Avermectins structures

DJ MacNeil, JL Occi, KM Gewain, T MacNeil. Correlation of the avermectin polyketide synthase genes to the avermectin structure. Implications for designing novel avermectins. Ann NY Acad Sci 123-132, 1994. 

The avermectins are a group of closely related 16-membered macrocyclic lactones extracted from a fermentation broth produced by a culture of Strepto-myces avermitilis MA-4680 (NRRL 8165) isolated at the Kitasato Institute from a soil sample collected at Kawana, Ino City, Shizuoka Prefecture, Japan [4]. They are the most potent anthelmintic and acaricidal compounds known. Avermectin structures are shown in Fig. 1. 

Kao CM, Luo G, Katz L, Cane DE, Khosla C. Engineered biosynthesis of structurally diverse tetraketides by a trimodular polyketide synthase, J Am Chem Soc 1996 118 9184-9185. MacNeil DJ, Occi JL. Gewain KM, MacNeil 1. Correlation of ihe avermectin polyketide synthase genes to the avermectin structure Implicarions for deigning novel avermeccins. Ann NY Acad Sci 1994 721 123-132. 

Cross-cyclization of epoxides with homoallylic amines is an easy way to access tetrahydropyran moieties, which form the core structure of many biologically important natural products such as avermectins, aplysiatoxin, oscillatoxins, latrunculins, talaromycins, acutiphycins, and apicularens. Even though many methods are available for the synthesis of this moiety [14—24], its importance and wide applicability demands further methods. 

The avermectins (Figure 3.67) have no antibacterial activity, but possess anthelmintic, insecticidal, and acaricidal properties, and these are exploited in human and veterinary medicine. The avermectins are also 16-membered macrolides, but their structures are made up from a much longer... 

Eight naturally occurring, structurally related avermectins are produced by Streptomyces avermitilis [7], The avermectin polyketide structure is derived from seven acetate and five propionate residues, together with a single 2-methylbutyric acid or isobutyric acid residue which forms the sec-butyl or isopropyl group attached to the C25 of the spiroketal moiety [8,9] (Fig. 1). The avermectin agly-cone is further modified by glycosylation at C13, with the attachment of two O-methylated oleandrose residues and O-methylation at C5. Thus, S. avermitilis... 

Figure 1 Structure of the avermectin molecule. As discussed in the text, there are eight naturally occurring, structurally related avermectins, which arise from the presence of (1) either a methoxy or a hydroxyl group at C5 (OR3), (2) the presence of either double-bond carbons at C22,23 or a hydroxyl group at C23 (Ri), and (3) the presence of either a methyl or an ethyl residue (R2) located at the isopropyl or the sec-butyl group, respectively, that is attached to C25.

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

Fig. 16. Chemical structure of abamectin avermectin R = C2H5, and avermectin B15, R = CH3. (Tritium label at the 5 position)... 

The avermectins, particularly, have been the subject of intense commercial interest because they possess potent activity against both nematode and arthropod parasites of livestock (229). A full discussion of structure-activity relationships would be out of place here, not least because the data are voluminous, so we shall concentrate on the development of ivermectin, which has been a major success. 

Structural designation of avermectins is quaintly based on three series A, B a, b and 1, 2. These are illustrated diagrammatically. Greater activity resides in the B series, with a free OH at position 5. There is little difference in potency between the a and b series. In the more potent B series there are important differences between the 1 series and the 2 series ... 

Despite their macrolide structure, avermectins lack activity against bacteria... 

---