Glucose-based spiro-heterocycles as potent inhibitors of glycogen phosphorylase

Abstract

Glucopyranosylidene-spiro-1,4,2-oxathiazoles were prepared in high yields by NBS-mediated spiro-cyclization of the corresponding glucosyl-hydroximothioates. In an effort to synthesize analogous glucopyranosylidene-spiro-1,2,4-oxadiazolines, with a nitrogen atom instead of the sulphur, attempted cyclizations resulted in aromatization of the heterocycle with opening of the pyranosyl ring. Enzymatic measurements showed that some of the glucose-based inhibitors were active in the micromolar range. The 2-naphthyl-substituted 1,4,2-oxathiazole displayed the best inhibition against RMGPb (K(i)=160 nM), among glucose-based inhibitors known to date.

Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as potential inhibitors of glycogen phosphorylase

“…Ring closure of the thiohydroximates was effected by NBS under irradiation as reported for the preparation of several glycoenzyme inhibitors of this spiro-oxathiazole type. 26,44,45 Expectedly, the for-160 mation of two spiro epimers was observed, however, in contrast to earlier findings with hexopyranose derived compounds where the anomeric configuration of the thiohydroximate was retained in the major cyclized product, in these reactions compounds of the inverted configuration 42-44 were isolated as the main products. configurations were assigned by utilizing these coincidences.…”

“…Among the recently designed and synthesized 5-b-D-glucopyranosyl-3-substituted-1,2,4-triazoles submicromolar inhibitors of GP (e.g., G) were found. 22,23 Best compounds in series of other types of anomeric spirocycles like isoxazolines 24 (e.g., H) and oxathiazoles 25,26 (e.g.,…”

Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods

“…24 These observations shifted the focus of inhibitor design towards interactions in the β-channel and led to new principles 25 stating that efficient inhibitors advantageously have a rigid spirobicyclic scaffold which should not necessarily have an H-bond donor towards His377 (although this can be beneficial if available), but a suitably oriented, large aromatic substituent must be present to fit into the β-channel. These principles were first validated by the synthesis and enzymatic evaluation of glucopyranosylidene-spiro-oxathiazolines 25,26 (e. g. F in Chart 1) and further corroborated by spiro-isoxazolines 27 G among which the 2-naphthyl derivatives proved to be nanomolar inhibitors.…”

Glucose derived inhibitors of glycogen phosphorylase

“…Combining these facts with the spirobicyclic structure of hydantoins, a novel design principle for efficient glucose-based inhibitors of GP could be set up [69,70] : 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 such molecules should have a rigid spirobicyclic scaffold in which a (preferably five-membered hetero) cycle is attached to the anomeric carbon of D-glucopyranose; this cycle, although it may, should not necessarily be a Hbond donor towards His 377; a suitably oriented, large aromatic appendage must be present on this cycle to fit into the b-channel.…”