Chemical Modification and Biological Evaluation of New Semisynthetic Derivatives of 28,29-Didehydronystatin A₁ (S44HP), a Genetically Engineered Antifungal Polyene Macrolide Antibiotic

Abstract

Twenty-three new derivatives of the heptaene nystatin analogue 28,29-didehydronystatin A(1) (1) (S44HP) were obtained by chemical modification of C16 carboxyl and amino groups of mycosamine. These derivatives comprised 15 carboxamides, 4 N-alkyl derivatives, 3 N-derivatives containing additional N-linked monosaccharide or disaccharide moiety (products of Amadori rearrangement), and 1 N-aminoacyl derivative. The derivatives have been tested in vitro against yeasts Candida albicans, Cryptococcus humicolus, and filamentous fungi (molds) Aspergillus niger and Fusarum oxysporum, as well as for hemolytic activity against human erythrocytes. Structure-activity relationships for the compounds obtained are discussed. The most active and least hemolytic derivative 3-(N,N-dimethylamino)propylamide of S44HP (6) was tested for acute toxicity and antifungal activity in animal model. Whereas amphotericin B and S44HP were active in vivo at doses close to the maximal tolerated dose, 6 was considerably less toxic and more active compared to these two antibiotics.

Synthesis and study of the antifungal activity of new mono- and disubstituted derivatives of a genetically engineered polyene antibiotic 28,29-didehydronystatin A1 (S44HP)

“…8 The in vitro antifungal activities of DMAP-amide against four tested fungal strains were comparable with those of AmB and 1, but the in vivo studies clearly showed superior pharmacological properties of this derivative over AmB. 8 The marked antifungal activity shown by a number of 28,29-didehydronystatin A 1 derivatives and particularly by the DMAPamide of 28,29-didehydronystatin A 1 (3) promoted a further structural modification study in our laboratory. On the basis of previously obtained structure-activity relationships, we designed and synthesized derivatives of 1, substituted both at the carboxyl and amino groups, and studied their antifungal activity.…”

“…8 The corresponding N-Fmoc derivatives of amides 2-4 were purified by column chromatography and deprotected, resulting in amides 2-4 with high purity.…”

“…6 Recently, a novel genetically engineered antifungal heptaene nystatin analog, 28,29-didehydronystatin A 1 (S44HP) 7 (see structure 1 on Scheme 1), was used as a scaffold for chemical modification. 8 Synthesis and structure-activity relationship of 23 new derivatives of 1 modified on the C16-COOH or the C3¢-NH 2 group have been reported. 8 3-(N,N-dimethylamino)propylamide (DMAP-amide) of 28,29-didehydronystatin A 1 (3) (Scheme 1) showed the best biological properties.…”

“…8 Synthesis and structure-activity relationship of 23 new derivatives of 1 modified on the C16-COOH or the C3¢-NH 2 group have been reported. 8 3-(N,N-dimethylamino)propylamide (DMAP-amide) of 28,29-didehydronystatin A 1 (3) (Scheme 1) showed the best biological properties. 8 The in vitro antifungal activities of DMAP-amide against four tested fungal strains were comparable with those of AmB and 1, but the in vivo studies clearly showed superior pharmacological properties of this derivative over AmB.…”

“…8 3-(N,N-dimethylamino)propylamide (DMAP-amide) of 28,29-didehydronystatin A 1 (3) (Scheme 1) showed the best biological properties. 8 The in vitro antifungal activities of DMAP-amide against four tested fungal strains were comparable with those of AmB and 1, but the in vivo studies clearly showed superior pharmacological properties of this derivative over AmB. 8 The marked antifungal activity shown by a number of 28,29-didehydronystatin A 1 derivatives and particularly by the DMAPamide of 28,29-didehydronystatin A 1 (3) promoted a further structural modification study in our laboratory.…”