端霉素完整立体化学的修订,Organic Chemistry Frontiers

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端霉素完整立体化学的修订
Organic Chemistry Frontiers ( IF 4.6 ) Pub Date : 2023-11-23 , DOI: 10.1039/d3qo01411h
Sandra Resa ₁ , Marta González ₁ , Fernando Reyes ₁ , Ignacio Pérez-Victoria ₁

Affiliation

Telomycin 是 20 世纪 50 年代末发现的一种非核糖体环缩酚肽抗生素，最近被证明基于与细菌二聚磷脂心磷脂的特定相互作用，显示出独特的溶解作用模式。值得注意的是，涉及端霉素和相关同系物的化学结构和自然存在的参考书目揭示了重要的矛盾，这些矛盾对目前接受的这种抗生素的所有L -氨基酸立体化学提出了质疑。_{此外，其 β-MeTrp 残基的 C β}构型仍未确定，其 Δ _2,3 -Trp 残基的烯烃几何结构同样需要澄清。因此，需要对端霉素氨基酸的相对和绝对立体化学进行全面修订，还包括明确确定这种令人兴奋的抗生素中存在的非对映体残基的序列位置。在此，我们通过对其非核糖体肽合成酶序列进行基于系统发育的生物信息学分析，确定了端霉素生物合成中涉及的典型缩合结构域的对映选择性，并且我们还通过 NMR 和先进的 Marfey 方法进行了严格的手性氨基酸分析，以明确地确定抗生素的正确结构和绝对立体化学，从而对端霉素家族进行明确的立体化学修正。

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Revision of the full stereochemistry of telomycin

Telomycin, a nonribosomal cyclic depsipeptide antibiotic discovered in the late 1950s, has recently been shown to display a unique lytic mode of action based on a specific interaction with the bacterial dimeric phospholipid cardiolipin. Noticeably, the bibliography dealing with the chemical structure and natural occurrence of telomycin and related congeners reveals important contradictions that put into question the currently accepted all L-amino acid stereochemistry for this antibiotic. Furthermore, the configuration at C_β of its β-MeTrp residue remains undetermined and the olefin geometry of its Δ_2,3-Trp residue likewise demands clarification. A full revision of the relative and absolute stereochemistry of telomycin amino acids, also including the unambiguous determination of the sequence position of the diastereomeric residues present in this exciting antibiotic, was thus needed. Herein, we have ascertained the enantioselectivity of the canonical condensation domains involved in telomycin biosynthesis by phylogeny-based bioinformatic analysis of its nonribosomal peptide synthetases sequence and we have also carried out rigorous chiral amino acid analysis, by NMR and the advanced Marfey's method, to unequivocally determine the correct structure and absolute stereochemistry of the antibiotic, leading to a definitive stereochemical revision of the telomycin family.

更新日期：2023-11-23

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