title: Rational design of a supra C-1027: kinetically stabilized analogue of the antitumor enediyne chromoprotein.
abstract: C-1027, an extremely potent antitumor agent, is composed of a highly reactive chromophore and an apoprotein. While the chromophore causes DNA cleavage, the apoprotein functions as its carrier. Despite these ideal properties as an anticancer agent, C-1027 slowly self-decomposes through chromophore-mediated abstraction of hydrogens from the apoprotein. In this paper, we report the design and preparation of an engineered C-1027 apoprotein that decelerates this self-decomposition pathway. Our design is based on the kinetic isotope effect, and deuterium is incorporated instead of protium into the hydrogen-abstraction site. The deuterated supra C-1027 was found to have a 4-fold longer lifetime than the natural C-1027.
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Toyonobu
authors.initials: T
authors.lastname: Usuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D001059:Apoproteins / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000737:chemistry / Q000235:genetics; D004355:Drug Stability; D053281:Enediynes; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives; D007700:Kinetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D001059:Apoproteins; D053281:Enediynes; D011994:Recombinant Proteins; C058024:C 1027; D005998:Glycine