1440917-68-9

Upstream product

• 1440917-62-3 C₂₀H₃₂O₅Si 
• 18162-48-6 tert-butyldimethylsilyl chloride 
• 1440917-04-3 C₂₀H₃₄O₅Si 
• 124-63-0 methanesulfonyl chloride 
• 1268624-99-2 4-methoxybenzyl 2,3-anhydro-6-deoxy-α-D-allopyranoside 

Downstream Products

• 1440917-73-6 C₂₀H₃₃N₃O₄Si 

Relevant academic research and scientific papers

AMPHOTERICIN B DERIVATIVE WITH REDUCED TOXICITY

Provided are an amphotericin B (AmB) derivative with an improved therapeutic index over amphotericin B, pharmaceutical compositions comprising the AmB derivative, methods of making the AmB derivative and the pharmaceutical composition, and their use in methods of inhibiting growth of a yeast or fungus and treating a yeast or fungal infection. The amphotericin B derivative, denoted C2'deOAmB, differs from the parent compound in that it lacks the hydroxyl group at the 2' position on mycosamine. This difference in structure results in (i) retained capacity to bind ergosterol and inhibit growth of yeast, (ii) greatly reduced capacity to bind cholesterol, and (iii) essentially no toxicity to human cells.

C2′-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells

Amphotericin B (AmB) is a clinically vital antimycotic but is limited by its severe toxicity. Binding ergosterol, independent of channel formation, is the primary mechanism by which AmB kills yeast, and binding cholesterol may primarily account for toxicity to human cells. The leading structural model predicts that the C2′ hydroxyl group on the mycosamine appendage is critical for binding both sterols. To test this, the C2′-OH was synthetically deleted, and the sterol binding capacity of the resulting derivative, C2′deOAmB, was directly characterized via isothermal titration calorimetry. Surprisingly, C2′deOAmB binds ergosterol and, within the limits of detection of this experiment, does not bind cholesterol. Moreover, C2′deOAmB is nearly equipotent to AmB against yeast but, within the limits of detection of our assays, is nontoxic to human cells in vitro. Thus, the leading structural model for AmB/sterol binding interactions is incorrect, and C2′deOAmB is an exceptionally promising new antifungal agent.