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• 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 amphoteronolideii. Glycosidationi. 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.