1. Synthesis of the novel pi-(benzyloxymethyl)-protected histidine analogue of statine. Inhibition of penicillopepsin by pepstatin-derived peptides containing different statine side-chain derivatives
J Maibaum, D H Rich J Med Chem. 1989 Jul;32(7):1571-6. doi: 10.1021/jm00127a028.
The synthesis of aspartic proteinase inhibitors derived from a new histidine side-chain analogue of statine (Sta), (3S,4S)-4-amino-3-hydroxy-5-(imidazol-4-yl)pentanoic acid (HiSta, 20), is reported. Boc-HiSta(BOM)-OMe (7) was prepared in 16% overall yield from Boc-His(pi-BOM)-OH via formation of the tetramic acid derivative 11 and stereoselective cis reduction with NaBH4 to the 4-hydroxy lactam 12. Removal of the Boc group from ester 7 (enantiomeric purity ee = 88-90%) and coupling to the tripeptide segment Iva-Val-Val-OH (13) by the DCC/HOBt preactivation method followed by hydrogenolytic removal of the pi-BOM group over Pd(OH)2 on carbon gave Iva-Val-Val-HiSta-OMe (16). This new peptide 16 is a very potent inhibitor of the fungal aspartic proteinase penicillopepsin (Ki = 4.5 x 10(-9) M) that is 10 times more active than the comparable Sta-containing inhibitor 3 and 2-3 times more potent than the new (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) analogue 17 (Ki = 1.5 x 10(-8) M). However, compound 16, which has an imidazole residue at the P1 position, is a significantly weaker inhibitor of the enzyme than the corresponding analogues with the lysine (5) and ornithine (6) side chains at P1. Considerations that led to the synthesis of 16 and the results of the enzyme kinetics are discussed in detail.
2. A 1 : 2 copper(II)-tripeptide complex for DNA binding and cleavage agent under physiological conditions
Pulimamidi R Reddy, Pallerla Manjula, Tushar K Chakraborty, Rajarshi Samanta Chem Biodivers. 2009 May;6(5):764-73. doi: 10.1002/cbdv.200800079.
A 1 : 2 copper-tripeptide complex, [Cu(II)(Boc-His-Gly-His-OMe)(2)](2+), was synthesized and structurally characterized. The absorption band at 577 nm suggests a square-planar geometry around Cu(II). The DNA-binding and DNA-cleavage properties of the Cu(II) complex were investigated. The complex binds to calf thymus DNA (CT DNA) in an intercalative fashion and cleaves plasmid pUC-19 DNA hydrolytically at micromolar concentrations under physiological conditions. The intrinsic binding constant (K(b)=1.2x10(2) M(-1)) for the binding of Cu-tripeptide complex with DNA suggests that this complex is suitable for rapid diffusion on the pharmacological time scale.
3. Side reactions in solid-phase peptide synthesis and their applications
K H Hsieh, M M Demaine, S Gurusidaiah Int J Pept Protein Res. 1996 Sep;48(3):292-8. doi: 10.1111/j.1399-3011.1996.tb00844.x.
Side reactions in peptide synthesis indicate steps needing improvement as well as opportunities for structural diversification in combinatorial design. Among the side reactions observed in this study, transesterification of Boc-Glu(OBzl) occurred in TMAH-catalyzed resin attachment, leading to Boc-DKKREE(OMe) in solid-phase synthesis of Boc-DKKREE. Acetylation of Boc-Arg(NO2)-resin occurred during resin capping with Ac2O/Et3N, leading to GPR (Ac) in GPR synthesis. His- and Lys-modification occurred during GHRPLDKKREE cleavage from resin by Pd(OAc)2-catalyzed hydrogenation in DMF. To verify these side reactions, model experiments were performed, which indicated rapid transesterification of Boc-Glu(OBzl) in methyl, isopropyl, or tert-butyl alcohol into the corresponding ester by TMAH, but studies of acetylation showed that both Boc-Arg(NO2) and Boc-Arg(Tos) were stable to Ac-Im treatment, but were modified by Ac2O/Et3N. Since transfer hydrogenation of Boc-His(Bzl) and Boc-Lys(Z) in HCOOH or ammonium formate did not generate the formylated side-products of catalytic hydrogenation, DMF and not its decomposed product, HCOOH, appeared involved in side-chain modification. Elimination of the side reactions, by using Cs-derived Boc-Glu(OBzl)-resin for peptide synthesis and catalytic hydrogenation in NMP-HOPr for peptide cleavage, increased the GHRPLDKKREE yield by 1/3. On the other hand, the side reactions provided modified peptides, whose bioassays revealed different importance of the modified side-chains.
