In vitro and in vivo antifungal activities of BMS-181184.

Abstract

BMS-181184 is a water-soluble pradimicin derivative with a broad antifungal spectrum in vitro and demonstrable efficacy against systemic infections with Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus in normal and cyclophosphamide-treated immunosuppressed mice. The pradimicins1~4) and benanomicins5) are family of benzo[a]naphthacenequinone antifungal agents which have comeinto prominence in recent years because of their anticipated use for the treatment of fatal systemic fungal infections. Pradimicin A (PRMA) which was isolated from the cultured filtrates of Actinomadura hibisca V\ 51-2 (ATCC53557)6) exhibited broad-spectrum fungicidal activity including activity against a variety of Candida species that were resistant to other antifungal agents2>7). Its modeof fungicidal action appears to be unique; PRMA binds to the surface of Candida albicans in the presence of Ca2+, causing perturbation of the fungal membrane8). Although PRMA is relatively non-toxic when compared with amphotericin B (AMPH), its poor solubility in aqueous media has severely curtailed the usage of this compound. Nevertheless, a promise for a safe, broad-spectrum therapy9~1 1} provided a formidable challenge to the drug industry. Chemical modification ofPRMA and PRMFA-2 focused on the substituent at C4' afforded a number of active derivatives12). BMS-181184 is one of the semisynthetic compounds that were derived from PRM FA-2 (Fig. 1). It showed potent activity in vitro against C. albicans, Cryptococcus neoformans and Aspergillusfumigatus, and excellent water solubility at physiological pHs. These profiles prompted us to study and compare the efficacies of BMS-181184 with those of PRMA and AMPHin vitro against a wide variety of fungi as well as in vivo against experimental systemic C. albicans, C. neoformans

In vitro antifungal and fungicidal spectra of a new pradimicin derivative, BMS-181184

“…Generally, at BMS-181184 concentrations at or close to the MIC, a 95% reduction in the final inoculum size was observed with Aspergillus strains. In an acute systemic fungal infection model in mice, BMS-181184 was less efficacious against A. fumigatus than it was against Candida or Cryptococcus strains (10). However, similar efficacies of BMS-181184 were achieved against Aspergillus strains with more frequent doses of the drug (10 Thus, the antifungal and fungicidal spectra of BMS-181184 included all of the yeast species tested and some but not all filamentous fungal species.…”

“…In an acute systemic fungal infection model in mice, BMS-181184 was less efficacious against A. fumigatus than it was against Candida or Cryptococcus strains (10). However, similar efficacies of BMS-181184 were achieved against Aspergillus strains with more frequent doses of the drug (10 Thus, the antifungal and fungicidal spectra of BMS-181184 included all of the yeast species tested and some but not all filamentous fungal species. When BMS-181184 reduced the viable counts of filamentous fungi in the final inoculum, the decrease was generally smaller than that for yeasts.…”

“…1), was identified. It had the antifungal properties of BMY 28864, good water solubility, and an improved toxicity profile (10). In this report we describe the in vitro activity of BMS-181184 against 35 fungal species.…”

Current Advances in Antifungal Targets and Drug Development

“…Compound 28 (BMS-181184) (Fig. 6), a pradimicin derivative underwent intensive research [60,61] until discarded in Phase I of clinical studies due to hepatotoxicity. Similarly, benanomicin A 26 met the same fate and its development was abandoned because of apparent cardiotoxicity after preclinical studies.…”

Biomimetic-Type Synthesis of the Racemic Non-Aromatic Angucyclinones of the SF 2315 and SS 228Y Types

“…[1,2] They exhibit a variety of interesting biological activities, such as antibacterial, [3][4][5] antifungal, [6][7][8] antitumor, [9,10] and vincristine-cytotoxicity potentiating activity, [11] platelet aggregation inhibition, [12,13] activity as endothelin receptor antagonists, [14] and inhibition of prolyl, [15] tyrosine, [16] or dopamine hydrolases. [17] The biological activity is most often linked (with the exception of antitumor and weak antibacterial activity) to a nonaromatic ring B and one or more glycosidic connections to deoxy sugars.…”