N-glycosyl derivatives of polyene macrolide antibiotics.

Sir: The polyene macrolides are known as potent antifungal agents. However their use in therapy is limited by considerable toxicity and very poor water solubility. Many efforts had been taken to obvert these undesirable properties1-5). We report now a new group of derivatives of polyene macrolides exhibiting improved solubility in water and organic solvents and retaining the biological activity of parent compounds. These derivatives are prepared in the reaction of an antibiotic, containing a free aliphatic amino group, with a carbohydrate or its appropriate derivative. Optimal conditions of the reaction are the following: dimethyl formamide as solvent, temperature range 3540°C and 0.5 molar excess of carbohydrate. The course of the reaction can be followed by thin-layer chromatography on silica gel with the solvent system, ethyl acetate acetic acid water (4 : 1 : 1, v/v). The reaction is completed within 12~40 hours, depending on the polyene macrolide and carbohydrate used. The products are isolated by precipitation and washing with ethyl ether, followed by drying under vacuum. The yields are almost quantitative. The derivatives can be purified by counter-current distribution (chloroform methanol water, 2 : 2 : 1, v/v) or butanol ethyl acetate methanol water (20 : 10 : 5 : 35, v/v) or by partition chromatography on silica gel or Sephadex LH-20 (chloroform methanol water, 20 : 10 : 1, v/v). Derivatives of polyene macrolides representing major structural groups (pimaricin, nystatin, amphotericin B, mycoheptin, candicidin, levorin and trichomycin) with various carbohydrates (such as glucose, mannose, fructose, ribose, maltose and glucuronic acid) were synthesised and characterised. In an exampler synthesis, 1 g of amphotericin B (E 1% 1cm 480 at 382 nm) and 0.3 g of glucose were dispersed in 15 ml of DMF and left for 16 hours at 37°C. The product was precipitated with 300 ml of ethyl ether, centrifuged, washed 3 times with ether and dried in vacuum to obtain 1.28 g of crude derivative (E 1% 1cm 120 at 382 nm). Crystallization from methanolbutanol mixture, followed by washing with acetone yielded 0.65 g of derivative exhibiting E 1% 1cm 1350 at 382 nm. The minimum inhibitory concentration (MIC) against Saccharomvices cerevisiae determined in liquid SABOURAUD medium was 0.1 mcg/ml (MIC for parent am-