Sugar–Oligoamides: Synthesis of DNA Minor Groove Binders

Abstract

Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-minor groove DNA interactions. Here we report an efficient solution-phase synthetic strategy to obtain two broad families of sugar-oligoamides. The first type, structure vector A (-Py[Me]-γ-Py-Ind), has a methyl group present as a substituent on the nitrogen of pyrrole B, connected to the C terminal of the oligoamide fragment. The second type, structure vector B (-Py[(CH(2))(11)OH]-γ-Py-Ind), has an alkyl chain present on the nitrogen of pyrrole B connected to the C terminal of the oligoamide fragment and has been designed to access to di- and multivalent sugar-oligoamides. By using sequential DIPC/HOBt coupling reactions, the oligoamide fragment -Py[R]-γ-Py-Ind has been constructed. The last coupling reaction between the anomeric amino sugar and the oligoamide fragment was carried out by activating the acid derivative as a BtO- ester, which has been performed by using TFFH. The isolated esters (BtO-Py[R]-γ-Py-Ind) were coupled with selected amino sugars using DIEA in DMF. The synthesis of two different selective model vectors (vector A (1) and vector B (2)) and two types of water-soluble sugar-oligoamide ligands, with vector A structure (compounds 3-7) and with vector B structure (compound 8), was carried out.

D‐ and L‐Mannose‐Containing glyco‐­Oligoamides Show Distinct Recognition Properties When Interacting with DNA

“…This route has previously been used [10] to obtain neutral glyco-oligoamides with different substitution at pyrrole B, close to the sugar moiety, The key coupling reaction between glycosylamine II and activated carboxylic acid III at the C terminal of the oligoamide was performed in the solution phase to give the β-glyco-oligoamides in good yields (see below).…”

“…The additionelimination reaction between the glycosylamines and activated carboxylic acid 16 [10] in DMF/DIEA (diisopropylethylamine) gave the corresponding acetylated glycooligoamides (i.e., 17-19) in yields of 28-70 %. (Scheme 4).…”

“…This was achieved using MeONa/ MeOH [10,14] to give the target water soluble β-sugar-oligoamides (i.e., 1-3) in yields of 70-79 %.…”

“…We have previously characterized a hairpin structure for free glyco-oligoamides with equatorial 2-OH groups. [10,15] Following an analogous protocol, compound 1 (β-d-Man) was shown to have a hairpin-like conformation, with its α face pointing towards the indole ring. [7] The NMR spectroscopic data for 2 and 3 in the free state ( Figure S18 in the Supporting Information) also indicated the presence of a major hairpin structure.…”

“…The β anomer is described as follows: R f = 0.1 (hexane/ EtOAc, 4:1). 1 658 mol) and activated acid 16 (which was synthesized previously in our group) [10] (0.2 g, 0.33 mmol) were dissolved in anhydrous DMF (5 mL), and DIEA (85 μL, 0.658 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. Compound 8 (0.2 g, 0.57 mmol) was added, and the reaction mixture was stirred for a further 92 h. When the reaction reached completion, the solvent was removed, and the residue was purified with column chromatography (toluene/MeOH, 10:1 to 8:1) to give compound 17 (189 mg, 70 %) as a mixture of α/β anomers.…”