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含叔胺基团的高级吡咯烷-氨基甲酸酯自毁间隔基诱导超快环化药物释放。

Advanced Pyrrolidine-Carbamate Self-Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release.

机构信息

Università degli Studi di Milano, Dipartimento di Chimica, via C. Golgi, 19, 20133, Milan, Italy.

Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, via G. Venezian 21, 20133, Milan, Italy.

出版信息

ChemMedChem. 2022 Aug 3;17(15):e202200279. doi: 10.1002/cmdc.202200279. Epub 2022 Jun 14.

DOI:10.1002/cmdc.202200279
PMID:35620983
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9544318/
Abstract

Amine-carbamate self-immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine-carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pK calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state-of-art analogues.

摘要

胺基-氨基甲酸酯自毁（SI）间隔物在靶向前药中是实用且多功能的工具，但它们的缓慢降解机制限制了疾病部位的药物激活。我们设计了一种带有叔胺柄的吡咯烷-氨基甲酸酯 SI 间隔物，它可以强烈加速间隔物的环化，生成双环脲和细胞毒性（喜树碱）或免疫刺激（瑞喹莫德）药物的游离羟基。计算化学构象分析和 pK 值表明，与现有类似物相比，先进的 SI 间隔物具有优越疗效的合理机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/19176c7f6c4d/CMDC-17-0-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/42792c60a7e2/CMDC-17-0-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/ace7aa54bbba/CMDC-17-0-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/36c6c0a2e78c/CMDC-17-0-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/19176c7f6c4d/CMDC-17-0-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/42792c60a7e2/CMDC-17-0-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/ace7aa54bbba/CMDC-17-0-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/36c6c0a2e78c/CMDC-17-0-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd90/9544318/19176c7f6c4d/CMDC-17-0-g002.jpg

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