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Synthesis 2006(6): 0914-0942  
DOI: 10.1055/s-2006-926368
REVIEW
© Georg Thieme Verlag Stuttgart · New York

Amphotericin B: 50 Years of Chemistry and Biochemistry

Damiano M. Cereghetti, Erick M. Carreira*
Laboratorium für Organische Chemie, ETH Hönggerberg, HCI H335, 8093 Zürich, Switzerland
Fax: +41(1)6321328; e-Mail: carreira@org.chem.ethz.ch;
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Publication History

Received 7 February 2006
Publication Date:
10 March 2006 (online)

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Abstract

The last century has seen the isolation and synthesis of a multitude of molecules with remarkable biological activity. Some of them represent milestones in chemical space and points of reference in the various disciplines of chemical synthesis, medicine, and biology that they beneficially impact. The notable history of natural products as antibiotics dates back to the 18th century. They continue to play an indispensable role in the advances that have been seen in the quality of life for the general population. This has come about because of the rich dialog that can be found at the interfaces between chemistry, biochemistry, biology, and medicine. In this review we examine amphotericin B as an important representative of antibiotics with a long rich history. Its impact continues to be felt today in its use in the clinic to combat fungal infections. In the first part, we review the biochemical efforts aimed at the explanation of amphotericin B’s mechanisms of action; in the second part, we take a look at the impact amphotericin B has had on the chemical community in the last two decades. The continuous interest aroused by amphotericin B reveals how much we still do not know about this space.

  • 1 Introduction

  • 2 Amphotericin B from Isolation to Structure-Activity Relationship­ Studies

  • 2.1 Amphotericin B in the Context of Antibiotic Research

  • 2.2 Studies on Amphotericin B

  • 2.2.1 Structure of Amphotericin B

  • 2.2.2 Mechanism of Action of Amphotericin B

  • 2.2.3 Structure-Activity Relationship Studies, Part I

  • 2.2.4 Degradation Studies

  • 2.2.5 Structure-Activity Relationship Studies, Part II

  • 2.2.6 Biosynthesis of Deoxyamphotericins

  • 3 Studies toward the Total Synthesis of Amphotericin B

  • 3.1 Synthesis of Macrolides at the Beginning of the 1980s

  • 3.1.1 Macrocyclization Reactions

  • 3.1.2 Addressing the Stereochemistry of Complex Molecules

  • 3.2 Synthetic Studies on Amphotericin B

  • 3.2.1 Retrosynthetic Analysis

  • 3.2.2 Synthetic Studies on the B1 and B2 Fragments

  • 3.2.3 Synthetic Studies on the B3 Fragment

  • 3.2.4 Synthetic Studies on the A2 Fragment

  • 3.2.5 Synthesis of the B Fragment (B1B2 + B3)

  • 3.2.6 Synthesis of the A Fragment (A2 + Polyene)

  • 3.2.7 Assembly of the A and B Fragments and Glycosidation

  • 4 Conclusion

Key words

amphotericin B - antifungal agents - macrolides - asymmetric synthesis - bioorganic chemistry

3

This somewhat-unfortunate name indicates an ‘n-dimen-sional space defined by the value of n descriptors; these descriptors can be of a chemical or biological nature and are either computed or measured’ (see ref. 6c). It seems more appropriate to call this abstract space a QSAR- or QSPR-space where QSAR and QSPR are the more familiar (and general) acronyms for ‘quantitative structure-activity relationship’ and ‘quantitative structure-property relation­-ship’, respectively (see ref. 56).

19

Amphotericin A is biosynthesized along with amphotericin B and needs to be removed from the latter during purification.

49

Monomers have been shown to exist below the critical self-association concentration, estimated to be 1 M. See ref. 45b.

147

In a later study, epoxide 103 was accessed from the known acetonide 104 which, in turn, could be prepared from
l-malic acid dimethyl ester (Scheme [51] ). See ref. 146c.

172

Glycoside 266 was prepared in 14 steps from the glucose derivative 268 (Scheme [52] ). The synthesis encompassed deoxygenation at C-5′ and double inversion at C-3′ in order to install the azide functionality, which after the glycosid-ation was reduced to the required amine. See ref. 145b.