4467-55-4Relevant articles and documents
Efficient access to enantiopure γ4-amino acids with proteinogenic side-chains and structural investigation of γ4- asn and γ4-ser in hybrid peptide helices
Jadhav, Sandip V.,Misra, Rajkumar,Singh, Sumeet K.,Gopi, Hosahudya N.
supporting information, p. 16256 - 16262 (2013/12/04)
Hybrid peptides composed of α- and β-amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ- and hybrid γ-peptides composed of γ4-amino acids are less studied than their β-counterparts. However, recent investigations reveal that γ4-amino acids have a higher propensity to fold into ordered helical structures. As amino acid side-chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ4-residues with functional proteinogenic side-chains and their structural analysis in hybrid-peptide sequences. Here, the efficient and enantiopure synthesis of various N- and C-terminal free-γ4-residues, starting from the benzyl esters (COOBzl) of N-Cbz-protected (E)-α,β-unsaturated γ-amino acids through multiple hydrogenolysis and double-bond reduction in a single-pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ4-amino acids (γ4-Val, γ4-Leu, γ4-Ile, γ4-Thr(OtBu), γ4-Tyr, γ4-Asp(OtBu), γ4- Glu(OtBu), and γ-Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central Cγi￡ Cβ bond. To study the behavior of γ4- residues with functional side chains in peptide sequences, two short hybrid γ-peptides P1 (Ac-Aib-γ4-Asn-Aib-γ4-Leu- Aib-γ4-Leu-CONH2) and P2 (Ac-Aib- γ4-Ser-Aib-γ4-Val-Aib-γ4-Val- CONH2) were designed, synthesized on solid phase, and their 12-helical conformation in single crystals were studied. Remarkably, the γ4-Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side-chain amide groups. Furthermore, the hydroxyl side-chain of γ4-Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ4-residues in peptide single-crystals reveal that the γ4-residues in 12-helices are more ordered as compared with the 10/12- and 12/14-helices. Copyright
In the search for new anticancer drugs. XXIV: Synthesis and anticancer activity of amino acids and dipeptides containing the 2-chloroethyl- and [N'- (2-chloroethyl)-N'-nitroso]-aminocarbonyl groups
Sosnovsky,Prakash,Rao
, p. 1 - 10 (2007/10/02)
A series of L,L-(42, 44, 46, and 60) and D,D-(43, 45, 47, and 61) dipeptide derivatives composed of phenylglycine, phenylalanine, homophenylalanine, and valine and containing a 2-chloroethylamino group at the C-terminus and an N'-(2-chloroethyl)-N'-nitrosoaminocarbonyl group at the N-terminus of the dipeptides were prepared. The dipeptide derivatives (42- 47, 60, and 61) were first evaluated in vivo for their anticancer activities against the murine lymphocytic leukemia P388. Compounds 42, 44, 46, and 60 possessed activities ranging from 46 to 111 percent increase in life span (%ILS), whereas 43 was marginal (%ILS = 31) and 45, 47, and 61 were inactive. In general, the L,L-series exhibited low to good activity (%ILS = 46-111), whereas the corresponding D,D-series, except for 43 (%ILS = 31), was devoid of activity. The analogously structured monoamino acid derivatives of L- alanine (74), L-phenylalanine (75), and L-aspartic acid (76) exhibited higher activity against P388 than the dipeptide derivatives (i.e., 481, 297, and 481 %ILS, respectively). The more active representatives of dipeptides (i.e., 42, 44, and 60) and the amino acids derivatives 74-76 were then tested in vivo against the murine lymphoid leukemia L1210. Compounds 42, 44, and 60 exhibited either low or marginal activity (i.e., the %ILS values were 46, 31, and 26, respectively). Compounds 74, 75, and 76 possessed low to moderate activity, as evidenced by the %ILS values of 56, 48, and 64, respectively. The %ILS parameters obtained against the P388 and L1210 tumor lines were correlated with the corresponding lipophilicities, and there is a trend towards higher activity with concomitant decrease in hydrophobicity.
