Synthesis and protein degradation capacity of photoactivated enediynes.
[structure: see text] The viability of proteins as targets of thermally and photoactivated enediynes has been confirmed at the molecular level. Model studies using a labeled substrate confirmed the efficacy of atom transfer from diyl radicals produced from enediynes to form captodatively stabilized carbon centered aminoacyl radicals, which then undergo either fragmentation or dimerization. To exploit this finding, a family of enediynes was developed using an intramolecular coupling strategy. Derivatives were prepared and used to target specific proteins, showing good correlation between affinity and photoinduced protein degrading activity. The findings have potential applications in the design of artificial chemical proteases and add to our understanding of the mechanism of action of the clinically important enediyne antitumor antibiotics.
Fouad
Farid S
FS
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA.
Wright
Justin M
JM
Plourde
Gary
G
Purohit
Ajay D
AD
Wyatt
Justin K
JK
El-Shafey
Ahmed
A
Hynd
George
G
Crasto
Curtis F
CF
Lin
Yiqing
Y
Jones
Graham B
GB
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D006801:Humans; D015394:Molecular Structure; D009113:Muramidase / Q000737:chemistry* / Q000378:metabolism; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000475:Alkenes; D000480:Alkynes; D017319:Photosensitizing Agents; D011960:Receptors, Estrogen; D012710:Serum Albumin, Bovine; D009113:Muramidase