Synthesis of Somatostatin Mimetics Based on 1‐Deoxynojirimycin

Abstract

The synthesis of novel somatostatin mimetics from 1-deoxynojirimycin (DNJ) is described. The dipeptide mimetic, which respectively displayed the side chains of tryptophan and lysine at the nitrogen and O6 atoms of the iminosugar scaffold is a ligand (K(i)=3.2 microM) for the human somatostatin receptor subtype 4 (hSSTR4) but has lower affinity (K(i)>100 microM) for hSSTR5. A benzylated analogue of the Trp-Lys mimetic displays higher affinity for hSSTR5 (K(i)=5 microM).

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

“…Analogue 21 confirms that the presence of an aromatic moiety at the N-terminus is not necessary for binding to sst 4 and sst 5 . An iminosugar based sst 4 -selective mimetic with affinity in the micromolar range was very recently reported by Chagnault et al 30 Adding a benzyl substituent resulted in a substantial increase in sst 5 affinity, indicating that this aromatic residue makes an important binding interaction with sst 5 but not with sst 4 . In our case, removing the aromatic moiety at the N-terminus does not have any influence on sst 4 or sst 5 binding affinities.…”

Total Synthesis of Hapalindole‐Type Natural Products

“…We made recourse to the free boronic acids. [16] Treatment of known aldehyde 29 [17] with cis boronic acid 30 [16] in liquid NH 3 [15] provided amine 31 (53 % yield, ca. 10:1 d.r.…”

“…We applied the above strategy and method to the synthesis of racemic hapalindole H [5b] and hapalonamide H (Scheme 4). Compound 36 was constructed from 30 and 4-Br-29 [17,18] (39 % yield) in a similar fashion to that described above. The cyclization afforded compound 37 (58 % yield), which was subjected to Barans conditions for reductive Heck annulation.…”

Somatostatin Receptor-4 Agonists as Candidates for Treatment of Alzheimer’s Disease

“…The β-D-glucose analogue 1 contained the Phe7, Trp8, and Lys9 functional groups in a similar spatial orientation as octreotide; however, the compound demonstrated only weak binding in AtT-20 cells [89]. Using iminosugars based on the structure of 1-deoxymannojirimycin, Murphy and co-workers [93,94] prepared SRIF-mimetics 4-6 (Fig. Introduction of an (imidazol-4-yl)methyl group at C-2 and a (pyridine-3-yl)methyl moiety at C-4 gave the β-D-glucose analogue 3.…”