Studies on 1-deoxy-D-fructose, 1-deoxy-D-glucitol, and 1-deoxy-D-mannitol as antimetabolites

Abstract

1-Deoxy-D-fructose was synthesized in 27% yield from D-glucosamine in a three-step procedure involving Raney nickel desulfurization and oxidative deamination with 3,5-di-tert-butyl- 1,2-benzoquinone applied to appropriate intermediates. 1-Deoxyfructose and its reduction products, 1-deoxyglucitol and 1-deoxymannitol, were tested as substrates and antimetabolites. For sheep liver glucitol dehydrogenase, the Km is 53 mM for 1-deoxymannitol, were tested as substrates and antimetabolites. For sheep liver glucitol dehydrogenase, the Km is 53 mM for 1-deoxyglucitol and 89 mM for 1-deoxymannitol with maximal velocities 33 and 18%, respectively, of that with glucitol as substrate. These results require substantial revision of the long-accepted polyol substrate structural requirements for this enzyme which have been reported to include a 1-hydroxy group and a cis-2,4-dihydroxy configuration. Km is 614 and 280 mM for yeast and muscle hexokinases, respectively, acting on 1-deoxyfructose; maximal velocities are 2 and 5% of those obtained with fructose. 1-Deoxyfructose 6-phosphate is a competitive inhibitor of phosphoglucose isomerase with a Ki of 1.1 mM; this is about the same as Km for the natural substrates. It is also an effective inhibitor of phosphofructokinase but does not alter the cooperativity of the enzyme interaction with fructose 6-phosphate nor exhibit cooperativity in its own interaction therewith. These results suggest that the 1-hydroxy group is not crucial for binding but does play a role in the cooperative interactions of this allosteric protein. At equivalent concentrations, 1-deoxyfructose is somewhat better than 2-deoxyglucose as an inhibitor of erythrocyte glycolysis; the 1-deoxypolyols are ineffective. All three 1-deoxy compounds are readily, though incompletely, absorbed from the intestine of mice; most of the absorbed dose appears in the urine unchanged within 24 h. Whether given by oral or intraperitoneal routes, 2 to 6% of administered deoxypolyol or deoxyketose appears in the urine as ketose or polyol, respectively. No acute toxic effects or growth retardation are noted for any of the 1-deoxy analogues when given to mice at levels where 2-deoxyglucose has such effects. The properties of these 1-deoxy sugar analogues recommend them for further studies of enzyme mechanisms, for metabolic studies, and for testing as therapeutic agents against such organisms as certain mammalian parasites with heavy reliance on glycolysis.

Substrate specificity of sheep liver sorbitol dehydrogenase

“…This is corroborated by the previous observations that the 1-deoxy derivatives of sorbitol, -mannitol and -fructose are substrates for sheep liver SDH [36]. The present study shows that a kCH # NH # , kCH # SH, kCHO or kCH # OCH $ group adjacent to C2 is also possible.…”

“…The present study shows that sheep liver SDH catalyses the reversible NAD-linked oxidation of most polyols -including -mannitol and galactitol, the 2-and 4-epimers of sorbitol, respectivelyinto their corresponding ketoses. Numerous reports corroborate that -mannitol [12,[27][28][29][30][34][35][36][37][38] and galactitol [12,27,[29][30][31]38], as well as -arabitol [12,27,29,30,38], are substrates for SDH. Hence, the putative -cis-2,4-dihydroxy requirement for the polyol substrates of SDH is not absolute.…”

“…A corollary is that substitution of the kCH # OH moiety at C2 with a nonpolar group should have opposite effects on the k cat \K m of epimeric substrates. Indeed, whereas various 1-deoxy analogues of sorbitol are comparatively poor substrates, 1-deoxy--mannitol has been reported to show a specificityconstant forty times higher than that of -mannitol [36].…”

Stereospecific Benzyne‐Induced Olefination from β‐Amino Alcohols and Its Application to the Total Synthesis of (−)‐1‐Deoxy‐D‐fructose

“…The monoclinic crystals of 6 c, as shown in These results clearly indicate the trans relationship of the two phenyl groups that are attached directly to the 1,3-thiazolidine-2-thione nucleus. Furthermore, trans-stilbene (7 b) was produced as the exclusive product from 6 b, 6 c, and 6 d', as determined by 1 H NMR and 13 C NMR spectroscopy, which gave peaks at d = 7.11 and 128.7 ppm, respectively (vs. d = 6.59 and 130.2 ppm, respectively, for cis-stilbene), corresponding to the vinylic protons and the sp 2 carbons, respectively. These spectroscopic results confirm the stereospecificity for the conversions of erythro-5 b to trans-stilbene (7 b) and threo-5 a to cis-stilbene (7 a).…”

Metabolic enzymes of helminth parasites: potential as drug targets

“…Modified monosaccharides have been suggested as general inhibitors or antimetabolites targeting hexokinase [97]; however, little work has been done to exploit this suggestion with hexokinases from helminth parasites.…”