The 4' -7V-alkyl (1~10) and 4' -7V-acyl derivatives (ll~21) ofpradimicins (PRMs) were synthesized by trimethylsilylation of PRMsA, C and FA-1 followed by condensation with appropriate alkylating and acylating agents. The 4'-hydroxy derivatives (23 and 24) were synthesized from PRMFA-2 in a 3-step sequence. Among these compounds, the 4'-N-carboxylsubstituted alkyl (1, 5, 8 and 10), 4'-Af-formyl (ll) and 4'-axial-hydroxy (23) derivatives retained the antifungal activity of the parent compoundsand showedgreat improvementin water solubility.The pradimicins (PRMs) are a new family of antibiotics ( Fig. l)1^that exhibited broad-spectrum antifungal activity both in vitro and in vivo. Although they are relatively non-toxic, their limited solubility in aqueous media prompted us to initiate chemical modification of PRMsfocused on the C4'-position6'7) in order to improve water-solubility. The objectives in this program were to determine the limitations of modification, establish structure-activity relationships and identify a compoundfor development. Herein, wedescribe the syntheses and in vitro activities of the PRMderivatives prepared.
A series of pradimicin analogs were designed and synthesized to investigate the effect of the amino acid side chain on the antifungal activity. The alanine-exchanged analogs (3a~3q) were synthesized from 4'-7V-Cbz-pradimic acid by coupling with appropriate amino acids or their equivalents followed by deblocking. All the D-a-amino acid derivatives except D-proline analog, 3k retained the antifungal activity.Pradimicin A (PRM A), is the original member of the pradimicin family of antibiotics produced by Actinomadura hibisca P1 57-2 (ATCC 53557)1>2). It is a broad-spectrum antifungal agent with demonstrable efficacy against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus infections in mice. Structurally, it is a glycosylated dihydrobenzo[>]naphthacenequinone having a D-alanine side chain at C-1 5. The D-alanine may be replaced by glycine (PRM D)3) or D-serine (PRM FA-1)4) without impairing antifugal activity, but the change to L-alanine resulted in a complete loss of antifungal activity, suggesting the importance of the amino acid side chain at C-15 in expression of antifungal activity5). The purpose of the present study was to design and synthesize a series of pradimicin analogs to investigate the effect of the amino acid side chain on the antifungal activity with a hope of identifying a derivative having an increased potency. This report describes the synthesis and antifungal activity of the alanine-exchanged analogs of THFgave an active ester, which was allowed to react with an appropriate amino acid or amino compound in 50% aqueous dioxane in the presence oftriethylamine (Method A). Alternatively, the same active ester was reacted with an appropriate amino acid methyl ester in the presence of AT,0-bis(trimethylsilyl)acetamide in THF followed by
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