Constrained Glu‐Gly and Gln‐Gly dipeptide surrogates from γ‐substituted α‐amino‐δ‐lactam synthesis

Ramakotaiah Mulamreddy and William D. Lubell*

Département de Chimie, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal H3C 3J7 QC, Canada

Abstract:

In the context of studies of biologically active peptides towards the design of peptidomimetics, alpha-amino-delta-lactams (Adl) have been used as conformationally constrained analogs in structure-activity relationships and biological studies [1]. For example, enhanced selectivity and oral bioavailability were achieved by replacement of the D-Phe-Pro residue by (S)-Adl-Gly in thrombin inhibitors [2]. Ring substituted Adl analogs have been pursued to mimic both backbone and side-chain geometry in peptide structures such as b-turns [3]. Our presentation will describe the synthesis of gamma-substituted Adl analogs [4].

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2. Semple, J. E. et al. Design, synthesis, and evolution of a novel, selective, and an orally bioavailable class of thrombin inhibitors: P1-argininal derivatives incorporating P3-P4 lactam sulfonamide moieties J. Med. Chem. 1996, 39, 4531.
3. Zydowsky, T. M.; Dellaria Jr, J. F.; Nellans, H. N. Efficient and versatile synthesis of dipeptide isosteres containing. gamma- or delta-lactams. J. Org. Chem. 1988, 53, 5607-5616.
4. Mulamreddy, R.; Lubell W. D. Constrained Glu‐Gly and Gln‐Gly dipeptide surrogates from γ‐substituted α‐amino‐δ‐lactam synthesis Peptide Sci. 2020, 12, e24149.