Natural Resistance of Plants to Pests - American Chemical Society

17 Insect Ecdysis Inhibitors Isao Kubo and James Klocke

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Downloaded by UNIV OF AUCKLAND on May 3, 2015 | http://pubs.acs.org Publication Date: January 16, 1986 | doi: 10.1021/bk-1986-0296.ch017

Division of Entomology and Parasitology, College of Natural Resources, University of California, Berkeley, CA 94720

A requisite for developmental growth in insects is molting, the entire process of the shedding of the old cuticle. The process of molting is initiated when the insect molting hormone, ecdysterone or 20-hydroxyecdysone (Figure 1), stimulates the epidermis to retract from the cuticle. This retraction, termed apolysis, is immediately followed by mitotic division of the epidermal cells and their subsequent secretion of both a protective procuticle and a gel-like molting fluid. Following activation of the molting fluid, enzymatic digestion of the old cuticle for resorption and reuse results in a thin (undigested) remnant of the old exocuticle, termed exuvia, which is subsequently split and cast off. The casting off of the exuvia, termed ecdysis, is accomplished by hydrostatic pressures brought about by the swallowing of air or water and the performance of muscular activities (1). When new cuticle is synthesized, it is soft and flexible so that the hydrostatic pressures unfold and expand the new cuticle thereby increasing its surface area and concomitantly casting off the old cuticle. After ecdysis, expansion of the new cuticle is brought to an end by the onset of sclerotization (tanning) (2), which involves the cross-linking of cuticular protein with ortho-quinone. The source of the ortho-quinone is tyrosine, whose mobilization is controlled by ecdysterone, as well as by a peptide hormone called bursicon. The major events of the molting process are apolysis, cuticular synthesis, ecdysis, and sclerotization (3, 4). The complexity of the sequence of physiological and developmental events occurring in the molting process, and the high degree of hormonal coordination with which the entire process must proceed, render the insect which must molt particularly vulnerable to exogenously applied chemicals. Molts are recurrent crises in the lives of arthropods (5). Chemicals which can trigger any of the major events of the molting process out of their normal sequence may be useful as insect control agents both because of their adverse effects on molting and also because of their possible 1

Current address: NPI-Plant Resources Institute, 417 Wakara Way, Salt Lake City, UT 84108. 0097-6156/86/0296-0206$06.00/0 © 1986 American Chemical Society

In Natural Resistance of Plants to Pests; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.


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s p e c i f i c i t y f o r organisms which molt (e.g., i n s e c t s ) . The present manuscript w i l l discuss those synthetic and natural chemicals which i n h i b i t or prevent ecdysis and, as such, either are presently available as or are candidates f o r Insect control agents. The actual shedding of the old c u t i c l e during molting i s termed ecdysis. Ecdysis i s triggered by a neurosecretory peptide, e clos ion hormone, which acts on the central nervous system to e l i c i t the ecdysial motor programmes (6). The release of ecloslon hormone i s i n turn regulated by the t i t r e of the molting hormone, ecdysterone (7). The i n h i b i t i o n of ecdysis, which can occur through a disruption of the normal t i t r e s of ecdysterone or ecloslon hormone or through other factors i n the complex pathway, i s e a s i l y observed as a gross morphological event i n which the "old" c u t i c l e remains enveloping the insect i n the pharate condition. The abnormal pharate condition prevents feeding and locomotion, and eventually r e s u l t s i n the death of the affected i n s e c t . The i n h i b i t e d ecdysis of a Bombyx mori (silkworm) l a r v a i s shown i n Figure 2. The l a r v a underwent normal apolysis, but f a i l e d to complete ecdysis and could not remove i t s head capsule or trunk exuvia and eventually died. u n t i l recently, most of the compounde which were found to i n t e r f e r e with ecdysis were steroids, either i d e n t i c a l to or s t r u c t u r a l l y s i m i l a r to ecdysterone. Ecdysterone, and many analogs of i t , have been isolated from both animal (zooecdysones) (8) and plant (phytoecdysones) (9) sources. Some of these compounds have been found to i n h i b i t ecdysis when applied exogenously to insects. For example, ponasterone A, which d i f f e r s from ecdysterone only i n the absence of a hydroxyl group at the C-25 p o s i t i o n (Figure 1), i n h i b i t e d the ecdysis of Cecropia silkworms (10), Tribolium confusum (confused f l o u r beetle) larvae (11), and Pectinophora gossypiella (pink bollworm) larvae (12). Ponasterone A, i s o l a t e d from the conifer Podocarpus g r a c i l i o r (Podocarpaceae), fed i n a r t i f i c i a l d i e t to P. gossypiella larvae resulted i n insects each with three head capsules because they underwent two f a i l e d molting cycles before death (Figure 3). Even though feeding became impossible a f t e r the f i r s t i n h i b i t e d ecdysis, because the adhering second head capsule covered the mouthparts, the larva synthesized a t h i r d head capsule before death · Ecdysis was i n h i b i t e d i n the insect to which ponasterone A, a molting hormone analog, was administered because a rapid decline of the ecdysteroid t i t r e below a certain c r i t i c a l l e v e l i s necessary to trigger the release of ecloslon hormone which i n turn triggers ecdysis (7). More potent dietary e f f e c t s on insects were found with synthetic steroid analogs, such as A7-53-cholestene-23,33,l4atriol-6-one, which i n h i b i t e d ecdysis i n B l a t t e l l a germanlca (German cockroach), and s c l e r o t i z a t i o n and metamorphosis i n Musca domestica (house f l y ) and T. confusum (13). Other synthetic analogs, the azasterole, i n h i b i t e d the d A?2,24 sterolreductase enzymes i n Manduca sexta (tobacco hornworm) and the growth and development of Aedes aegyptl (yellow-fever mosquito), T. confusum, and M. domestica (14)· None of the ecdysones or t h e i r analogs have been commercially exploited f o r insect control because of t h e i r limited e f f i c a c y when t o p i c a l l y applied or fed to many species of economically important insects and because of the complexity of the s t e r o i d nucleus (15). a n


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OH

R

HO.


OH HjC/^'XH, 20-Hydroxyecdysone (Ecdysterone)

H H,C^""CH,

Ponasterone A

R =

Figure 1. Stereostructures of the insect molting hormone, ecdysterone and the phytoecdysone, ponasterone A.

Figure 2. Ecdysis i n h i b i t i o n of a l a r v a of the silkworm, Bombyx morl. The insect underwent normal apolysis, but f a i l e d to complete ecdysis and could not remove i t s head capsule or trunk exuviae. Magnification X 12.



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Synthetic analogs o f other insect hormones ( i . e . , juvenile hormones) which i n h i b i t insect ecdysis have been commercialized f o r the control o f mosquitoes, f l i e s , fleas and some stored-products pests (16). Juvenile hormones (JH), a group of three c l o s e l y related terpenoids of which JH 3 predominates i n insects (Figure 4), can antagonize the function of ecdysterone i n some Insects which can result i n ecdysis I n h i b i t i o n (17). In a number of lepldopteran crop pests, exposure to analogs of juvenile hormone (e.g., methoprene, Figure 4) can also r e s u l t i n a delayed and usually abortive ecdysis (17). Similar e f f e c t s have been observed on the endoparasitlc wasps Apanteles congregatus (18) and Nasonla v l t r i p e n n i s (19), and on the small f r u i t f l y , Drosophila melanogaster (20). A derivative of f a m e s o i c a c i d , known to have JH-like a c t i v i t y i n silkworms, has been shown to i n h i b i t ecdysis of A. aegypti and Culex pipiens (house mosquito) larvae (21). One hypothesis on the mechanism of a c t i o n o f JH i n the I n h i b i t i o n o f ecdysis implicates the active r o l e o f JH i n the regulation o f ecdysone t i t r e s i n the insect body (17), possibly a consequence of an e f f e c t on the prothoracic glands (22). Another hypothesis implicates an e f f e c t o f JH on ecloslon hormone or I t s action (20, 18). Other groups of ecdysis i n h i b i t o r s act by i n h i b i t i n g c h i t i n synthesis. The most prominent of these are the synthetic 2,6-dihalogenated benzoyl-phenylurea compounds exemplified by the commercial i n s e c t i c i d e , Dimilin (diflubenzuron) (Figure 5) (23, 24). Dimilin acts by i n t e r f e r i n g with the normal deposition of the endocuticle causing i t t o be loosely attacked or detached from the epidermal layer (25). The Interference of Dimilin i n c u t i c l e deposition, controlled by the a c t i v i t y rate of c h i t i n synthetase (UDP-N-acetylglucosamine: c h i t i n N-acetylglucosaminyl transferase), r e s u l t s i n ecdysis I n h i b i t i o n and the death of affected insects (26, 27). A s i m i l a r e f f e c t was caused by the f u n g i c i d a l compound polyoxin D, a peptidyl pyrlmldine nucleoside a n t i b i o t i c produced by Streptomyces cacoi var. asoensis (28, 29). Polyoxin D was found to be a competitive i n h i b i t o r of c h i t i n synthetase i n fungi (30) and In insects (25, 27, 29). A natural plant compound that was found to i n h i b i t ecdysis through an i n h i b i t i o n of c h i t i n synthetase i s the naphthoquinone plumbagin (Figure 6) (31, 32). Plumbagin, i s o l a t e d from the roots o f the t r o p i c a l medicinal shrub, Plumbago capensis (Plumbaginaceae), i n h i b i t e d the ecdysis of four lepldopteran species o f a g r i c u l t u r a l pests (Table I ) . The larvae of P. gossypiella were the most susceptible since 90% died i n the pharate condition during the f i r s t molt ( E I O Q ) from the ingestion of 400 ppm plumbagin i n a r t i f i c i a l d i e t . The Elan value of plumbagin against the larvae of Heliothis zea ( c o m earworm), H. virescens (tobacco budworm), and Trichoplusia n i (cabbage looper) was approximately 1400 ppm. Concentrations of plumbagin lower than those causing ecdysis i n h i b i t i o n caused growth i n h i b i t i o n . The e f f e c t i v e concentration f o r 50% growth I n h i b i t i o n ( E C 5 0 ) was lowest f o r P. gossypiella (EC50 " 150 ppm) and higher for the other species (EC50 - 325 - 350 ppm) (Table I ) . In order to test f o r the p o s s i b i l i t y that the ecdysis i n h i b i t o r y a c t i v i t y of plumbagin was due to an i n h i b i t i o n of c h i t i n synthetase, an i n v i t r o assay was employed· Chitin




Figure 3. Ecdysis i n h i b i t i o n of a l a r v a of the pink bollworn, Pectinophora g o s s y p i e l l a . The l a r v a three head capsules which masked the functional mouthparts. The insect eventually starved to death. Magnification X 125.

Figure 4. Structures of the insect hormone, juvenile hormone 3 (JH 3) and a commercial analog of JH 3, methoprene.


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Inhibitors

synthetase extracted from T. n i integuments was preincubated with d i t h i o t h r e i t o l f o r 15 min. The ^H-chitin synthesized from UDP- H-N-acetylglucosamine ( f o r 60 min at 21° C) was collected on glass ndcrofiber f i l t e r s and the r a d i o a c t i v i t y measured. The results i n Table I I indicate that plumbagin i n h i b i t e d about 30% of the c h i t i n synthetase extracted from T. n i integuments at a concentration of 3 χ 10"^ M. This c h i t i n synthetase i n h i b i t o r y a c t i v i t y i s almost comparable to that a c t i v i t y of polyoxin D (Table I I ) . The integumental defect caused by the lowered c h i t i n synthetase a c t i v i t y resulted i n a c u t i c l e which could not provide adequate support f o r the muscular a c t i v i t y and high hemolymph pressure required f o r normal ecdysis to occur (33). Attempts were made to enhance the ecdysis i n h i b i t o r y a c t i v i t y of plumbagin (32). Two analogs of plumbagin based on a l k y l elongation at C-2 (n-pentyl and n-decyl) were synthesized and tested. Neither of these analogs showed ecdysis i n h i b i t o r y a c t i v i t y . Absence of the methyl group at C-2, such as found i n the natural plant compound juglone, also resulted i n a loss of ecdysis Inhibitory a c t i v i t y (31). Thus, while a methyl group i s necessary at the C-2 p o s i t i o n f o r a c t i v i t y , elongation of t h i s position with an a l k y l side chain resulted i n a loss of a c t i v i t y . Acetylation of the hydroxyl group at C-5 of plumbagin had no e f f e c t on the b i o l o g i c a l a c t i v i t y . However, elongation of the ester group at t h i s position resulted i n a l o s s of ecdysis i n h i b i t o r y a c t i v i t y . Thus, plumbagin and i t s acetate were more potent i n our bioaesaye than were the synthetic analogs (32). Although assays with other insects should be conducted, i t does not seem from an economic standpoint that plumbagin and i t s acetate themselves are of s u f f i c i e n t potency to warrant adaptation into pest management s t r a t e g i e s . However, the ease of synthesis of plumbagin (34) and i t s mode of action make i t a possible model f o r synthetic pesticide research. Although the l i m i t e d attempts to enhance the a c t i v i t y of plumbagin have been thus f a r unsuccessful, a d d i t i o n a l work w i l l hopefully r e s u l t In enhanced activity. Already discussed are three types of ecdysis i n h i b i t o r s , ecdysterone and i t s analogs, JH and i t s analogs (juvenoids), which antagonize the action of ecdysterone, and phenylurea compounds (e.g., Dimilin) and polyoxin D, which act by I n h i b i t i n g c h i t i n synthetase. Other chemicals i n h i b i t ecdysis by d i f f e r e n t , yet unknown, mechanisms. Thiosemicarbazones i n h i b i t e d ecdysis when t o p i c a l l y applied to f i f t h i n s t a r Oncopeltus fasciatus (large milkweed bug) (35). Similar to the e f f e c t found with juvenoids on B. germanlca nymphs and P i e r i s brassicae (cabbage b u t t e r f l y ) larvae T l 7 ) , thiosemicarbazones delayed the onset of the ecdysteroid peak i n 0. fasciatus (35), yet d i s s i m i l a r to the former, restoration of the ecdysteroid t i t r e by Injection d i d not prevent the molting aberrations. Topical application of a juvenoid to f i f t h i n s t a r 0. fasciatus resulted i n an accelerated production of ecdysteroid, and a shortened molting period (22), opposite to the effects found with the thiosemicarbazones. The thiosemicarbazones had no c h i t i n synthesis-Inhibiting e f f e c t s i n an i n v i t r o system which i s highly s e n s i t i v e to Dimilin (35). Possibly, the thiosemicarbazones a f f e c t the neurosecretory mechanism by which ecdysterone i s regulated. A natural plant compound which was found to i n h i b i t ecdysis 3


211


212


Table I. I n h i b i t i o n of ecdysis and growth i n four species of lepldopteran larvae fed plumbagin i n an a r t i f i c i a l d i e t . Assay period was f o r 10 days i n a dark incubator a t 25°C and 80% RH


Species

Instar

Pectinophora gossypiella (Gelechiidae) H e l i o t h i s zea (Noctuidae) H. virescens Trichoplusla n i (NoctuidaeT" a)

EIQQ

(ppm)

a

EC50

(ppm)

first

400 + 55

150 + 35

first first second

1400 + 225 1300 + 195 1400 + 250

350 + 50 325 + 50 350 + 75

EI90

values are the concentrations (ppm) of plumbagin causing 90% ecdysis i n h i b i t i o n - death and they are the means of 3 determinations + SE with 30 larvae/determination. b) E C 5 0 values are the concentrations (ppm) of plumbagin causing 50% growth i n h i b i t i o n and they are the means of 3 determinations + SE with 40 larvae/determination.

Table I I .

I n h i b i t i o n of c h i t i n synthetase extracted from fourthins tar Trichoplusia n l integuments. 100 y l of enzyme suspension were preincubated f o r 15 min at 21°C with 200 y l t r i s - H C l buffer (pH 7.25), lOmM MgCl , ImM DTT, 18 mM GlcNAc, and either plumbagin dissolved i n 10 μΐ DMSO or simply 10 u l pure DMSO. Reaction i n i t i a t e d at room temperature with 0.3 uCi UDP- H-GlcNAc. Following 60 min incubation (room temperature), reaction stopped by 5 ml 5% TCA. Acid-insoluble material was c o l l e c t e d on g l a s s - f i b e r f i l t e r s , washed repeatedly with TGA, dried and radioassayed 2

3

Inhibitor Plumbagin

Polyoxin D

Inhibitor Concentration (M) 3 3 3 3

χ χ χ χ

10-6 10-5 10-4 10-4

C h i t i n Synthetase I n h i b i t i o n (as % of control) 1.0 4.3 28.7 31.3



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i n insects, by some unknown mechanism, i s azadirachtin (Figure 7), a tetranortrlterpenoid of the limonoid type i s o l a t e d from the seeds of the neem tree, Azadirachta i n d i c a (Meliaceae) (36) and the f r u i t s of the chinaberry tree, Melia azedarach (Meliaceae) (37). Although the s k e l e t a l structure and stereochemistry of azadirachtin have not been t o t a l l y resolved (Figure 7) (38), the potent ecdysis i n h i b i t o r y a c t i v i t y of t h i s compound i s well known (39, 40, 41). The ecdysis i n h i b i t o r y a c t i v i t y of azadirachtin fed i n a r t i f i c i a l d i e t to three species of a g r i c u l t u r a l pests i s shown i n Table I I I . Azadirachtin was the most a c t i v e against Spodoptera frugiperda ( f a l l armyworm), the e f f e c t i v e concentration f o r 95% ecdysis i n h i b i t i o n ( E I 9 5 ) being 1 ppm i n a r t i f i c i a l d i e t . The ecdysis i n h i b i t o r y a c t i v i t y of azadirachtin against H. zea and P. gossypiella was 2 ppm and 10 ppm, respectively. Concentrations of azadirachtin lower than those causing ecdysis i n h i b i t i o n ( i . e . , l e s s than 1 ppm) i n h i b i t e d the growth of the treated larvae. Thus, as a growth i n h i b i t o r , azadirachtin was more potent against ϋ · frugiperda and P. gossypiella, the e f f e c t i v e concentration f o r 50% growth i n h i b i t i o n ( E C 5 0 ) being 0.4 ppm, than against H. zea ( E C 5 0 - 0.7 ppm) (Table I I I ) . Another natural product which was i s o l a t e d from A. indica and found to have potent ecdysis i n h i b i t o r y a c t i v i t y i s deacetylazadirachtinol (Figure 8) (42). The b i o l o g i c a l a c t i v i t y of deacetylazadlrachtinol fed i n a r t i f i c i a l d i e t to H. virescens i s shown i n Table IV. Although deacetylazadlrachtinol was about 2.5-fold l e s s active than was azadirachtin as an Insect growth Inhibitor ( E C 5 0 - 0.17 and 0.07 ppm, r e s p e c t i v e l y ) , the two compounds had the same ecdysis i n h i b i t o r y a c t i v i t y ( E I 5 0 0.80 ppm). Comparison of the structure (Figure 7) and a c t i v i t y (Table IV) of azadirachtin with those o f deacetylazadlrachtinol (Figure 8 and Table IV) seems to Indicate that the k e t a l i n the C-ring of azadirachtin i s not necessary f o r potent ecdysis i n h i b i t o r y a c t i v i t y , at l e a s t against H. virescens. This may be analogous to the observation of Dreyer (1983) that many of the most potent of the Insect feeding deterrent limonoids are either of the C-ring secotype or with features which allow C-ring opening. Several derivatives of azadirachtin were prepared and tested for b i o l o g i c a l a c t i v i t y . 3-Deacetylazadirachtin was found to have the same ecdysis i n h i b i t o r y a c t i v i t y as that found with azadirach t i n against H. virescens, while 13-acetylazadlrachtln was found to be about one-half as active i n the same bioassay. A number of other limonoids which were Isolated from plants i n the Meliaceae and the Rutaceae were tested f o r ecdysis and growth i n h i b i t o r y a c t i v i t i e s (Table V). Cedrelone (Figure 9) was unique among the compounds tested i n Table V since i t was the only limonoid, besides azadirachtin, whose t o x i c i t y ( L C 5 0 • 150 ppm) Included ecdysis i n h i b i t i o n when fed to pink bollworm larvae (43). Although i t i s unknown how azadirachtin acts as an ecdysis i n h i b i t o r , i t apparently does not act by i n h i b i t i n g c h i t i n synthetase (32). Possibly, ecdysis i n h i b i t i o n i s caused by a disruption of the t i t r e of ecdysterone (40, 44) or by an interference with the neuroendocrine system, prothoracicotropic hormone and a l i a t o t r o p i c hormone, which controls the t i t r e s of molting hormone and juvenile hormone, respectively (45).




Figure 5. Dimilin, insect ecdysis and c h i t i n synthetase inhibitor.

Figure 6. Plumbagin, insect ecdysis and c h i t i n synthetase i n h i b i t o r i s o l a t e d from Plumbago capensis (Plumbaginaceae).

Figure 7. Upper: previously accepted stereostructure of azadirachtin (36); Lower: recently proposed stereostructure of azadirachtin (38).


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Table I I I .

Insect Ecdysis

Inhibition of ecdysis and growth i n three species of f i r s t - i n s t a r lepldopteran larvae fed azadirachtin i n an a r t i f i c i a l d i e t . Assay period was 10 days i n a dark i n c u l a t o r at 25°C and 80% RH

Species

EI95

H e l l o t h i s zea Spodoptera frugiperda Pectinophora gossypiella


a)

215

Inhibitors

(ppm) 2 1 10

a

EC50

(ppm)k 0.7 0.4 0.4

EI95

values are the concentrations (ppm) of azadirachtin causing 95% ecdysis i n h i b i t i o n . b) E C 5 0 values are the e f f e c t i v e concentrations (ppm) of azadirachtin causing 50% growth i n h i b i t i o n .

Figure 8. Stereostructure of the insect ecdysis i n h i b i t o r y limonoid deacetylazadlrachtinol. Skeleton based on the structure of azadirachtin proposed by Zanno et a l . (36).

OH Figure 9. Structure of the limonoid, cedrelone, the t o x i c i t y of which included insect ecdysis i n h i b i t i o n .


216


Table IV.

I n h i b i t i o n of ecdysis and growth i n f i r s t - i n s t a r Heliothls virescens larvae fed two neem o i l limonoids i n an a r t i f i c i a l d i e t . Assay period was 10 days i n a dark incubator at 25°C and 80% RH

Test Compound

h

EC

5Q

(ppm) Deacetylazadlrachtinol

(ppm) 0.17

0.80 Azadirachtin

c

95% Confidence Limits 0.12-0.23 0.66-0.97

0.07

0.05-0.10 0.46-1.39


0.80

E I 5 0 values are the concentrations (ppm) causing 50% ecdysis inhibition. b) E C 5 0 values are the concentrations (ppm) causing 50% growth inhibition. c) The 95% confidence l i m i t s were determined using the methods of L i t c h f i e l d and Wilcoxon (46).

a)

Table V.

Insect growth i n h i b i t o r y a c t i v i t y of some Meliaceae and Rutaceae limonoids. Values are the dietary concentrations for 50% growth i n h i b i t i o n (EC ) n

Pectinophora gossypiella

Limonoid Azadirachtin Cedrelone Anthotheol Sendanin Methylangolensate Nkolbisonin 7-Deacetylgedunin Gedunin Azadlradione 7-Ke togedunin Nomilln Obacunone Evodoulone 7-Deacetylproceranone Tecleanine Limonin 7-Deacetylazadiradione Deactylnomllln

0.4 3 8 9 15 20 22 32 42 51

-96 175 210

-

290 950

Insect Species Spodoptera frugiperda 0.4 2 3 11 40 65 60 47 130 800 72 70 120 350 320 756 5000 NE*

Heliothls zea 0.7 8 24 45 60 71 165 50 250 900 95 97 80 740

-

900 3500 NE*

*NE - no e f f e c t at 2000 ppm.



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The mode of action of chemicals, besides those i n h i b i t i n g c h i t i n synthetase, which i n h i b i t ecdysis i s d i f f i c u l t to ascertain. Predominantly t h i s i s due to the complexity of the molting process and the number o f hormones involved i n i t s coordination. The effects o f several of these hormones ( i . e . , ecdysterone and JH) vary depending on the exogenous dose applied, the endogenous t i t r e at the time of application, the species and stage of the treated insect, etc. Nevertheless, the use of ecdysis i n h i b i t o r s i n insect control i s possible since the endpoint e f f e c t , that of ecdysis i n h i b i t i o n and concomitant death, i s e a s i l y observed as the most v i s u a l l y dramatic aspect of the molting process (7). Their use i n insect control i s desirable since ecdysis i n h i b i t o r s are s p e c i f i c f o r c h i t i n bearing organisms. Thus, i t might be expected that both natural (e.g., phytoecdysones, juvenoid hormones, polyoxin D, azadirachtin) and synthetic (e.g., d i m i l i n , thiosemicarbazones) ecdysis i n h i b i t o r s w i l l play an Increasingly important r o l e i n Insect control strategies. Acknowledgment s The authors thank Dr. M. F. Balandrln for h e l p f u l discussions. This work was supported i n part by a grant awarded by the U.S. National Science Foundation (PCM-8314500).

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41. Kubo, I.; Klocke, J. A. Agric. Biol. Chem. 1982, 46, 1951-3. 42. Kubo, I.; Matsumoto, Α.; Matsumoto, T.; Klocke, J. A. Tetrahedron 1985, in press. 43. Klocke, J. A. Ph.D. Thesis, University of California, Berkeley, 1982. 44. Rembold, H.; Klaus-Peter, S. Z. Naturforsch. Sect. C Biosci. 1981, 36, 466-9. 45. Rembold, H. In "Advances in Invertebrate Reproduction 3"; Engels, W.; Clark, W. Η., Jr.; Fischer, Α.; Olive, P. J. W.; Went, D. F., Eds.; Elsevier Science Publishers: New York, 1984; pp. 481-91. 46. Litchfield, J. T. Jr.; Wilcoxon, F. J. Pharmacol. Exp. Ther. 1949, 96, 99-113. RECEIVED September

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Natural Resistance of Plants to Pests - American Chemical Society

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