Furanosyl Nucleoside Analogues Embodying Triazole or Theobromine Units as Potential Lead Molecules for Alzheimer's Disease

Abstract

The synthesis of novel types of furanosyl nucleoside analogues, namely N‐(benzyltriazolyl)methyl glucuronamide derivatives, N‐dodecyl glucuronamide‐based phenyltriazole nucleosides, and theobromine xylosyl 5′‐isonucleosides, as potential cholinesterase inhibitors is described herein. O‐Substituted and partially O‐substituted N‐propargyl glucuronamides, accessed from glucofuranurono‐6,3‐lactone, were engaged in CuI‐catalyzed cycloaddition with benzyl azide, whereas their N‐dodecyl uronamide counterparts were converted in three steps into glycosyl azides, which were subjected to cycloaddition with phenylacetylene. A xylofuranose derivative having a free 5‐OH group was coupled with theobromine by Mitsunobu reaction and the obtained isonucleoside was functionalized at C‐1′ with a sulfonamide moiety, leading to a prospective nucleotide mimetic. Five compounds displayed selective inhibition of acetylcholinesterase in the micromolar concentration range, with an α‐glycosyl triazole (Ki = 3.53 µm) and its 1‐azido‐uronamide precursor (Ki = 1.73 µm) being the most active. Docking studies were performed to give insights into the different inhibitory behavior within glycosyl azide anomers. Two of the best inhibitors showed low toxicity in both a neural cell line and human fibroblasts, rendering them promising lead compounds and supporting further investigations.

Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

“…N -isonucleosidation of methanesulfonamide with 11 in the presence of BF 3 ·Et 2 O provided the N -isonucleosidyl sulfonamide 12 in 81% yield, as a 3- O -dodecyl analog of isonucleoside B (Figure 1). An anomeric mixture (β/α ratio, 1:0.4) was obtained, which may be a result from the α and β-directing effects exerted by the neighboring acetate group participation and by the remote participation of theobromine carbonyl group, respectively, as well as from anomerization via the acyclic N -sulfonyl imine intermediate, as previously described in the synthesis of B (Figure 1) [17]. On the other hand, the isonucleosidyl acetate 11 was subjected to MW-assisted anomeric azidation with trimethylsilyl azide (TMSN 3 ), mediated by trimethylsilyl triflate (TMSOTf), leading to the α- and β-isonucleosidyl azides 13 in a 1:0.8 ratio and 86% yield.…”

“…Motivated by our previous studies, which revealed the interest of theobromine isonucleosides as promising lead molecules for AD (Figure 1) [14,17], we further focused our synthetic work on a variety of theobromine derivatives. The theobromine xylofuranosyl isonucleoside 3 was the precursor for the synthesis of isonucleotide analogs via derivatization at the anomeric center (Scheme 2).…”

“…On the other hand, the isonucleosidyl acetate 11 was subjected to MW-assisted anomeric azidation with trimethylsilyl azide (TMSN 3 ), mediated by trimethylsilyl triflate (TMSOTf), leading to the α- and β-isonucleosidyl azides 13 in a 1:0.8 ratio and 86% yield. The formation of the α-anomer is likely to arise also from the above mentioned remote group participation in assisting the isonucleosidyl cation intermediate, an effect already described to influence the stereochemical outcome of the anomeric azidation of glucuronamide derivatives [17,20]. Moreover, the xylonolactone-containing theobromine isonucleoside 14 was formed as a secondary product in 14% yield and was obtained in a mixture containing the β-isonucleosyl azide, the separation of which could not be achieved by column chromatography.…”

“…Isonucleosides comprising 2-acetamido-6-chloropurine or theobromine units linked to methyl glucoside moieties and a bis-glucopyranosid-6-yl thymine derivative were the most significant inhibitors with K i values ranging from 7.1 µM to 4.3 µM. The good inhibitory effect of the theobromine 6′-isonucleoside ( A , Figure 1) motivated the synthesis of furanosyl analogs, which included an N -isonucleosidyl sulfonamide derivative ( B , Figure 1) [17]. This isonucleotide analog, in which a sulfonamide is a neutral surrogate and a potential mimetic of a phosphate group, also showed micromolar and selective inhibition of AChE, besides revealing low toxicity in normal fibroblasts and in a neuronal cell, indicating therefore the interest of this type of skeleton in the search for new lead molecules for AD.…”

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

“…soln. ), r. t., 2.5-4 h; (b) NaBH4, EtOH/H2O (2/1), r. t., 1 h, 58 (5), 57% (6) [47], 64% (7) [48], 82% (8) [49], 2 steps; (c) TsCl, CH2Cl2/pyridine (1:1, from 7), pyridine (from 8), r. t., 16 h; (d) NaN3, DMF, 80 °C, 16 h, 77 % (14) [48], 80% (15) [47], 2 steps; (d) DPPA, DBU, toluene, r. t., 16 h (from 5), 24 h, then 40°C, 16 h (from 6), 98% (9), 68 % (10) [47]; (e) RBr, NaH, DMF, r. t., 16 h (for R = C3H5), 5 min. (for R = C3H3), 87% (12), 95 % (13) [47].…”