The role and significance of unconventional hydrogen bonds in small molecule recognition by biological receptors of pharmaceutical relevance.

The discovery and optimization of nonbonded interactions, such as van der Waals interactions, hydrogen bonds, salt bridges and the hydrophobic effect, between small molecule ligands and their receptors is one of the main challenges in rational drug discovery. As the theory of molecular interactions advances more evidence accumulates that nonbonded interactions, such as unconventional hydrogen bonds (X-H...Y interactions, where X can be either C, N or O atom and Y can be either an aromatic ring system O or F atom), contribute to ligand recognition by biological receptors. This review provides an overview of unconventional hydrogen bonds between ligands and their receptors of pharmaceutical relevance by dissecting their structure activity relationships and 3D structural elements. Gaining an understanding of the energetic and the structural properties of unconventional hydrogen bonds in ligand-receptor interactions leads us to the elucidation of their practical significance. Ultimately, this enables us to consciously apply these interactions in hit and lead optimization in rational structure based drug design.

Biosynthetic studies on the alpha-glucosidase inhibitor acarbose: the chemical synthesis of isotopically labeled 2-epi-5-epi-valiolone analogs.

2-epi-5-epi-valiolone is a cyclization product of the C(7) sugar phosphate, sedoheptulose 7-phosphate, involved in the biosynthesis of the aminocyclitol moieties of acarbose, validamycin, and pyralomicin. As part of our investigation into the pathway from 2-epi-5-epi-valiolone to the valienamine moiety of acarbose, we prepared 1-epi-5-epi-(6-(2)H(2))valiolol [(6-(2)H(2))-6], 5-epi-(6-(2)H(2))valiolol [(6-(2)H(2))-17], 1-epi-2-epi-5-epi-(6-(2)H(2))valiolol [(6-(2)H(2))-12] and 2-epi-5-epi-(6-(2)H(2))valiolamine [(6-(2)H(2))-11]. Compounds (6-(2)H(2))-6 and (6-(2)H(2))-17 were synthesized from 2,3,4,6-tetra-O-benzyl-D-glucopyranose in 10 and seven steps, respectively, whereas (6-(2)H(2))-12 and (6-(2)H(2))-11 were synthesized from 2,3,4,6-tetra-O-benzyl-D-mannopyranose in eight and 10 steps, respectively.

Biosynthesis of the cyclitol moiety of pyralomicin 1a in Nonomuraea spiralis MI178-34F18.

The biosynthetic pathway leading to the cyclitol moiety of pyralomicin 1a (1) in Nonomuraea spiralis MI178-34F18 has been studied using a series of 2H-labeled potential precursors. The results demonstrate that 2-epi-5-epi-valiolone (7), a common precursor for acarbose (4) and validamycin A (5) biosynthesis, is an immediate precursor of pyralomicin 1a. 5-epi-Valiolone (8) was also incorporated into 1, albeit less efficiently than 7. Other potential intermediates, such as valiolone (9), valienone (10), valienol (11), 1-epi-valienol (12), 5-epi-valiolol (13), and 1-epi-5-epi-valiolol (14) were not incorporated into pyralomicin 1a. To explain this surprising observation, it is proposed that either 2-epi-5-epi-valiolone (7) is specifically activated (e.g., to its phosphate) and that the further transformations take place on activated intermediates (which can not be generated directly from their unactivated counterparts), or that the transformation of 7 into 1 involves a substrate-channeling mechanism in which enzyme-bound intermediates are directly transferred from one enzyme active site to the next in a multi-enzyme complex.

Biosynthetic studies on the alpha-glucosidase inhibitor acarbose: the chemical synthesis of dTDP-4-amino-4,6-dideoxy-alpha-D-glucose.

To study the biosynthesis of the pseudotetrasaccharide acarbose, dTDP-4-amino-4,6-dideoxy-alpha-D-glucose (3) was prepared from galactose in 16 steps. After initial protecting-group manipulations, the 6-position of galactose was deoxygenated by hydride displacement of a tosylate. Similarly a tosyl group at the 4-position was displaced upon reaction with sodium azide. Conversion of the resulting glycoside to a glycosyl phosphate was accomplished by reaction of a glycosyl trichloroacetimidate with dibenzyl phosphate. Subsequent removal of the benzyl protecting groups and reduction of the azide by hydrogenation and coupling with an activated nucleoside phosphate gave dTDP-4-amino-4,6-dideoxy-alpha-D-glucose.