Nereistoxin

Nereistoxin is a toxin produced by a marine polychaete. It is too toxic to be a safe pesticide, but when built into another molecule, it is very useful. 

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Nereistoxin (C H jNS2) kills fish and insects but is relatively non-toxic to homeotherms. The LD q value in mice varies from 30-1000 mg/kg depending on... 

A variety of derivatives of 2-dimethylamino-l,2-propanedi-thiol have been synthesized and evaluated as proinsecticides of nereistoxin (29). The most prominent of these at present is, -[2-(dimethylamino)-l,3-propanediyl] bis(benzenethiosulfo-... 

In searching for other proinsecticides of nereistoxin it must be kept in mind that the compound must possess labile groups bonded to the thiolsulfur atoms so that nereistoxin may be formed readily. Cartap and bensultap represent two types of compounds which may be transformed into nereistoxin by two different processes. A plausible mechanism for cartap is split of the S-C(O) bond by attack of a nucleophile, e.g. water, on the carbonyl carbon atoms, generating the 2-dimethylaminopropanedithiol which is then oxidized to nereistoxin. 

In contrast, attack of water on bensultap should take place through a bis-sulfenic acid intermediate to eventually give nereistoxin (30) ... 

Thus, the thiol sulfur may act as either a leaving group in car-tap or as an electrophile in bensultap on route to the formation of nereistoxin. Therefore, the number of nereistoxin analogs which may be prepared for insecticidal evaluation is very large. This includes the possibility of derivatives formed from the reaction between 2-dimethylamino-propane-l,3-dithiol and the chlorosulfenyl and chlorosulfinyl intermediates described in Figure 2. 

Animal Sources. The marine annelid worm Lumbrineris hetero-poda produces an insect toxin nereistoxin, 24, 4-N,N-dimethyl-amino-1,2-dithiolane (5 ). The mink MusteXa vison) affords 2,2-dimethylthietane, 14, and 3,3-dimethy1-1,2-dithiolane, 25 (28,63, 64), the ferret Musteta putoris) secretes 14, 25, cis- and trans-2,3-dimethylthietane, 2-propyl- and 2-pentyl-thietane, cis and trans-3,4-dimethyl-l,2-dithiolane, and 3-propyl-l,2-dithiolane (65), and the stoat (Mustela erminea) contains 2-ethyl-, 2-propyl-, and 2-pentyl-thietane, and 3-ethyl- and 3-propyl-l,2-dithiolane in its anal gland (5, ). These several thiaheterocycles from mustela species probably function as scent markers. 

Nereistoxin (44) is a 1,2-dithiolane neurotoxic derivative isolated from a marine annelid, Lumbriconercis heteropoda Marenz.61 Nereistoxin served as a model for the commercial insecticide Padan. 

The tobacco alkaloid nicotine (96) (B-67MI10702) is insecticidal by virtue of its action on the acetylcholine receptor. It was used widely as an aphicide, especially as a fumigant. Another natural product thought to act on the same receptor is the 1,2-dithiolane nereistoxin (97) (B-72MI10703), isolated from the marine annelid Lumbriconereis heteropoda. The active form has been shown to be the ring opened dithiol (98), and the protected form of it, cartap (99), is sold as a rice insecticide. The 1,2,3-trithiane thiocyclam (100) (72SAP7007824) is also active, presumably because of metabolic conversion to (98). 

A number of naturally occurring compounds with a disulfide unit have shown interesting biological activity [28, 29]. Nereistoxin, charatoxin, asparagusic acid, a plant growth inhibitor, and lipoic acid, a key co-factor in the oxidative decarboxylation of pyruvate, are examples taken in the 1,2-dithiolan series. 

Acetylcholineesterase A nereistoxin sensor is prepared from a combination of AChE, ChO and an O electrode. Good linearity was observed. Used for determination of ACh and phosphate. [73]... 

The members of this class of insecticides are all analogs of nereistoxin, a natural toxin of the marine worm Lumbriconcrcis heteropoda. This class includes thiocyclam, cartap, and bensultap. 

Figure 7.23 Diagrammatic representation of cross section of nicotinic acetylcholine receptor showing various sites that bind acetylcholine, insecticides, toxins, and drugs. ACh, acetylcholine NTX, nereistoxin a-BGT, a-bungarotoxin H12-HTX, pH]perhydrohistrionicotoxin PCP, phencyclidine. (From Eldefrawi, M.E. and Eldefrawi, A.T., in Safe Insecticides Development and Use, Hodgson, E. and Ruhr, R.J., Eds., Marcel Dekker, New York, 1990, p. 155. With permission.)...

The nereistoxin analogs (cartap hydrochloride, bensultap, and thiocyclam) are all proinsecticides that must be activated in vivo to become nereistoxin (see Chapter 4, subsection 4.2.12.8 for nereistoxin structure). Nereistoxin acts as an antagonist of the acetylcholine receptor. Unlike with nicotine, insects treated with nereistoxin are rapidly immobilized without convulsive symptoms, possibly because nereistoxin does not induce depolarization (Corbett et al., 1984). 

Several naturally occurring organosulfur compounds show pesticidal activity examples include nereistoxin (77), isolated from the marine worm Lumbriconereis heteropoda, which is insecticidal, and the antifungal antibiotic gliotoxin (78) (Figure 10), produced by the soil fungus Trichoderma viride. 

Of the 25 animal phyla, almost half are worms. Thus, it is not at all surprising that some worms contain toxins. The nemertines are a phylum of over 800 known species which resemble flatworms but are active predators on crustaceans and other worms. This phylum is exceptionally toxic among the various worm phyla. The Heteronemertine side possesses peptide toxins which appear to be only defensive, as these animals have no means of injecting a venom. The peptides include neurotoxins, which enhance excitability of nerve membranes, and cytolysins, which permeabilize and destroy cell membranes. Members of the Hoplonemertine class inject a venom into their prey using a mineralized stylet located in their proboscis, which is also used to immobilize the prey. Their toxins are alkaloids similar to nicotine which in minute amounts paralyze crustaceans and annelid worms and primarily activate nicotinic acetylcholine receptors. Another well-known worm toxin is nereistoxin, a disulfide-containing alkaloid which also binds to nicotinic... 

Cartap is also an important insecticide acting at the nicotinic acetylcholine receptor site. It causes insects to stop feeding, is systemic, and has a low mammalian toxicity. It should therefore be a perfect insecticide. Cartap is not toxic per se, but is biologically converted to the cholinergic agonist nereistoxin, described later. 

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