Synthesis and biological evaluation of amphotericin B derivatives

Volmer, Astrid A.; Szpilman, Alex M.; Carreira, Erick M.

doi:10.1039/b820743g

Cited by 109 publications

(108 citation statements)

References 105 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…First, a dissociation between the membrane-permeabilizing and antifungal activities of AmB has been observed in some strains of yeast (20). To rationalize these findings, a second mechanism involving oxidative membrane damage caused by the putatively redox active heptaene motif of AmB is often invoked (9,10,12). However, we found that AmdeB (Fig.…”

Section: Small Molecules | Protein-like Functions | N-methyliminodiaccontrasting

confidence: 55%

“…Interestingly, microbial resistance long predates modern medi- cine (43), which suggests that the quest for resistance-refractory mechanisms of antimicrobial action also has a rich natural history. In this vein, despite extensive utilization in the treatment of life-threatening systemic fungal infections for more than half a century, clinically significant resistance to AmB remains exceptionally rare (10,12,13). Thus, clinically relevant antimicrobial mechanisms that can evade resistance exist, and the mode of action(s) of AmB is one of them.…”

Section: Discussionmentioning

confidence: 99%

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

“…This channel model has been extended to also rationalize the unique lack of resistance to AmB as well as its dose-limiting toxicity (12)(13)(14)(15)(16). This perceived understanding has stimulated extensive research toward the goals of developing new channel-forming compounds as putative resistance-refractory antimicrobial agents (19) and/or less toxic derivatives of AmB that more selectively form channels in fungal cells versus human cells (12)(13)(14)(15). Moreover, this model suggests that the capacity of AmB to form ion channels and exert cytocidal effects are inextricable, which challenges the notion that ion channels formed by AmB or one of its derivatives might have therapeutic benefit in the setting of protein ion channel deficiencies.…”

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

“…In the now widely accepted leading model, AmB kills yeast via ion channel-mediated membrane permeabilization (12)(13)(14)(15)(16)(17)(18). This channel model has been extended to also rationalize the unique lack of resistance to AmB as well as its dose-limiting toxicity (12)(13)(14)(15)(16). This perceived understanding has stimulated extensive research toward the goals of developing new channel-forming compounds as putative resistance-refractory antimicrobial agents (19) and/or less toxic derivatives of AmB that more selectively form channels in fungal cells versus human cells (12)(13)(14)(15).…”

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

See 4 more Smart Citations

Amphotericin primarily kills yeast by simply binding ergosterol

Gray

Palacios

Dailey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

498

408

View full text Add to dashboard Cite

Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings (i) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, (ii) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and (iii) suggest that the capacity for AmB to form proteinlike ion channels might be separable from its cytocidal effects.small molecules | protein-like functions | N-methyliminodiacetic acid boronates

show abstract

Section: Small Molecules | Protein-like Functions | N-methyliminodiaccontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

Section: Small Molecules | Protein-like Functions | N-methyliminodiacmentioning

confidence: 99%

See 3 more Smart Citations

Amphotericin primarily kills yeast by simply binding ergosterol

Gray

Palacios

Dailey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

498

408

View full text Add to dashboard Cite

show abstract

Non‐Toxic Glycosylated Gold Nanoparticle‐Amphotericin B Conjugates Reduce Biofilms and Intracellular Burden of Fungi and Parasites

Ghosh

Varela‐Aramburu

Eldesouky

et al. 2021

Advanced Therapeutics

View full text Add to dashboard Cite

Infections by intracellular pathogens cause significant morbidity and mortality due to lack of efficient drug delivery. Amphotericin B, currently used to treat leishmaniasis and cryptococcosis, is very toxic and cannot eradicate intracellular Cryptococcus neoformans (C. neoformans). Glycosylated gold nanoparticles are water dispersible and biocompatible with very little toxicity. While amphotericin B is insoluble in water at neutral pH, conjugates of amphotericin B and ultra‐small gold nanoparticles (AuNP) are better dispersible in water. Amphotericin B conjugated glycosylated gold nanoparticles (AmpoB@AuNP) are more efficacious in treating both extracellular and intracellular forms of Leishmania mexicana (L. mexicana) than amphotericin B alone. In addition, AmpoB@AuNP are effective in reducing C. neoformans biofilms by 80% and intracellular C. neoformans burden by >90%. Furthermore, AmpoB@AuNP are not haemolytic at 50 µg mL−1 and are significantly less toxic to murine macrophages than amphotericin B. Ultra‐small AuNPs are attractive delivery agents to treat intracellular infections and AmpoB@AuNP may be useful for treating C. neoformans infections in immunocompromised patients.

show abstract

Neurotrophe Naturstoffe – ihre Chemie und Biologie

Lacoske

Theodorakis

2013

Angewandte Chemie

View full text Add to dashboard Cite

Neurodegenerative Erkrankungen und Rückenmarksverletzungen betreffen weltweit etwa 50 Millionen Menschen und verursachen Gesundheitskosten von insgesamt mehr als 600 Milliarden Dollar pro Jahr. Nervenwachstumsfaktoren, d. h. Neurotrophine, sind potenzielle Therapeutika für diese Erkrankungen, denn sie können die Regeneration von Nerven fördern. Durchschnittlich 500 Publikationen jährlich belegen die Bedeutung der Neurotrophine in den biomedizinischen Wissenschaften und ihr Potenzial für therapeutische Anwendungen. Allerdings ist die klinische Verwendung von Neurotrophinen wegen ihres schlechten pharmakokinetischen Profils stark eingeschränkt. Niedermolekulare Verbindungen, die die neurotrophe Aktivität modulieren, bieten hingegen einen vielversprechenden Therapieansatz bei neurologischen Erkrankungen. Die Natur hat für eine beeindruckende Zahl von Naturstoffen mit starken neurotrophen Wirkungen gesorgt. Die aktuellen Strategien zur Synthese dieser Verbindungen sowie deren Fähigkeit, das Wachstum und die Erneuerung von Nervenzellen zu induzieren, bilden den Schwerpunkt dieses Aufsatzes. Es ist davon auszugehen, dass neurotrophe Naturstoffe nicht nur als Leitstrukturen in der Wirkstoffentwicklung genutzt werden können, sondern auch für das nächste große Projekt der Biomedizin: die Kartierung der Hirnaktivität (BAM, Brain Activity Map).

show abstract

Synthesis and biological evaluation of amphotericin B derivatives

Cited by 109 publications

References 105 publications

Amphotericin primarily kills yeast by simply binding ergosterol

Amphotericin primarily kills yeast by simply binding ergosterol

Non‐Toxic Glycosylated Gold Nanoparticle‐Amphotericin B Conjugates Reduce Biofilms and Intracellular Burden of Fungi and Parasites

Neurotrophe Naturstoffe – ihre Chemie und Biologie

Contact Info

Product

Resources

About