Synthesis and Use of Pseudopeptides Derived from 1,2,4-Oxadiazole-, 1,3,4-0xadiazole-, and 1,2,4-Triazole-based Dipeptidomimetics

Abstract

This chapter focuses on the isosteric replacement of peptide bonds with three different types of heterocyclic ring systems (1); 1,2,4-oxadiazole (2), 1,3,4-oxadiazole (3), and 1,2,4-triazole rings (4-6). The ring systems are similar in size and shape but show variations in aromatic, electrostatic, and hydrogen bonding properties. These variations provide opportunities to study properties of importance for amide bond mimicry. The derivatives are synthesized from protected natural amino acids, and the reaction conditions have been chosen so that the enantiopurity is retained during the reaction sequences. Two series of mimetics will be described, one in which the carboxylic acid functionality is directly attached to the heterocyclic ring (1) and one series with a methylene group inserted between the ring and the carboxylic acid group (7). Since we have focused on the design and synthesis of Phe-Gly mimetics, the synthetic examples described here start from L: -phenylalanine. However, we have used the same synthetic scheme also for other amino acids and notes will be given when other derivatives require differences in reaction conditions (1). The use of the dipeptidomimetics as building blocks in pseudopeptide synthesis will also be described (7). These syntheses are performed on solid phase using Boc-chemistry. Also, the deprotection and purification of the pseudopeptides by reversed phase HPLC will be discussed.

Small molecule peptidomimetic trypsin inhibitors: validation of an EKO binding mode, but with a twist

“…2a). These fivemembered rings may be saturated (illustrative [13][14][15][16][17][18][19][20][21][22][23][24] ) or unsaturated (e.g. ref.…”

Design, semisynthesis and cytotoxic activity of novel ester derivatives of betulinic acid-1,2,4 oxadiazoles

“…In addition, anticancer activity of some 3,5-disubstituted-1,2,4-oxadiazoles has recently been reported [16]. The 1,2,4-oxadiazoles are also widely used as heterocyclic amide or ester bioisosteres [17] and in the design of dipeptidomimetics as peptide building blocks [18].…”

“…The use of Cs 2 CO 3 in the preparation of esters from betulinic acid and alkyl halides is known [19]. The process has been applied here for the synthesis of betulinic acid-oxadiazole esters (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The synthesized compounds were screened for their in vitro cytotoxicity against three human cancer cell lines.…”

The design and synthesis of Ala-Glu/iGln mimetics: heterocyclic building blocks for pseudopeptides

“…2 In the context of bioisosterism, it has long been known that the 1,2,4-oxadiazole moiety can be used as a non-classical bioisostere of the ester/amide moiety, and its use as a peptide bond replacement in the construction of peptide mimics has been widely reported. [3][4][5][6] While peptides in general are susceptible to metabolic degradation, 1,2,4-oxadiazole-containing surrogates are, in many cases, as active as the parent peptide but exhibit greater metabolic stability than their ester/amide counterparts. [3][4][5] Further, several amino acid derived 1,2,4-oxadiazole compounds have been described.…”

“…[3][4][5][6] While peptides in general are susceptible to metabolic degradation, 1,2,4-oxadiazole-containing surrogates are, in many cases, as active as the parent peptide but exhibit greater metabolic stability than their ester/amide counterparts. [3][4][5] Further, several amino acid derived 1,2,4-oxadiazole compounds have been described. [6][7][8][9][10][11] The L-Ala-D-iGln/D-Glu dipeptide motif is present in several bioactive compounds, in particular in agonists of intracellular pattern recognition receptors, nucleotide-binding oligomerization domains (NOD1 and NOD2), as well as in Mur ligase inhibitors.…”