Synthesis of Nodulisporic Acid 2‘ ‘-Oxazoles and 2‘ ‘-Thiazoles

Abstract

[reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three heterocyclic side chain derivatives provided compounds, highlighted by 6, with an improved spectrum of ectoparasiticidal activity and pharmacokinetic profile relative to the natural product.

Synthesis of Side Chain Truncated 3‘ ‘-Aldehyde, 3‘ ‘-Carboxylic Acid, and 1‘ ‘-Aldehyde from Nodulisporic Acid A

“…A systematic structural modification of 1 led to the identification of the key constituents that are responsible for the biological activity and delineated the molecule into so-called “permissive” and “nonpermissive” regions, as illustrated below (Figure ). 6a,b In addition, a series of amide derivatives ( 2 ) of 1 with significantly improved efficacy against fleas was also identified. , Furthermore, formation of two truncated aldehydes 3 and 5 in small quantities was observed during preliminary chemical degradation of 1 , resulting from the oxidative cleavage at 3‘ ‘,4‘ ‘- and 1‘ ‘,2‘ ‘-double bonds, respectively. It was envisaged that an adequate supply of aldehyde 3 would permit ready access to structurally diverse, side chain modified analogues of NsA A with potentially improved biological activity and/ or an altered spectrum thereof . Since 1 was only available in limited quantities, the development of a synthesis of 3 was critical to success.…”

Nodulisporic Acid A Synthetic Studies. 2. Construction of an Eastern Hemisphere Subtarget

“…3 However, modifications of the C(8) side chain afforded several nodulisporic acid A derivatives which exhibit enhanced activity. 4 (+)-Nodulisporic acid A (1) possesses an intriguing array of architectural features including a highly substituted indole core, nine stereogenic carbons, and an eight-ring fused array, including the unique, highly strained five-membered βketodihydropyrrole. Ring D, derived from isoprenylation of the indole moiety, is unprecedented among the indole mycotoxins.…”

Functional analysis of Hypoxylon pulicicidum genes required for heterologous biosynthesis of nodulisporic acids

“…Importantly, previous studies of the nodulisporic acid pharmacophore established that the carboxylic acid handle of nodulisporic acids is readily modified using chemical synthesis to enhance the bioactivity and insecticidal specificity of the natural compounds. 11,[54][55]60 Thus, the identification of nodW provides access to a key modifiable core structure, nodulisporic acid F (82), for exploration of novel indole diterpenes. Additionally, the functional confirmation of the nodWCDS coding sequence establishes a new subclass of indole diterpene cytochrome P450 oxygenases and will facilitate the identification of other oxygenases that may modify the indole diterpene cores in a similar but discrete manner.…”

“…59 Nodulisporic acid A (1) was further tested against the hard tick (Dermacentor variabilis) in a similar in vivo bioassay to that used with C. lectularius, but no observable activity was observed when mice were treated with a single oral dose of 2.5 mg/kg. 60 Notably, anthelmintic activity was also tested using in vitro and in vivo assays but no desirable activity was observed. 11…”

“…Figure 1.43. Depiction of the key dimethylamino oxazole that installed potent anti-tick activity onto the nodulisporic acid A (1) core [Berger et al (2001)] 60. …”