a Z-configured methoxyimino group positioned alpha to a ketone carbonyl leads to higher reactivity and mostly excellent enantioselectivity within this substrate class. Density functional theory calculations of competing transition states were used in rationalizing the origins of enantioselectivity and the possible role of the methoxyimino group in the reaction outcome.

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Short Synthesis of (+)‐Actinobolin: Simple Entry to Complex Small‐Molecule Inhibitors of Protein Synthesis

Cited by 6 publications

References 48 publications

Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

Asymmetric transfer hydrogenation of fluorinated ketone and imine derivatives: An efficient access to valuable building blocks

Enantioselective Transfer Hydrogenation of α-Methoxyimino-β-keto Esters

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