Design and Synthesis of .ALPHA.-Glucosidase Inhibitor Having DNA Cleaving Activity

Abstract

The cell is perturbed by environmental stress conditions. In order to avoid cell death from the stress, cells must sense and respond to stress, including viral infection, genetic mutation, chemical insult, and nutrient depletion. 1) In the ER, stress is a condition that accumulates mis-folded or unfolded proteins by disturbing these ER circumstances. Specific response programs are activated to circumvent each type of stress. The ER stress induces a coordinated adaptive program called the unfolded protein response (UPR). 2) The UPR is activated upon disruption of the ER environment by such events as the inhibition of Nlinked oligosaccharide processing, which results in the accumulation of unfolded or misfolded proteins in the ER. 3) NLinked oligosaccharide processing is carried out by ER glucosidases I and II. Both enzymes are key enzymes in the biosynthesis of Nlinked oligosaccharides that catalyze the first processing event after the transfer of Glc3Man9GlcNAc2 to proteins. 4) The inhibition of ER glu-cosidases induces the accumulation of unfolded proteins in the ER, and increases ER stress. The UPR caused by ER stress is insulted due to DNA damage, and the cell is led to apoptosis. Apoptosis targets are currently being explored for antitumor agent discovery, such as the tumor necrosis factor (TNF)related apoptosisinducing ligand (TRAIL) receptors, the BCL2 family of antiapoptotic proteins, and inhibitor of apoptosis (IAP) proteins. 1,5) We think that the inhibition of ER glucosidases can be used to trigger ER stress, and that the ER stress may trigger the UPR. Further, following interruption of the UPR by DNA damage, the cell is led to apoptosis. We think that compounds that have αglucosidase inhibitory activity and DNA breakage activity may be developed into an ER targeted small molecule apoptosis inducer for use as an antitumor agent. We have already elucidated the molecular recognition properties 613) and the inhibition 13,14) of α glycosidases necessary for the molecular design of gly-cosidase inhibitors using synthetic probes. Based on our knowledge, we designed compounds 112 to have α glucosidase inhibitory activity and DNA breakage activity (Fig. 1). The enzymatic liberation of the aglycon from compounds 112 might be followed by the ejection of a R 2 SO2H with the concomitant formation of pbenzoqui-none or pbenzoquinone imine, 15) which would then generate reactive oxygen species (ROS), leading to DNA breakage, 16) shown in Fig. 2. The group of Taylar et al. has developed a series of 4(sulfonylamino)phenyl αD glucopyranosides. 15) These compounds have been reported to act as competitive yeast αglucosidase inhibitors. We suspect that these compounds may also be enhanced in their inhibitory activity by changing the sulfonamide of 4 (sulfonylamino)phenyl αDglucopyranoside to sulfonate, since the liberation of pbenzoquinone is easier than that of pbenzoquinone imine. In this report, we first describe the design and synthesis series of 4sulfonylphenyl αDglucopyranoside derivatives 16 and 4(sulfonylamino)phenyl αDglucopyrano-side derivatives 712. These compounds 112 were evaluated with regard to their ability to inhibit three kinds of αglucosidases, and the effects of αglucosidase triggered Abstract: Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The present study was designed to explore small molecule apo-ptosis inducers for antitumor agents. The synthesis of 4-sulfonylphenyl α-D-glucopyranoside derivatives 16 and 4-(sulfonylamino)phenyl α-D-glucopyranoside derivatives 712, endoplasmic reticulum (ER)-targeted small molecules that were designed to induce apoptosis from ER stress by ER glucosidase inhibition and DNA damage is described. Compounds 6 and 12, with a terminal 2-naphthyl group, indicated inhibitions of α-glucosidases from S. cerevisiae (IC50=51.7 µM and IC50=74.1 µM) and B. stearothermophilus (IC50=60.1 µM and IC50=89.1 µM). Moreover, compound 12 strongly induced the DNA strand breakage condition. When compounds 112 were assayed for their ability to inhibit processing by glucosidases at the cellular level, no effects on glycoprotein processing were observed.