pseudomycin-b and Candidiasis

During the course of a structure-activity relationship (SAR) study on novel depsinonapeptide pseudomycin B, we synthesized a total of 12 8-amidopseudomycin analogues via standard two-step sequence from either ZPSB 2 or AllocPSB 3. A number of these amides exhibited good in vitro antifungal activities.

Topics: Animals; Antifungal Agents; Aspergillus fumigatus; Candida albicans; Candidiasis; Combinatorial Chemistry Techniques; Cryptococcus neoformans; Dose-Response Relationship, Drug; Mice; Microbial Sensitivity Tests; Models, Animal; Nuclear Magnetic Resonance, Biomolecular; Peptides, Cyclic; Structure-Activity Relationship

As a result of our core SAR effort, we discovered a large number of 3-amido pseudomycin B (PSB) analogues (e.g., 4e LY448212 and 5b LY448731) that retain good in vitro and in vivo (IP) activities against Candida and Cryptococcus without inherent tail vein irritation. Several dimethylamino termini bearing 3-amides (e.g., 5b) also exhibited improved potency against Aspergillus in vitro. When evaluated in a two-week rat toxicology study, it was found that all animals receiving 4e (up to 75 mg/kg) were found to be normal. On the basis of these observations, we are convinced that it is possible to broaden the antifungal spectrum and improve the safety profile of pseudomycin analogues at the same time.

Topics: Amides; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Cryptococcus; Male; Mice; Microbial Sensitivity Tests; Peptides, Cyclic; Rats; Structure-Activity Relationship; Toxicity Tests

We describe herein the synthesis, bioconversion, antifungal activity, and preliminary toxicology evaluation of a series of N-acyloxymethyl carbamate linked triprodrugs of pseudomycins. The syntheses of these prodrugs (3-6) were achieved via simple N-acylation of PSB (1) or PSC' (2) with various prodrug linkers (7-9). As expected, upon incubation with mouse and/or human plasma, many of these prodrugs (3, 5, and 6) were converted to the parent compound within a few hours. Of particular significance, two pseudomycin triprodrugs (5 and 6) showed excellent in vivo efficacy against systemic Candidiasis without tail vein irritation being observed.

Topics: Animals; Antifungal Agents; Aspergillus fumigatus; Biotransformation; Candida albicans; Candidiasis; Carbamates; Cryptococcus neoformans; Disease Models, Animal; Esterases; Humans; Mice; Microbial Sensitivity Tests; Peptides, Cyclic; Prodrugs

With the aim of identifying safer pseudomycin derivatives, we synthesized and evaluated a number of N-acyloxymethyl carbamate linked prodrugs of 3-amido pseudomycin analogues. To our satisfaction, all of the prodrug-amide combinations prepared exhibited good in vivo efficacy against murine Candidiasis. When evaluated in a dose elevation study, all of the newly synthesized combinations (e.g., 4A, 6A, 8A, and 8B) demonstrated improved toxicity profiles in comparison to their corresponding 3-amides as well as the parent pseudomycin B.

Topics: Amides; Animals; Antifungal Agents; Aspergillus fumigatus; Candida albicans; Candidiasis; Carbamates; Cryptococcosis; Cryptococcus neoformans; Disease Models, Animal; Mice; Microbial Sensitivity Tests; Peptides, Cyclic; Prodrugs

With the aim of increasing therapeutic indexes of novel cyclic depsinonapeptide pseudomycins, we synthesized and evaluated a series of mono-, di-, and trioxodioxolenylmethyl carbamate prodrugs (2 and 4) of pseudomycin B 1 and pseudomycin C' 3. It is rather encouraging to note that several members of the newly synthesized prodrugs described herein (e.g., 2a, 2e, and 4e) exhibited comparable in vivo efficacy to that achieved by the parent compounds, yet free of tail vein irritation and histamine induced toxicity in vivo.

Topics: Animals; Antifungal Agents; Candidiasis; Carbamates; Dioxoles; Histamine Release; Immunocompromised Host; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Peptides, Cyclic; Prodrugs; Rats; Structure-Activity Relationship; Tail; Veins