Solid-phase synthesis of tetrahydro-1,4-benzodiazepine-2-one derivatives as a beta-turn peptidomimetic library.
The beta-turn has been implicated as an important conformation for biological recognition of peptides or proteins. We adapted the concept of general Calpha atom positioning from the cluster analysis and recombination of each ideal beta-turn conformation pattern by Garland and Dean (J. Comput.-Aided Mol. Des. 1999, 13, 469) as one strategy of designing non-peptide beta-turn scaffolds. Herein, the Calpha positions of tetrahydro-1,4-benzodiazepin-2-one scaffold were analyzed after the calculation of the low-energy conformer using a semiempirical protocol. Three points of corresponding Calpha carbons for diverse substitutions in the scaffold were designated, and an efficient solid-phase synthesis of the peptidomimetic library was developed. The scaffold itself was synthesized in solution phase starting from 5-hydroxy-2-nitrobenzaldehyde and loaded to the 4-formyl-3,5-dimethoxyphenoxy (PL-FDMP) resin with high efficiency of reductive amination. Various building blocks for the derivatization of the 7-hydroxyl and N-1 amide nitrogen could be introduced via selective alkylation. Cleavage, parallel column chromatography, and NMR analysis of 62 final compounds confirmed the feasibility of this peptidomimetic library synthesis.
Im
Isak
I
Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
Webb
Thomas R
TR
Gong
Young-Dae
YD
Kim
Jae-Il
JI
Kim
Yong-Chul
YC
D000478:Alkylation; D000577:Amides / Q000737:chemistry; D000586:Amination; D001570:Benzodiazepinones / Q000138:chemical synthesis*; D002244:Carbon / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis*; D012117:Resins, Synthetic
D000577:Amides; D001570:Benzodiazepinones; D019151:Peptide Library; D010455:Peptides; D012117:Resins, Synthetic; D002244:Carbon