Heterocyclic-Dithol Click Chemistry

INV-18001

 

As exemplified by thiolate-ene “click” chemistry, the unique properties of thiolates enable highly selective reactions. Dithiol-diene reaction partners can template high order structures and are employed (in vitro) in polymer syntheses, in biochemical probes, and to stabilize proteins. Unfortunately, ‑enes react with a myriad of essential protein cysteine residues, resulting in toxicity that limits their applicability in vivo. 

 

This invention has a more biocompatible method for crosslinking thiolate pairs. Northeastern University researchers reasoned that cyclic thiosulfinates – S-oxo derivatives of well-tolerated cyclic disulfide natural products – would selectively crosslink dithiols by the following mechanism. 

A nucleophilic attack by thiolateA upon the thiosulfinate disulfide results in thiolate-disulfide interchange concomitant to ring cleavage, and a disulfide tethered terminal sulfenic acid moiety. Next, a nucleophilic attack by thiolateB on the sulfenic sulfur results in the formation of a second disulfide bond coupled to the release of water and a crosslink. This could include crosslinking two molecules via their two (respective) thiol functionalities, using cyclic thiosulfinates or crosslinking two molecules, via their respective cyclic thiosulfinate functionalities, using a crosslinker endowed with a pair of dithiols. 

 

- Analogous reactions to using dienes (or other commonly used electrophiles) to crosslink thiols 

- Most of the attributes of click chemistry including orthogonality with other protein functional groups, high reaction yields, rapid reactions, stereoselectivity, compatibility with aqueous solvents, and a ring strain-dependence that is orders of magnitude higher than existing period 2 element systems 

 

- Biopolymers

- Self-healing biopolymers

- Biocompatible hydrogels

- Functionalized surfaces

- Wound healing

- Surgical site healing

- Implants

 

- License

- Partnering

- Research collaboration