Molecular Umbrella–Amphotericin B Conjugates

Abstract

A tetrawalled and an octawalled molecular umbrella conjugate of amphotericin B (AmB) have been synthesized. Both conjugates exhibit high water solubility, a low tendency to aggregate, negligible hemolytic activity at 100 μM, and an ability to release a derivative of AmB under reducing conditions that exhibits high antifungal activity. Whereas the larger, octawalled conjugate shows slight adsorption to liposomal membranes and an ability to cross them by passive transport, the tetrawalled analogue shows significant adsorption and much lower bilayer transport activity. The potential of molecular umbrella–AmB conjugates as therapeutic agents is briefly discussed.

The antifungal pipeline: a reality check

“…These include changing the structure of amphotericin B from ‘molecular umbrella conjugates’ (REF. 94) to alternative structures, such as nanoparticles 95 and conjugated polysaccharides 96,97 , that may be able to penetrate certain body compartments and reduce membrane toxicity 97,98 . One proposed mechanism for this reduced toxicity is that the aggregated forms of amphotericin B have very different activities (specifically toxicities) compared with monomers: aggregates target host cells and thereby increase toxicity, whereas the monomers should target fungi preferentially over the host cells 99 .…”

Molecular Umbrella as a Nanocarrier for Antifungals

“…The presence of the cell wall surrounding the cytoplasmic membrane might theoretically constitute a physical barrier for molecules as large as molecular umbrellas and their conjugates. In this respect, it is worth mentioning that small but not large dendrimers were used as nanocarriers for some antimicrobials [ 22 ] and, on the other hand, tetra- and octawalled molecular umbrellas were not effective as components of conjugates with Amphotericin B [ 23 ]. Now, we have been able to demonstrate that at least conjugates incorporating a diwalled molecular umbrella are able to transgress this obstacle in Candida cells.…”

Influence of 5% dextrose volume on amphotericin B deoxycholate preparation

“…AmB‐d got FDA approval initially in 1959, and it has been well recognized for the treatment of various invasive fungal infection . Currently, the development of less‐toxic and effective alternatives of amphotericin B‐based therapy is the concern of scientists . However, the basic preparation methods for clinical application were still in dilemma due to the special property and chemical characteristics of AmB‐d.…”