Antijuvenile hormones

Information relating to the 13C spectra of chromenes is sparse, being restricted to some 2,2-disubstituted derivatives (cf. Figure 5). Substituents in the aromatic ring of chromenes affect the electron density at the double bond and an attempt has been made to relate the antijuvenile hormone activity of the precocenes (76 R = H or OMe) to the electron density at C-3 and C-4, using I3C chemical shifts as a measure of the latter property. Whilst C-4 is essentially unaffected by substitution, it appears that a 13C shift of C-3 at less than 130 p.p.m. is a necessary condition for activity (81MI22200). 

Isolation and identification of the two natural antijuvenile hormones revealed two simple chromenes 7-methoxy-2,2-dimethyl chromene and 6,7-dimethoxy-2,2-dimethyl chromene (Figure 3). Since these compounds induced precocious metamorphosis, we called them Precocene I and II respectively. Subsequently we found that both compounds had been previously identified and synthesized ( 15, 16, 17). We developed an efficient synthesis for these compounds shown in Figure 4. 

As previously stated, these compounds do not show antijuvenile hormone activity against all insects, but open the door to a new mode of insect control which affects most insect stages and provides a broader dimension to the endocrinologic strategy of insect control. 

Precocenes I and II are natural products with a simple chromene structure (7-methoxy- and 6,7-dimethoxy-2,2-dimethylchromene) which were isolated from plant sources and exhibited powerful antijuvenile hormone activities in several types of insects (1). 

On the other hand, the recent discovery of antijuvenile hormone activity in several o-isopentenylphenols, compounds biogenetically related to chromenes, has led to the proposal of a direct alternative alkylation pathway, via rearrangement of precocenes to quinone me-thides (3). 

Preliminary results of antijuvenile hormone bioassays for precocious metamorphosis in immature stages of Oncopeltus fasciatus revealed that some of the non-linear derivatives (VI) showed higher activities and lower toxicities that those exhibited by natural precocenes or 7-ethoxy-6-methoxy-2,2-dimethylchromene, one of the most active synthetic analogs known. In addition, some of these compounds were unexpectedly inactive in the sterilization bioassay with adults of the same species (8). Further investigation of antijuvenile hormone activities of selected compounds of this series in other insects is now in progress. 

In searching for a relationship between antijuvenile hormone activities and epoxide chemical reactivity, we attempted to apply as a chemical probe the m-chloroperoxybenzoic-alkaline fluoride system, a reagent developed in this laboratory for preparation of acid labile epoxides (20). However, formation of hemiesters of 3,4-dihydroxy precocene, was the predominant reaction in the case of activated chro-mene structures. 

Recently much work has been devoted in understanding the antijuvenile hormone action of plant chromenes from Ageratum spp. (10, 31,32). The allatocidal activity of precocenes is apparently due to a balance of decreased detoxification in peripheral tissues and... 

As screening techniques become more sophisticated, the range of compounds that are potentially valuable as leads should increase. As, an example, the antijuvenile hormone action of the precocenes has been cited. Their spectrum of activity is limited, but the study of their action has revealed potential biochemical target sites. 

Ethyl-4-[2-(t-butylcarbonyloxy)butoxy] benzoate (ETB, ZR-2646, 71) occupies an intermediate position between the juvenile hormone mimics and the antijuvenile hormones to be discussed later. It acts as an anti-JH at low doses and as a JH mimic at high doses. The nature of this JH agonist/antagonist action is not understood, yet its interference with the induction of juvenile hormone esterase seems to elucidate at least partly its action on insects (Staal, 1977 Sparks et al., 1979). 

Phytochemicals, such as the precocenes, isolated from Ageratum houstonianum [126], interfere with JH biosynthesis. In sensitive insect species, application of these dichromenes to larval instars results in precocious metamorphosis to sterile adults or sterility in adult females following treatment. Pesticides based on these compounds would be useful in the control of insects which are primarily destructive in their immature stages. Other phytochemicals which potentially function as "antijuvenile hormones" include dimethyl sciadinonate, isolated from the leaves of avocado, Persea americana Mill [127, 128], Ingestion of this... 

Considerable interest has followed from the early work on precocenes 1 and 2 (ref. 37), compounds having antijuvenile hormone activity and in consequence a number of syntheses have been developed. In the original work known methodology (ref. 85) was used. Thus, the reaction of 3-methoxyphenol and of... 

Bowers, W. S. and M. Aregulun, Discovery and identification of an antijuvenile hormone from Chrysanthemum coronarium, Mem. Inst. Oswaldo Cruz, Riodegeneiro, 82, Suppl. 3, 51-54 (1987). 

Other representatives of this group of compounds (such as compounds 13 and 14) from Ageratum houstonianum have antijuvenile hormone activity and cause precocious production of adult insects. Because of these properties, the compounds are called precocenes. Female insects that are exposed to these compounds never reach sexual maturity. External application of the compounds to second-instar larvae of the milkweed bug, Oncopeltus fasciatus, causes the nymphs to molt to normal third- and fourth-instar larvae and then to precocious, sterile adults (Proksch and Rodriguez, 1983, 1984 Rodriguez, 1983). 

Precocene I and precocene II are two natural products isolated from Ageratum houstonnianum (Figure 11) (24). Studies showed these compounds possess antijuvenile hormone activity, and they are able to induce precocious metamorphosis, cause sterilization, and/or force diapause in certain insects. 

Other natural precocenes and synthetic analogs have been prepared and biologically evaluated (Isman, 1989). Synthetic chromanes showed significantly less activity than the parent chromenes (precocenes) while the acetylchromenes showed antijuvenile hormone... 

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