Spinosyn

Roush and coworkers developed a new one-pot sequence consisting of an intramolecular Diels-Alder- and an intramolecular vinylogous Morita-Baylis-Hillman-cyclization for the synthesis of spinosyns [31]. These compounds are poly-ketide natural products possessing extraordinary insecticidal activity. 

Kirst HA, Creemer LC, Naylor SA, Pugh PT, Snyder DE, Winkle JR, Lowe L, Rothwell JT, Sparks TC, Worden TV. (2002) Evaluation and development of spinosyns to control ectoparasites on cattle and sheep. Curr Topics Med Chem 2 675-699. 

The peer-reviewed literature is full of reports on natural products possessing insecticidal activity and references therein] therefore, the focus of this section will be on both recent and well investigated natural products. Of those well investigated natural products, at least three natural product derived products (neem, spinosyn, and pyrethrum) seem to be used more than all the others. 

Spinosad (Fig. 9) is a mixture of spinosyn A and spinosyn D, originally isolated from the soil Actinomycete, Saccharopolyspora spinosa. Spinosad is recommended for the control of a very wide range of caterpillars, leaf miners, thrips and foliage-feeding beetles. Spinosad is sold as an aqueous based suspension concentrate formulation under several trade names. 

Figure 8.7 Spinosyn derivatives obtained by combining gene inactivation, gene expression and feeding experiments.

Spinosyn A and D are new natural product-based pesticidal macrolides originally discovered by Eli Lilly scientists in search for new pharmaceuticals. 

Erythromycin A 64 and spinosyns A and D 65a/65b are important macrolides produced by Saccharopolyspora erythraea and Sacch. spinosa, respectively. Compound 65a contains per-O-methylated L-rhamnose and D-forosamine attached O-glycosidically to the aglycone. Gene knockouts in respective strains as well as expression of various sugar cassettes (along with appropriate GT gene(s)) in Sacch. erythraea mutants led to production of many derivatives of 64 and 65a and tylosin [111-114],... 

Gaisser S, Lill R, Wirtz G et al (2001) New erythromycin derivatives from Saccharopoly-spora erythraea using sugar O-methyltransferase from the spinosyn biosynthetic gene cluster. Mol Microbiol 41 1223-1231... 

Gaisser S, Martin CJ, Wilkinson B et al (2002) Engineered biosynthesis of novel spinosyns bearing altered deoxyhexose substituents. Chem Commun 21 618-619... 

Gaissser S, Carletti I, Schell U et al (2009) Glycosylation engineering of spinosyn analogues containing an L-olivose moiety. Org Biomol Chem 7 1705-1708... 

Spinosad is an insecticide that contains a mixture of spinosyn A and spinosyn D as active ingredients. It is derived from the soil actinomycete Saccharopolyspora spinosa under aerobic fermentation conditions. Spinosad is very effective in controlling lepidopterous insects. Its oral LD50 in rats is >5000 mg/kg. 

Nicotinic acetylcholine receptor Nicotine, neonicotinoids, spinosyns Agonism... 

Resistance genes can be dominant, recessive, incompletely dominant, or incompletely recessive. Resistance to carbamates and organophosphates is usually dominant or incompletely dominant. Resistance to DDT, Bt, and spinosyns is usually recessive. Resistance to dieldrin is usually incompletely dominant. Resistance to pyrethroids is usually incompletely recessive. As shown in Figure 10.1 and 10.2, diamondback moth resistance to per-methrin was inherited as an incompletely recessive, autosomal factor, whereas resistance to methomyl was inherited as an incompletely dominant, autosomal factor. In cases of monofactorial inheritance of resistance to insecticides, the degree of dominance (D) in the progeny can be calculated, as described by Stone (1968), as follows ... 

Gaisser S, Martin CJ, WiUdnson B, Sheridan RM, Lill RE, Weston AJ, Ready SJ, Waldron C, Crouse GD, Leadlay PE, Staunton J (2002) Engineered Biosynthesis of Novel Spinosyns Bearing Altered Deoxyhexose Substituents. Chem Commun 618... 

Spinosyns were discovered from the fermentation broth of Saccharopolyspora spinosa by screening for mortality of blowfly larvae, and a mixture of spinosyns A (116) and D (117) was approved and used successfully as a crop protection and an antiparasitic animal health agent. (151) Nodulisporic acids are an indole diterpenoid class discovered from various species of Nodulisporium as orally active antiflea and antitick agents for dogs and cats (152, 153). The most active of the series is... 

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