Novel N-Derivatized-7-Nitroindolines for the Synthesis of Photocleavable Crosslinkers, and for Solid Phase Peptide Synthesis

Hector Patricio Del Castillo, University of Texas at El Paso


7-Nitroindoline-based photochemistry has focused mostly on N-acyl-7-nitroindolines, which have been used as photocleavable protecting groups for carboxylic acids that can be efficiently removed by illumination with UV-light. They offer an alternative to the more commonly used o-nitrobenzyl-based photocleavable protecting groups. N-acyl-7-nitroindolines can also be used as photochemical acylating agents in inert solvents. For example, they have found application in peptide fragment condensation, the convergent synthesis of N-glycopeptides, and the synthesis of peptide thioesters, forming amide and thioester bonds with amine and thiol nucleophiles, respectively, under neutral conditions. The photochemical activation of N-acyl-7-nitroindolines can occur with UV light (λ = 350 nm) by a one-photon absorption process, or with infrared femtosecond laser light (λ = 710 nm) by a two-photon absorption mechanism. Other 7-nitroindoline-based photoreactive moieties have been reported in the literature such as 7-nitroindoline-based ureas and carbamates, which inspired our discovery of 7-nitroindoline-based thiocarbamates, or N-thiocarbamoyl-7-nitroindolines. In this work, we developed a new N-acyl-7-nitroindoline-based linker for SPPS and devised a strategy for the concomitant cleavage and cyclization of a homodetic RGD-pentapeptide on Sieber Amide resin, which was compared to the photochemical cyclization of the same peptide in solution. We also discovered the novel N-thiocarbamoyl-7-nitroindoline moiety and studied its photolysis kinetics by UV-Vis spectroscopy, and characterized its photolysis product, a 7-nitroso-indoline, to pave the way for the development of a new class of photocleavable crosslinker. Lastly, we incorporated both, N-acyl-7-nitroindoline and N-thiocarbamoyl-7-nitroindoline moieties, into three photocleavable homobifunctional crosslinkers equipped with N-hydroxysuccinimide moieties for crosslinking amine-containing polymers. These photocleavable crosslinkers can generate functional materials with the capability of crosslinking reversal by light illumination. These crosslinkers were used to crosslink gelatin type B in dimethyl sulfoxide. Upon replacement of the dimethyl sulfoxide with water, hydrogels were obtained, which can be degraded by illumination with UV-light in water. Such photoreactive hydrogels could be useful in biophotolithography applications or as biomaterials whose rigidity or softness can be changed with light.

Subject Area

Organic chemistry

Recommended Citation

Del Castillo, Hector Patricio, "Novel N-Derivatized-7-Nitroindolines for the Synthesis of Photocleavable Crosslinkers, and for Solid Phase Peptide Synthesis" (2021). ETD Collection for University of Texas, El Paso. AAI28491361.