Synthesis and Evaluation as Glycosidase Inhibitors of Carbasugar‐Derived Spirodiaziridines, Spirodiazirines, and Spiroaziridines

Abstract

Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthdayThe spirodiaziridines 6 and 9, potential inhibitors of a-and b-glucosidases, were prepared from the validoxylamine A-derived cyclohexanone 5. The trimethylsilyl protecting groups of 5 are crucial for the formation of 6 in good yields. Oxidation of 6 gave 7. The diaziridine 6 (pK HA 2.6) and the diazirine 7 did not inhibit the b-glucosidases from almonds, the b-glucosidase from Caldocellum saccharolyticum, and the aglucosidase from yeast. The N-benzyl diaziridine 9 is a very weak inhibitor of the a-glucosidase, but did not inhibit the b-glucosidases. To see whether the weak inhibition is due to the low basicity of the diaziridines or to geometric factors, we prepared the spiro-aziridines 21 and 25 and 1-epivalidamine (32). The known cyclohexanone 10 was methylenated and epoxidised to 16 and 17. Azide opening of 16 and 17, mesylation, LiAlH 4 reduction, and deprotection gave the aziridines 21 and 25 respectively. 1-Epivalidamine (32) was prepared from the known carba-glucose 29. The aziridine 25 (pK HA 6.8) is a weak irreversible inhibitor of the b-glucosidase from Caldocellum saccharolyticum and a weak reversible inhibitor of the a-glucosidase from yeast, but did not inhibit the b-glucosidases from almonds. The poorly stable aziridine 21 weakly inhibited the three enzymes. Similarly, 1-epivalidamine (pK HA 8.4) proved only a weak inhibitor. The known cyclopentylamine 34 (pK HA 7.9), however, is a micromolar inhibitor of these enzymes. The much stronger inhibition by 34 is related to the pseudoaxial orientation of its amino group.Introduction. ± Alkoxydiaziridines of type 1 (Scheme 1) possess trans-oriented Natom lone-pairs located above and below the average plane of the pyranose ring and oriented more or less parallel to the ring plane. These diaziridines may, thus, inhibit both a-and b-glucosidases 3 ). The inhibition of b-glycosidases by diaziridines of this type may provide evidence for the correlation between the change of the pyranose-ring conformation, orienting the scissile bond in a pseudoaxial orientation, and the proton transfer to the glycosidic heteroatom characterising the reaction coordinate linking the ground and transition states of the rate-determining step. The diaziridines 1 may be accessible by deprotection of the known benzyl ethers 2 [2]. We were, however, concerned about the low basicity and the fragility of alkoxydiaziridines in aqueous solution. Exploratory experiments indeed showed that the diaziridines 1 are not sufficiently stable [3], so that we aimed at the synthesis of the carba analogues 6. To differentiate between the effects of shape and charge on the inhibition, we also required the related spiro-aziridines 21 and 25 4 ) (Scheme 2), and 1-epivalidamine

Covalent inhibitors of glycosidases and their applications in biochemistry and biology

“…Aziridine-based inhibitors enjoy the theoretical advantage of having a higher initial, noncovalent affinity for a glycosidase active site owing to the positively charged (when protonated) nitrogen atom, which should help direct the inactivator toward the negatively charged active site. The spiroaziridines 9a and 9b were tested against a few different enzymes and shown to be only very weak inactivators of a single β-glucosidase and a single α-glucosidase, respectively, possibly because of the steric demands imposed at the anomeric center (Kapferer et al 2003). Spiroaziridine 9c was shown to be a potent inactivator of one α-galactosidase, although it showed no activity against other enzymes (Tong and Ganem 1988).…”

Spiro Iminosugars: Structural Diversity and Synthetic Strategies

“…A limited number of polyhydroxylated spiroazacycles in which the hydroxyl groups are positioned on a cycloalkane ring has been described in the literature so far. In 2003, Vasella et al reported the synthesis of spiroaziridines 5 (Scheme 1) [19]. These compounds were designed as mechanistic probes to study the impact of the position of the basic nitrogen atom on the inhibition profile towards a panel of glycosidases.…”

Theoretical, ab initio and DFT, study of the structure and vibrational analysis of Raman, IR and INS spectra of (CH3)3SiNCO

“…[3][4][5] that is used to check and extend the existing assignments. In Table 7 the observed vibrational wavenumbers in each spectrum and the previous assignments from Refs.…”

“…Over the last 50 years, the knowledge and understanding of organosilane compounds has increased considerably, and these materials now have applications in nearly all aspects of modern industry (in the clinical testing, pharmaceutical, medical, chemical, research and manufacturing industries) [1,2], trimethylsilyl moiety being the most common protecting group used in organic synthesis [3,4]. Isocyanates are widely used in the manufacture of flexible and rigid foams, fibres, coatings such as paints and varnished, in the automobile industry and building insulation materials but they also have important effects for the health and are classified as potential human carcinogens.…”