Polyenes • A polyene is a molecule consists of multiple conjugated double bonds

Polyenes
• A polyene is a molecule consists of multiple conjugated double bonds.
• Polyenes possess of macrocyclic ring or compounds having several conjugated double bonds and separate lipophilic and hydrophilic region. It comprise of carbonyls, hydroxyls as well as sugar.
• Polyenes antifungal is a macrocyclic polyene consists of a large hydroxylated part on the ring opposed to the conjugated arrangement. Hence, it makes polyene antifungals amphiphilic.
• Examples of polyenes includes Amphotericin B and Nystatin.

Structure Activity Relationship of Polyenes

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• The polyenes antibiotics were produced by actinomycetes which consist of a large lactone ring with 4 to 7 unsubstituted conjugated double bond.
• In general, the conjugated systems are in all-trans configuration, thereby the ring contains a planner lipophilic segment and a fewer rigid hydrophilic portion.
• Addition of conjugation (double bond), will enhance the activity and toxicity .
• The polyenes having polyhydroxyl groups.
• Amphotericin B consists of 7 conjugated double bond while Nystatin having 6 conjugated double bonds. Therefore, Amphotericin B are more active and highly toxic.
• Generally, most of the polyene antifungal drugs are macrocyclic lactones.
• The ring size varies from12 to 37 atoms in size.

Antifungal Polyenes: Amphotericin B
• Amphotericin B was originally produced from a bacterium called Streptomyces nodosus at the Squibb Institute of Medical Research in 1955.
• Amphotericin B is used for systemic fungal infections via intravenously.
• The name Amphotericin B is originate from its amphoteric properties.

• Amphotericin B is a member of macrolide family from natural products and a sub-family of macrolide which is polyene.
• In 1987, Nicolaou’s group was the first to made an innovation in synthesizing polyene macrolides.

• Generally, the synthesis can be outline in 2 phases:
i. Synthesis of protected amphoteronolide
ii. Glycosidation

i. Synthesis of protected amphoteronolide
? The primary step of the synthesis was the formation of amphoteronolide B which aid as ketophosphonate 8.
? The starting material of 8 was the enantiomeric pair of xylose that underwent acetonide formation.
? This acetonide protects 1- and 2-OH, which allowed 3-OH to be removed by giving 3 deoxy compounds.
? (+) – Xylose was transformed into an aldehyde 2awhile (-) – Xylose formed the second portion 2b which have ketophosphonate group.
? Both compounds were connected via Horner-Wadsworth-Emmons reaction followed by hydrogenation and then transformed into ketophosphonate.
? In this phase, ketophosphonate 8 was formed with the OH goups are protected by either acetonide or TBS.

ii. Glycosidation
? In the second phase, the highly conjugated polyene-aldehyde was formed.
? Repetitively, this step ketophosphonate-aldehyde condensation is the key reaction to control the stereochemistry of the polyene component of 21.
? This compound was formed via condensation twice with the aldehyde and phosphonate.
? The aldehyde was prepared via Evans aldol followed by several steps of reduction and deprotection.
? In addition, the reagent 5 that was used in the first stepwas also synthesised from the same starting material which is (+)–diethyl-L-tartrate.
? Furthermore, an intermediate compound that is not quite related to 21 such as epoxide 11 that is formed under Sharpless condition was used.

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