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