Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors - Carbohydrate Chemistry: Chemical and Biological Approaches - page 434

O

90 , R = OH

HO 2 C

R

91

, R = D-Ala
92 , R = D-Ala-D-Ala NH 2

HN

O

O

peptide

O

O

O

O N

OH

O

O

HO
HO

HO 2 C H O

O NHAc

O

O

NHAc

HO NHAc

Natural compound

89

Fig. 26 Structures of the natural metabolite 89 and 1,6-anhydromuramyl derivatives
90-92.

transglycosylases. 117 Located in the periplasm, these enzymes degrade
the cell wall giving, as a major product, N-acetyl-b- D -glucosamine-(1

- 4)-

1,6-anhydro-N-acetyl-b- D -muramyl-peptide (Fig. 26).
Recently, Mobashery and co-workers described the synthesis of 1,6-
anhydromuramyl derivatives (90-92) and their utilization as substrates
with enzymatic reaction with the transglycosylase AmpD (Fig. 26). 118
Interestingly, by mimicking the natural metabolite 89, these compounds
decrease the activity of turn-over of the cell wall due to their ability to be
good substrates for AmpD. Thus, the metabolite 89 cannot be produced
anymore, resulting in the degradation of the cell-wall. 119 Other examples
of 1,6-anhydromuramyl derivatives, described by the same team, were
also reported acting by the same process. 117c,120

3.7 RAS inhibitors
Ras proteins are GTP-binding proteins; they play a significant role
in signaling pathways that control cell growth and differentiation. It
was proved that the mutated Ras protein was found in about 20-30% of
human tumors. 121 Their inhibition thus represents a potentially
powerful strategy for preventing tumors formation and growth. In 1997,
the Schering-Plough Research Institute developed Ras inhibitors. 122
The most potent of those compounds inhibited Ras activation with
an activity in the lower mMrange.Moreover,Nicotraet al. described
a bicyclic scaffold derived from the natural sugar D -arabinose
(Fig. 27). 123
The common bicyclic moiety is a conformationally rigid scaffold able
to orient the pharmacophores (the hydroxyl, amino and the two aromatic
groups) in a spatial arrangement potentially suitable for interaction with
Ras protein. 124 NMR spectroscopic studies indicated major interaction of
the aromatic residues with Ras protein, whilst the bicyclic moiety acts as
scaffold to provide the orientation and the required solubiliy. In addition,
these molecules behaved differently during in vitro assays on p21 h-Ras:
whilst 93b and 94b are more potent in blocking nucleotide exchange,
compound 95b is the strongest inhibitor of the GDP dissociation.
Moreover, only amide containing molecules 95b and 96b are active in
inhibiting cellular growth in both normal and k-Ras-transformed mam-
malian cells. 125