Syntheses of Antifungal Aureobasidin A Analogs with Alkyl Chains for Structure-activity Relationship

• Published in: Journal of antibiotics Vol. 51; no. 3; pp. 359 - 367
• Main Authors: KUROME, TORU, INOUE, TETSUYA, TAKESAKO, KAZUTOH, KATO, IKUNOSHIN, INAMI, KAORU, SHIBA, TETSUO
• Format: Journal Article
• Language: English
• Published: TOKYO JAPAN ANTIBIOTICS RESEARCH ASSOCIATION 01.03.1998; JAPAN ANTIBIOT RES ASSN; Japan Antibiotics Research Association
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Biological and medical sciences; Biotechnology & Applied Microbiology; Candida albicans - drug effects; Cryptococcus neoformans - drug effects; Depsipeptides; Immunology; Life Sciences & Biomedicine; Medical sciences; Microbiology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; ECHINOCANDIN-B; PEPTIDE; Antibiotic; Antifungal agent; Structure activity relation; Alkyl; Analog; Minimum inhibitory concentration; Chemical synthesis; In vitro; Biological activity
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.51.359

The syntheses of aureobasidin A (AbA) derivatives with alkyl chains and their in vitro structure-biological activity relationships are discussed. The analogs replaced at positions 6, 7, or 8 of AbA with either L-glutamic acid, δ-hydroxy-L-norvaline, or δ-hydroxy-N-methyl-L-norvaline are prepared. The γ-carboxyl or δ-hydroxyl group of these new amino acids was coupled with acids, alcohols, or amines with alkyl chains. While the analogs having L-glutamic acid residue at positions 6 or 8 showed weak activity, esterification of the γ-carboxyl group with benzyl or shorter alkyl (C4 or C6) alcohols, significantly enhanced the activities. Introduction of longer alkyl (C14) chain to the same amino acids residues at positions 6, 7, or 8 resulted in total loss of antifungal activity. Among the lipophilic analogs in [L-Glu6] derivatives, the C6 alcohol ester showed the strongest antifungal activity against Candida spp. so far tested. None of the derivatives showed activity against Cryptococcus neoformans.