Chaetomellic acid

Phellinus robiniae on Robinia pseudoacacia Chaetomella acutisea (endophytic on fungal endophyte) chaetomellic acid A and B 198, 203... 

Figure 5 (a) Chaetomellic acid A is a novel dicarboxylate-containing natural product that is thought to mimic farnesyl pyrophosphate and thus to inhibit the enzyme FTPase. This compound can exist in either the dicarboxylate or anhydride form, (b) As peptides that contain aromatic oxamic acids are good inhibitors of tyrosine kinase p56 SH2 domains, it is believed that the oxamic acid moiety may mimic the phosphate group, (c) A symmetric 3,5-disubstituted benzoate analog of S3P (substrate) and EPSP (product) inhibits EPSPS. 

Singh SB, Zink DL, Liesch JM, Goetz MA, Jenkins RG, Nallin-Omstead M, Silverman KC, Bills GF, Mosley RT, Gibbs JB, Albers-Schonberg G, Lingham RB. Isolation and structure of chaetomellic acids A and B from Chaetomella acutiseta Farnesyl pyrophosphate mimic inhibitors of ras farnesyl-protein transferase. Tetrahedron 1993 49 5917-5926. 

The chaetomellic acids A and B (43 and 44), isolated from Chaetomella acutiseta found in seeds of peas, are potent and highly specific famesyl-mimic inhibitors of ras farnesyl-protein transferase. Farnesylation by this enzyme is the first and obligatory step for the post-translational modification of ras. The modified ras protein appears to be involved in tumorigenesis (approximately 25% of tumours) and there is evidence that inhibitors of the transferase have the potential to be antitumorigenic agents. These metabolites can be considered to be assembled by condensation of a palmitoyl and oleic acid chain C2 with pyruvate or oxaloacetate (Scheme 2) [38, 39]. Two syntheses have been reported for chaetomallic acid A [39, 40], one of which is patterned on the probable biogenesis [39]. 

Chaetomellic acids (Figure 11) are alkyl dicarboxylic acids and were the first compounds isolated in late 1991 from fungal extracts of Chaetomella... 

Activity of Chaetomellic Acids against FPTase and GGPTase... 

While chaetomellic acids were isolated in the anhydride form [71] the integrity of the anhydride form in the aqueous assay environment was questionable. This raised questions as to which form, the diacid or the anhydride, was the species that inhibited FPTase enzyme activity. This uncertainty was resolved by demonstrating that the equilibrium between the diacid and the anhydride forms was pH dependent (Figure 12). The UV spectrum of the anhydride in CH3CN exhibited a maximum for a cyclic anhydride at 254 nm. When the anhydride was treated either with O.IN NaOH or HEPES buffer (pH = 7.5) the maximum shifted to X.max 243 nm with a concurrent hypochromic shift. As expected, the process could be reversed by addition of mineral acid indicating that the active species are the open dicarboxylates [71]. 

Fig. (13A). 2D Structural alignment of FPP and chaetomellic acid A showing similarity.

Chaetomellic acids have been the subject of a number of syntheses. In 1993, we reported the first synthesis of chaetomellic acid A based on the biogenetic type aldol condensation [73]. The aldol reaction of appropriate fatty acid methyl esters with methyl pyruvate yielded two diastereomeric... 

Subsequent modifications to the latter steps resulted in the significant improvement in the synthesis of chaetomellic acids. The mixture of the aldol products was hydrolyzed by LiOH and the resulting diacid was subsequently refluxed in acetic anhydride to give respective chaetomellic acid anhydrides in three steps in overall 80% yield (Scheme 2) [74]. 

Scheme 2. Modified Merck synthesis of chaetomellic acids.

The second example of synthesis of chaetomellic acids includes the use of a cobaloxime-mediated synthesis reported by Branchaud and Slate [75,76] from the University of Oregon. This synthesis (Scheme 3) made use of photochemical doubly chemoselective cross coupling reactions of myristyl cobaloxime with citraconic anhydride and diphenyldisulfide to give a 64% yield of chaetomellic acid A anhydride in three steps from myristyl bromide. 

Scheme 3. University of Oregon synthesis of chaetomellic Acid A.

Kates and Schauble from Villanova University reported [77] in 1996 the third synthesis of anhydrides of chaetomellic acids A and B. This five-... 

Scheme 4. Villanova University synthesis of chaetomellic acids A and B.

Scheme 5. Synthesis of chaetomellic acid A from the University of Alberta and the University of Utah.

Additional examples of syntheses of chaetomellic acid A comes from the Argades group at the National Chemical Laboratory of India. They reported two syntheses of chaetomellic acid A with overall yields of 62%... 

The last and the seventh synthesis of chaetomellic acid A was reported in 1997 by the Samadi group from CNRS, France [81]. This one step synthesis involves a Barton radical decarboxylation and gave 77% overall yield (Scheme 8). The method requires preparation of a thiohydroxamic ester of the corresponding alkyl acid followed by in-situ irradiation in the presence of citraconic anhydride and silica gel chromatography. The last intermediate in this synthesis is similar to the synthesis reported by Branchaud and Slate [75,76]. 

---