Total Syntheses of Casuarine and Its 6‐O‐α‐Glucoside: Complementary Inhibition towards Glycoside Hydrolases of the GH31 and GH37 Families

Abstract

Total synthesis of naturally occurring casuarine (1) and the first total synthesis of casuarine 6-O-alpha-glucoside (2) were achieved through complete stereoselective nitrone cycloaddition, Tamao-Fleming oxidation and selective alpha-glucosylation as key steps. Biological assays of the two compounds proved their strong and selective inhibitory properties towards glucoamylase NtMGAM and trehalase Tre37A, respectively, which place them among the most powerful inhibitors of these enzymes. The structural determination of the complexes of NtMGAM with 1 and of Tre37A with 2 revealed interesting similarities in the catalytic sites of these two enzymes which belong to different families and clans.

Isolation, Biological Activities, and Synthesis of the Natural Casuarines

“…nM, respectively against Tre37A [25]. The high potency of casuarine-6-O--glucoside 2 against Tre37A is most significant.…”

“…Thus inhibitors of this enzyme may have potential as insecticides [26,27]. X-ray crystal structures of the complexes of casuarine 1 with human NtMGAM and casuarine-O--glucoside 2 with Tre37A were determined and revealed similarities in the catalytic sites of these unrelated enzymes [25]. Computer-aided docking studies of casuarine 1 into the active site of NtMGAM were consistent with the X-ray crystal structure and both studies indicated that all 5 hydroxyl groups of casuarine 1 are involved in H-bonding to amino acid residues in the active site and the protonated nitrogen atom of casuarine 1 forms a salt bridge with Asp443 [28].…”

Synthesis, Biological Evaluation and Docking Studies of Casuarine Analogues: Effects of Structural Modifications at Ring B on Inhibitory Activity Towards Glucoamylase

“…For instance, for the synthesis of casuarine (1) a good regioselectivity of the cycloaddition was assured by using dipolarophile 13 with Y = SiMe 2 Ph and X = OEt. [11] Scheme 3. General procedure for the synthesis of the pyrrolizidine alkaloids.…”

“…[10] We recently reported that casuarine (1) is able to inhibit a human maltase-glucoamylase (MGAM, EC 3.2.1.20) more strongly than the pseudo-tetrasaccharide acarbose (Scheme 1) currently on the market as an antidiabetic drug (Glucobay, Precose) and thus has promise for the development of novel anti-diabetic drugs. [11] Table 1. Structures and inhibition activities (IC 50 ) of compounds 1-11 towards glucoamylase from aspergillus niger.…”

“…[11] Glucoamylase (1,4-α--glucan glucohydrolase, GA; EC 3.2.1.3; glycoside hydrolase family GH15, www.cazy.org) is an exo-hydrolase that catalyses the removal of glucose units from the non-reducing end of starch and related oligosaccharides. The hydrolytic reaction, which preferentially occurs at α-1,4 linkages, proceeds with inversion of configuration at the anomeric carbon atom.…”