Papulacandins - Synthesis and biological activity of papulacandin B derivatives.

Abstract

A series of papulacandin B derivatives was synthesized and their in vitro and in vivo activity against Candida albicans and other fungi was established. The biological data have shownthat some10-alkyl ether and 1 1-acylamino derivatives exhibit an improved in vivo activity comparedto papulacandin B whereas derivatization in other positions of the molecule led to less potent compounds. Some years ago, a group of antibiotics with a novel structure, the papulacandins, was isolated from cultures of Papularia sphaerosperma1*^'. The structures of the principal component papulacandin B and the accessory components A, C and D (Fig. 1) were subsequently elucidated by degradation reac-Fig. 1. Structures ofDapulacandins A, B, C and D. Biology All degradation products of 1 and their hydrogenation products are biologically inactive (data not Table 1. Antifungal activity in vitro (MIC) and in vivo (ED50) of ether derivatives of 1. %r OR2 Ri R2 MIC Gug/ml) Cm.

Treatment of Pneumocystis carinii pneumonia with 1,3-beta-glucan synthesis inhibitors.

“…The papulacandins are, for the most part, much less active than echinocandins against yeast in vivo while having comparable activity in vitro (22)(23)(24). In these studies, L-687,781 eliminated 80% of P. carinii cysts at 10.0 mg/kg and 73% at 5.0 mg/kg after 4 days ( Table 2).…”

In vitro antifungal activities and in vivo efficacies of 1,3-beta-D-glucan synthesis inhibitors L-671,329, L-646,991, tetrahydroechinocandin B, and L-687,781, a papulacandin

“…The number of current therapies available to counter the mycoses has been developed at approximately the same rate since the inception of antifungal drug therapy. Amphotericin B (AMB), developed in the 1950s, still remains the drug of choice for most fungal diseases mainly because it is broad spectrum and fungicidal, but it is considered to be relatively toxic (36,37). The broad-spectrum azole antifungal agents developed more recently, although considered to be safer and less toxic than AMB, are fungistatic, which has limited their utility in many clinical settings (28,36).…”

Fungal Cell Wall Inhibitors: Emphasis on Clinical Aspects

“…The clinical development of the papulacandins has been suspended because of the limited in vitro spectrum of activity and the lack of activity in animal models [62].…”