Cyclodepsipeptides represent a distinctive family of natural cyclic peptides endowed with diverse and potent biological activities,making them promising scaffolds for drug development and agrochemical applications.Inc...Cyclodepsipeptides represent a distinctive family of natural cyclic peptides endowed with diverse and potent biological activities,making them promising scaffolds for drug development and agrochemical applications.Incorporation of N-methylated amino acids further enhances their metabolic stability and oral bioavailability by resisting proteolytic degradation.However,the synthesis of such cyclodepsipeptides,especially those containing multiple sterically hindered N-methylated residues,remains a significant challenge for conventional solid-phase peptide synthesis(SPPS)due to inefficient on-resin acylation,sluggish coupling kinetics,and conformational constraints.Herein,we report the first successful application of a novel solid-phase peptide synthesis(SPPS)strategy based on immobilized ribosome-mimicking molecular reactors(RMMRs)for the efficient synthesis of two representative bioactive cyclodepsipeptides:destruxin B(a hexadepsipeptide with two consecutive N-methylated amino acids)and[2S,3S-Hmp]-aureobasidin L(a nonapeptide featuring four N-methylated amino acids).A crucial approach is the use of pre-assembled depsidipeptide building blocks,which mitigate side reactions associated with on-resin esterification,combined with the RMMR platform that accelerates the coupling of sterically hindered residues via an artificial pseudo-intramolecular acyl-transfer mechanism.The linear precursors were efficiently assembled on Oxyma-C RMMR-HMPA resin with high/moderate crude purities(90%for destruxin B,45% for[2S,3S-Hmp]-aureobasidin L)and much reduced synthesis times(≈15 h and≈60 h,respectively).Subsequent solution-phase macrocyclization using HATU/DIPEA yielded the target compounds in satisfactory yields(75% for destruxin B,50% for[2S,3S-Hmp]-aureobasidin L).This robust and time-economic methodology overcomes key limitations of conventional methods,providing a broadly applicable platform for the synthesis of complex cyclodepsipeptides and facilitating future medicinal chemistry exploration of this valuable class of bioactive molecules.展开更多
基金National Natural Science Foundation(No.22450003)Jiangsu Province Natural Science Foundation Basic Research Program(No.BK20253010).
文摘Cyclodepsipeptides represent a distinctive family of natural cyclic peptides endowed with diverse and potent biological activities,making them promising scaffolds for drug development and agrochemical applications.Incorporation of N-methylated amino acids further enhances their metabolic stability and oral bioavailability by resisting proteolytic degradation.However,the synthesis of such cyclodepsipeptides,especially those containing multiple sterically hindered N-methylated residues,remains a significant challenge for conventional solid-phase peptide synthesis(SPPS)due to inefficient on-resin acylation,sluggish coupling kinetics,and conformational constraints.Herein,we report the first successful application of a novel solid-phase peptide synthesis(SPPS)strategy based on immobilized ribosome-mimicking molecular reactors(RMMRs)for the efficient synthesis of two representative bioactive cyclodepsipeptides:destruxin B(a hexadepsipeptide with two consecutive N-methylated amino acids)and[2S,3S-Hmp]-aureobasidin L(a nonapeptide featuring four N-methylated amino acids).A crucial approach is the use of pre-assembled depsidipeptide building blocks,which mitigate side reactions associated with on-resin esterification,combined with the RMMR platform that accelerates the coupling of sterically hindered residues via an artificial pseudo-intramolecular acyl-transfer mechanism.The linear precursors were efficiently assembled on Oxyma-C RMMR-HMPA resin with high/moderate crude purities(90%for destruxin B,45% for[2S,3S-Hmp]-aureobasidin L)and much reduced synthesis times(≈15 h and≈60 h,respectively).Subsequent solution-phase macrocyclization using HATU/DIPEA yielded the target compounds in satisfactory yields(75% for destruxin B,50% for[2S,3S-Hmp]-aureobasidin L).This robust and time-economic methodology overcomes key limitations of conventional methods,providing a broadly applicable platform for the synthesis of complex cyclodepsipeptides and facilitating future medicinal chemistry exploration of this valuable class of bioactive molecules.
