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Avermectin isolation

Avermectins and Ivermectin. The avermectias are pentacycHc lactones isolated from fermentation products of Streptomjces avermitilis and ivermectin is a semisynthetic chemical, 22,23-dihydroavermectia (46). Ivermectin is effective in very low doses for the control of red spider mites on deciduous fmits, in baits for the control of imported fire ants, and as a parasiticide for Onchocerca volvulus in humans and for catde gmbs. These insecticides appear to function as agonists for the neuroinhibitory transmitter y-aminobutyric acid (GABA) (see Antiparasitic agents, avermectins). [Pg.297]

In 1976 scientists at the Merck Corporation discovered a complex of eight closely related natural products, subsequently named avermectins A through in a culture of Streptomjces avermitilis MA-4680 (NRRL8165) originating from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan and isolated by the Kitasato Institute. Their stmctures are shown in Figure 1 (1 6). They are among the most potent anthelmintic, insecticidal, and acaricidal compounds known. [Pg.278]

Since the avermectins exhibit unprecedented potency, they are used at unusually low doses of 6 —300 )-lg/kg, which makes the detection and isolation of residues and metaboUtes from animal tissue a new challenge. For this reason a sensitive analytical assay requires a derivative suitable for detection at concentrations down to 1/10 or 1/100 of one ppm. Ivermectin and avermectin B are therefore converted into an aromatic derivative which allows detection by fluorescence absorbance. To achieve this derivatization, avermectin B, ivermectin, or their derivatives are heated with acetic anhydride in pyridine at 100°C for 24 h (30). The reaction time can be reduced to 1 h by using /V-methylimidazole as a catalyst (31). The resultant... [Pg.282]

The avermectins also possess a number of aUyflc positions that are susceptible to oxidative modification. In particular the 8a-methylene group, which is both aUyflc and alpha to an ether oxygen, is susceptible to radical oxidation. The primary product is the 8a-hydroperoxide, which has been isolated occasionally as an impurity of an avermectin B reaction (such as the catalytic hydrogenation of avermectin B with Wilkinson s rhodium chloride-triphenylphosphine catalyst to obtain ivermectin). An 8a-hydroxy derivative can also be detected occasionally as a metaboUte (42) or as an impurity arising presumably by air oxidation. An 8a-oxo-derivative can be obtained by oxidizing 5-0-protected avermectins with pyridinium dichromate (43). This also can arise by treating the 8a-hydroperoxide with base. [Pg.283]

The double bonds of avermectins react with y -chloroperbenzoic acid to give 3,4-, 8,9-, and 14,15-epoxides. The 8,9-epoxide is the primary product and can be isolated in good yield (45). The 8,9-epoxide was opened by aqueous acids to the 8,9-diol (46). The 3,4-diol can be obtained readily and regiospecificaHy by osmium tetroxide oxidation. Neither peracids nor OsO will attack the 22,23-double bond. [Pg.283]

Based on a correlation of anthelmintic activity and HPLC analysis of the total avermectin complex, it was estimated that the third fermentation contained a minimum of 9 pg/ml. Improvement of the medium increased the yield by the original culture (MA-4680) to 120 yg/ml. A high-producing isolate (MA-4848) obtained from this culture produced nearly 500 pg/ml of total avermectins. Thus, this culture yielded readily to medium improvement and isolate selection to produce relatively large amounts of the avermectins. Accounts of the early fermentation studies and taxonomy have been published (1-2). [Pg.7]

Isolation. The avermectin complex, consisting of four major components designated Aj, ia 2a four lower... [Pg.9]

Both malonyl-CoA and methylmalonyl-CoA are then utilized as extender units. The heterocyclic rings are easily accounted for the spiro system is merely a ketal, though the tetrahydrofu-ran ring requires further hydroxylations of the basic skeleton for its construction. Avermectins are usually isolated as a mixture in which the main a component has a 2-methylpropyl group... [Pg.100]

Another important class of anti-infective natural products introduced in recent years is the avermectins, polyketide-derived macrolides that were originally isolated from several species of Streptomyces. The major drug in this class, ivermectin, was originally developed to treat and control nematodes and parasites in livestock. In recent years, however, the potential of ivermectin for the treatment of human disease has also been realized, and it is now used to treat onchocerciasis (river blindness), a disease that afflicts 40 million people worldwide (De Smet, 1997). [Pg.59]

Bu Lock et al. had shown initially [24] that supplementation of S. avermitilis fermentations with a range of fatty acids resulted in their uptake and incorporation to generate novel avermectins modified at the C25 side chain of the molecule. This approach, described as precursor-directed biosynthesis, has been employed to produce many new antibiotics [25], but the co-expression of the parent molecule interferes with the detection and isolation of the novel analogs. To circumvent these difficulties, the elegant technique of mutational biosynthesis [26] or mutasynthesis [27,28] was developed. In this approach, a mutant of an organism, deficient in the production of an essential precursor for the secondary metabolite of choice, is isolated, and precursor-directed biosynthesis is then employed to generate only the novel analogs. [Pg.121]

S. avermitilis and the biosynthesis of avermectins constitute an interesting example where traditional techniques such as chemical mutagenesis and protoplast fusion combined with recombinant DNA technology have been successfully applied in mutant isolation and strain improvement. In addition, this system offered the first opportunity to apply mutasynthesis to the production of better analogs, an application that had never before been exploited commercially. An intense doramectin development effort was therefore initiated with the Mrf-deficient mutants of S. avermitilis. The first step in this process involved the isolation of mutants deficient in 5-Omethyltransferase activity to maximize levels of the more bioactive class B avermectins [13], Thereafter, a combination of strain im-... [Pg.130]

Avermectins are a group of closely related compounds isolated from the fungus Streptomyces avermitilis that are used to control the parasites of humans and animals, as well as arthropod pests in crops. They have fairly high mammalian toxicity, but their movement into treated leaves, oral activity against insect pests, and rapid breakdown in sunlight are all favorable properties. In insects and worms poisoned by avermectin, inactivity and flaccid paralysis occur from its relaxing effect on muscles. [Pg.239]

Gene clusters (or parts thereof) controlling the biosynthesis of several other complex polyketides, including avermectin [25],rapamycin [26], oleandomycin [164], and soraphen [165], have been isolated and sequenced. In aU cases, the PKSs have been found to be organized into individual modules with each module containing the appropriate sets of active sites. Thus, the modular hypothesis appears to be well-substantiated now in several model systems. Intriguingly, in the case of rapamycin, biosynthesis of the entire macrocycle involves activity of a 12-module PKS as well as a peptide synthetase module (see below). [Pg.114]

There is no major distinction between the avermectins and milbemycins, which are based on the same complex polyketide macrocycle (168) the avermectins are oxygenated at C-13 and bear a disaccharide on this oxygen. They have been isolated from cultures of a... [Pg.891]

A variant of this process was used to achieve a chain extension at C5 of a pentose derivative, allowing the construction of the oxahydrinden part of avermectins [59,156]. As shown in Scheme 11.49, the D-ribose derived aldehyde 217 was treated with ( )-trimethylcrotylsilane in the presence of BF3-Et20 [157]. This produced a mixture of three isomers in an 8.9 1.1 1.0 ratio, from which compound 218 was isolated in a yield of 78%. The subsequent steps allowed deoxygenation of the sugar ring to give the diol 219. This compound was, in turn, transformed into the... [Pg.535]

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). [Pg.801]

Dutton and coworkers [21] have isolated about 36 avermectins (10) which are produced through mutational biosynthesis by Streptomyces avermitilis, a mutant strain ATCC-53568. These antibiotics exhibit broad-spectrum of antiparasitic activity. Several avermectin homologues (11) were produced by S. avermitilis in presence of externally supplied sodium 2-methylpentanoate and sodium 2-methylhexanoate. The homologues, thus produced, carry 2-pentyl and 2-hexyI groups, respectively, at the C-25 position of the aglycone moiety. These antibiotics are designated as avermectin "c" and "d", respectively, which possess high anthelmintic and insecticidal activities 1221. [Pg.73]

Milbemycin P3 (383) is a 16-membered macrocyclic lactone isolated from the fermentation broth of Streptomyces B-41-146 and is the simplest member of a family of compounds structurally related to the avermectins. Milbemycin P3 has been demonstrated to have marked insecticidal as well as limited antibiotic activity. Structurally, 383 is a 16-membered lactone fused to an aromatic ting. Although nearly devoid of asymmetric centers on the cyclic framework, it does contain the rather unusual spiroketal moiety. [Pg.88]


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See also in sourсe #XX -- [ Pg.3 , Pg.4 , Pg.5 , Pg.12 ]




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