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Novel Acyclic Deoxystreptamine Mimetics Targeting the Ribosomal Decoding Site
Author(s) -
Vourloumis Dionisios,
Winters Geoffrey C.,
Takahashi Masayuki,
Simonsen Klaus B.,
Ayida Benjamin K.,
Shandrick Sarah,
Zhao Qiang,
Hermann Thomas
Publication year - 2003
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200300688
Subject(s) - pharmacophore , aminoglycoside , ribosomal rna , translation (biology) , sisomicin , rna , computational biology , chemistry , ribosome , biology , stereochemistry , biochemistry , antibiotics , gentamicin , tobramycin , messenger rna , gene
Two scaffolds, one target : The bacterial ribosomal decoding site is the target for natural aminoglycoside antibiotics, which bind to an internal RNA loop and thereby interfere with translation fidelity. Synthetic aminoglycoside mimetics are thought to display similar antibiotic activity while avoiding established bacterial resistance mechanisms. We describe two complementary approaches towards novel aminoglycoside mimetics that recognize the decoding‐site RNA and inhibit bacterial translation. In the first study, elements of both rational structure‐based design and diversity‐driven exploration were used to synthesize flexible acyclic mimetics ( I a , b ) of 2‐deoxystreptamine. The second paper outlines the accurate replacement of the 2‐deoxystreptamine pharmacophore by stereochemically defined aminomethyl–piperidine scaffolds ( II a , b ).