Mixed amphotericin b derivatives with reduced toxicity
A technology of compounds, compositions, applied in the field of mixed amphotericin B derivatives with reduced toxicity, capable of solving the problems of lack of potency of yeasts and molds
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Embodiment 1
[0264] Example 1. Novel chemical design without mammalian toxicity
[0265] Achieved by the development of the disclosed leading-edge synthetic method for the efficient modification of new AmB derivatives, it was alternatively discovered that AmB kills fungi and human cells primarily by binding ergosterol and cholesterol, respectively ( Figure 1A ); no channel formation is required. All data are consistent with the "sterol sponge" model ( Figure 1B ) consistent with this model, AmB self-assembles into large extramembrane aggregates and rapidly extracts physiologically critical sterols from fungal and human cells, causing cell death. Frontier SSNMR studies further reveal key insights into the structure of the AmB sponge-sterol complex. Anderson, T. M. et al., Nat Chem Biol 2014, 10 (5), 400-6.
[0266] This pivotal discovery opens a route for the rational development of nontoxic AmB variants. To probe its expected role in sterol binding, the hydroxyl group was synthe...
Embodiment 2
[0271] Example 2. AmB derivatives with no observed animal toxicity
[0272] >100 mg of C2'epiAmB were prepared, formulated into the corresponding deoxycholate complexes, and this head-to-head derivative with AmB-deoxycholate was evaluated for toxicity and efficacy in animal models. Intravenous (IV) administration of AmB-deoxycholate to mice was found to be lethal at 2-4 mg / kg ( Image 6 ,Left). In contrast, no deaths were observed after IV injection of C2'epiAmB-deoxycholate even at 128 mg / kg (the highest dose tested). IV administration of AmB-deoxycholate (2.5 mg / kg) to rats caused a significant increase in blood urea nitrogen (BUN), alanine aminotransferase / aspartate aminotransferase (ALT / AST) and mortality ( Image 6 ,right). Alternatively, when rats were treated IV with C2'epiAmB at doses of 2, 10 and 17.5 mg / kg (the highest dose tested), no increase in BUN or ALT / AST was observed and no deaths were observed. C2'epiAmB at 17.5 mg / kg C max C compared to AmB at 1 mg...
Embodiment 3
[0275] Example 3. Partial retention of in vitro antifungal activity
[0276] The in vitro antifungal activity of C2'epiAmB and AmB was compared at Evotec (Oxfordshire, UK) against a broad range of clinical isolates of Candida and Aspergillus ( Figure 8A ). C2'epiAmB showed good activity against many Candida strains and several Aspergillus strains. However, there were several A. fumigatus strains (AF293, A1163 and ATC204305) against which C2'epiAmB was 1 / 4 as effective as AmB, and in one strain (AF91) C2'epiAmB was A. terreus ) ( Figure 8B ). C2'epiAmB was found to be 1 / 2-1 / 16 as potent as AmB (1 / 5.6 average potency across all 40 strains). Recently, Steinbach and Burke directly compared AmB, AmBisome ® , caspofungin, voriconazole and C2'epiAmB against an even broader group of clinically relevant invasive molds ( Figure 8C ). These studies again showed good antifungal efficacy of C2'epiAmB against a number of strains, including ubiquinazole-resistant strains (F14196),...
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