Zaragozic acid structures

F. (1993) The zaragozic acids structure elucidation of a new class of squalene synthase inhibitors. Tet Lett. 34, 399-402. 

FIGURE 2 Examples of the variety of structures obtained in natural product screens. I, zaragozic acid A, is an inhibitor of mammalian and fungal sterol synthesis, obtained from fungi (48) II, L-696,474, is an inhibitor of the HIV protease, obtained from fungi (51) III, dehydrosoyasaponin I, is an agonist of the calcium-activated potassium channel, obtained from a medicinal plant (58) IV, tetrandrine, is an inhibitor of L-type calcium channels, obtained from a plant (78). 

Zaragozic Acids The zaragozic acids (squalestatins) are a class of competitive inhibitors of mouse, rat, and HepG2 squalene synthases, which also display antifungal activity [104]. The characteristic structural feature of this family of natural products is its highly oxygenated core. 

C Dufresne, KE Wilson, D Zink, J Smith, JD Bergstrom, M Kurtz, D Rew, M Nallin, R Jenkins. The isolation and structure elucidation of zaragozic acid C, a novel potent squalene synthase inhibitor. Tetrahedron 48 10221-10226, 1992. 

The rhodium(II)-induced tandem cyclization-cycloaddition process has also been applied with notable success to the core structure of zaragozic acid by the Merck research group <94TL9185>. Zaragozic acid A (20) was discovered as a metabolite from an unidentified... 

To underscore the fact that the rate of deprotection is widely variable and very structure dependent, we cite an example in which a hindered trimethysilyl ether was surprisingly robust. In Nicolaou s synthesis of Zaragozic Acid A [Scheme 4.5] 4 treatment of 5.1 with 50 equivalents of trifluoroacetic acid in dichloro-... 

An efficient synthesis of the 7-deoxy zaragozic acid core was deveioped by M.A. Calter and co-workers. The assembly of this complex structure was based on the interrupted Feist-Benary reaction, which produces highiy oxygenated dihydrofuranols that can be isolated. To this end, the sodium enolate of malondialdehyde was reacted with 2-bromo-3-oxo-diethyl succinate in benzene at room temperature to afford 29% of the c/s-dihydrofuranol. This product was converted to the zaragozic acid core in four steps. 

Two different approaches to the core structure of the zaragozic acids are based on the generation of oxonium ylides. 

Scheme 1. Biosynthesis of the core structure of the viridiofungins and the zaragozic acids.

Extensive studies on the structure-activity relationships (SAR) in a series of compounds derived from squalestatins 1 (zaragozic acid A) (25) and 3 (27) have been performed, focusing on the role of the carboxylic acids at C-3, C-4 and C-5 positions of [15 -(la,3a,4p,5a,6a,7P)]-4,6,7-trihydroxy-2,8-dioxabicyclo-[3.2.1 ]-octane-3,4,5-tricarboxylic acid [58-61]. Consequently, the modification of the carboxylic acid at C-5 in squalestatin 1 analogues was not tolerated, but the carboxylic acids at C-3 and C-4 were not absolutely required for the retention of squalene synthase inhibitory activity [58J. 

Zaragozic acids D (31) and D2 (32) were further isolated from cultures of the keratinophilic fungus Amauroascus niger as potent inhibitors of rat liver squalene synthase with IC50 values of 6 and 2 nM, respectively. Structures of zaragozic acids D and D2 are related to those of the previously described zaragozic acids A, B and C, which contain 4,6,7-trihydroxy-2,8-dioxabicyclo-[3.2.1]octane-3,4,5-tricarboxylic acid core unit and hydrophobic alkyl and acyl side chains [63]. 

Fig. (15). Structures of zaragozic acids F-10863A through D isolated from Mollisia sp.

Once fractionation has led to some physical characteristics of the active component, such as UV spectra or putative molecular weight, another literature search can be executed. During the isolation and structure identification of the zaragozic acids (also known as squalestatins) (75), a literature search of the Chemical Abstracts database was carried out within hours of isolating sufficient material to obtain a COSY spectrum, since the two substructures (A and B) were readily identified from these data (see Fig. 12). When the Chemical Abstracts search revealed that no known compounds contained either of these substructures, it was obvious that the compound was novel and therefore patentable. It was several more days before enough NMR and MS experiments had been carried out and an exhaustive structure determination completed, at which point the truly novel 2,8-dioxabicyclo[3.2. l]octane-3,4,5-tricarboxylate core of the zaragozic acids could be searched for in Chemical Abstracts and shown to be unprecedented in the natural product literature. 

The biological activity of zaragozic acids and the complexity of their structures have attracted the attention of numerous synthetic... 

Figure 1. (a) Structure of the zaragozic acids with the 2,8-dioxabicyclo[3.2.1]-octane skeleton (red) (h) conformationally frozen citric acid partial structure (blue) in zaragozic acid C. 

The total synthesis of zaragozic acid C (1) by Evans [7] is shown in Schemes 11 and 12. Evans identified a tartaric acid unit in the C3-C4 partial structure of zaragozic acid. Accordingly, his synthesis commences from a tartaric acid derivative (Scheme 11). The... 

Pfizer reported the discovery of a new class of structurally complex alkyl carboxylic acids, as exemplified by CP-225917 and CP-263114 (Figure 20), that are weak and non-selective inhibitors of squalene synthase and FPTase. These compounds were isolated by acid base liquid-liquid partition, Sephadex LH20 chromatography and reverse phase HPLC from ethyl acetate extracts of an unidentified fungus that also produced zaragozic acid A [97]. 

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