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. 2024 Aug 26;29(17):4028.
doi: 10.3390/molecules29174028.

A Convenient Synthesis of Short α-/β-Mixed Peptides as Potential α-Amylase Inhibitors

Naeem Ahmed  1 , Fakhira Razzaq  1   2 , Muhammad Arfan  1 , Mansour K Gatasheh  3 , Hammad Nasir  1 , Joham Sarfraz Ali  4 , Hamna Hafeez  1
Affiliations

A Convenient Synthesis of Short α-/β-Mixed Peptides as Potential α-Amylase Inhibitors

Naeem Ahmed et al. Molecules. .

Abstract

Over the last decades, the increased incidence of metabolic disorders, such as type two diabetes and obesity, has motivated researchers to investigate new enzyme inhibitors. Inhibition of the α-amylase enzyme is one therapeutic approach in lowering glucose levels in the blood to manage diabetes mellitus. The objective of this study was to synthesize short α-/β-mixed peptides in the solution phase. The Boc-protected α-L-leucine was converted to β-analogue by using Arndt-Eistert synthesis with the advantage of no racemization and retention of configuration. Three novel short peptides were successfully synthesized: N(Boc)-Gly-β-Leu-OCH3(14), N(Boc)-O(Bz)α-Ser-β-Leu-OCH3(16), and N(Boc)-O(Bz)-α-Tyr-α-Gly-β-Leu-OCH3(17), characterized by FTIR and 1H NMR analysis. The synthesized peptide 16 showed highest inhibitory activity (45.22%) followed by peptide 14 (18.51%) and peptide 17 (17.05%), respectively. Intriguingly, peptide 16 showed higher inhibition on α-amylase compared with other α-/β-mixed peptides.

Keywords: Arndt–Eistert synthesis; postprandial hyperglycemia; α-/β-mixed peptides; β-amino acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Voglibose.
Figure 2
Figure 2
Miglitol.
Figure 3
Figure 3
Acarbose.
Figure 4
Figure 4
Benzofuran hydrazone.
Figure 5
Figure 5
Benzotriazole.
Figure 6
Figure 6
Indole hydrazone.
Figure 7
Figure 7
Structures of synthesized short α-/β-mixed peptides.
Scheme 1
Scheme 1
(i) (Boc)2O, (Et)3N, (1:1) Dioxane/Water, 8 h; (ii) Benzyl Bromide, NaH, DMF; (iii) 2M NaOH, CuSO4.5H2O, Benzyl Bromide; (iv) (Boc)2O,1N NaOH, NaHCO3, (2:1) Dioxane/Water.
Scheme 2
Scheme 2
(i) Ethyl chloroformate, Et3N, THF, N2, −15 to −5 °C, CH2N2 in ether; (ii) Silver Benzoate, Et3N, dark, −25 °C, dry MeOH; (iii) TFA dry DCM, 0 °C.
Scheme 3
Scheme 3
Synthesis of α-/β-mixed peptides: (i) EDC, HOBt, Et3N, 0 °C, CHCl3, N2, (ii) TFA, Dry CH2Cl2, N2 atmosphere.
See this image and copyright information in PMC

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