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This rich structural diversity enables HS to interact with many proteins and regulate key signaling pathways. Efforts to understand structure\u2010function relationships and harness the therapeutic potential of HS are hindered by the inability to synthesize an extensive library of well\u2010defined HS structures. We herein report a rational and expedient approach to access a library of 27 oligosaccharides from natural aminoglycosides as HS mimetics in 7\u201312 steps. This strategy significantly reduces the number of steps as compared to the traditional synthesis of HS oligosaccharides from monosaccharide building blocks. Combined with computational insight, we identify a new class of four trisaccharide compounds derived from the aminoglycoside tobramycin that mimic natural HS and have a strong binding to heparanase but a low affinity for off\u2010target platelet factor\u20104 protein.<\/jats:p>","DOI":"10.1002\/anie.202304325","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T14:06:34Z","timestamp":1686146794000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9376-0056","authenticated-orcid":false,"given":"Joseph","family":"Wakpal","sequence":"first","affiliation":[{"name":"Department of Chemistry Wayne State University  Detroit MI 48202 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