Bioregulators for Pest Control - American Chemical Society

16 Proallatocidins FRANCISCO CAMPS

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Instituto Quimica Bio-Orgánica (C.S.I.C.), Jorge Girona Salgado, 18-26, 08034-Barcelona, Spain

The rationale for design of proallatocidins related to chromenic structure of precocenes is discussed. Stabi lization against environmental conditions and insect metabolic pathways, as well as modification of trans port properties, are some of the leads followed for the synthesis of more powerful insect growth regulators of this type. Some aspects of the chemistry of 3,4-epoxyprecocenes are also examined. P r e c o c e n e s I and I I a r e n a t u r a l p r o d u c t s w i t h a s i m p l e chromene s t r u c t u r e (7-methoxy- and 6,7-dimethoxy-2,2-dimethylchromene) which were i s o l a t e d from p l a n t s o u r c e s and e x h i b i t e d p o w e r f u l a n t i j u v e n i l e h o r mone a c t i v i t i e s i n s e v e r a l t y p e s o f i n s e c t s ( 1 ) .

CH3O. U

Precocene I

Precocene II

There i s now s t r o n g e v i d e n c e t h a t p r e c o c e n e s a c t a s p r o a l l a t o c i d i n s , which a r e t r a n s f o r m e d by a l l a t a l mono-oxygenases i n t o a h i g h l y r e a c t i v e 3,4-epoxide. T h i s epoxide i s assumed t o be t h e t r u e c y t o x i c agent by s e l e c t i v e a l k y l a t i o n o f c e l l u l a r elements o f the i n s e c t c o r pora a l l a t a glands (2). On the o t h e r hand, t h e r e c e n t d i s c o v e r y o f a n t i j u v e n i l e hormone a c t i v i t y i n s e v e r a l o - i s o p e n t e n y l p h e n o l s , compounds b i o g e n e t i c a l l y r e l a t e d t o chromenes, has l e d t o the p r o p o s a l o f a d i r e c t a l t e r n a t i v e a l k y l a t i o n pathway, v i a r e a r r a n g e m e n t o f p r e c o c e n e s t o quinone methides (3). F o r the above c h a r a c t e r i s t i c s , p r e c o c e n e s were c o n s i d e r e d a s p o t e n t i a l l e a d compounds f o r t h e development o f a new g e n e r a t i o n o f i n s e c t i c i d e s . A c c o r d i n g l y , i n the l a s t y e a r s , e x t e n s i v e r e s e a r c h has

0097-6156/85/0276-0237S06.00/0 © 1985 American Chemical Society

Hedin et al.; Bioregulators for Pest Control ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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been c a r r i e d o u t i n a v a r i e t y o f academic and i n d u s t r i a l l a b o r a t o r i e s f o r the d e s i g n o f more p o w e r f u l i n s e c t growth r e g u l a t o r s o f t h i s type, which s h o u l d s i m u l t a n e o u s l y combine, among o t h e r f e a t u r e s , g r e a t e r r e s i s t a n c e t o the p e r i p h e r a l d e t o x i f i c a t i o n i n the i n s e c t and minimal t o x i c i t y a g a i n s t n o n - t a r g e t organisms, p a r t i c u l a r l y v e r t e b r a t e s . In the p r e s e n t communication, we summarize some o f our e f f o r t s i n t h i s area. Chemical

S t a b i l i z a t i o n o f Precocene

Structures


In view o f the r e p o r t e d l a b i l i t y o f the chromene s k e l e t o n under en v i r o n m e n t a l - l i k e c o n d i t i o n s , i . e . a c i d promotes d i m e r i z a t i o n and l i g h t causes rearrangement o f chromene t o quinone methide (4) one o f our f i r s t c o n c e r n s was t h e c h e m i c a l s t a b i l i z a t i o n o f the p r e c o c e n e structures for i t s potential application i n f i e l d t r i a l s .

Dimers

We a n t i c i p a t e d t h a t r e p l a c e m e n t o f one v i n y l hydrogen by f l u o r i n e i n the n a t u r a l compound would reduce the r e a c t i v i t y o f the chromene 3,4double bond w i t h o u t p r e v e n t i n g the above enzymatic e p o x i d a t i v e b i o a c t i v a t i o n o f t a k i n g p l a c e , due t o the s i m i l i t u d e o f atomic r a d i i o f f l u o r i n e and hydrogen. However, 3 - f l u o r o p r e c o c e n e a n a l o g I I I , p r e p a r e d by m o d i f i c a t i o n o f known p r o c e d u r e s f o r the s y n t h e s i s o f chromenes ( 5 ) was i n a c t i v e . L i k e w i s e , s u b s t i t u t i o n o f t r i f l u o r o m e t h y l group f o r one o f the two gem-dimethyl groups a t the C-2 s i t e ( 6 ) , t o s t r e n g h t e n the C-2 oxygen bond, p r e c l u d i n g the above rearrangement, r e s u l t e d i n a d e c r e a s e o f a c t i v i t y i n the c o r r e s p o n d i n g t r i f l u o r o m e t h y l a n a l o g IV.


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Proallatocidins

S t a b i l i z a t i o n against

Insect Metabolic

Degradation


One o f t h e c o n c l u s i o n s from AJH s t r u c t u r e a c t i v i t y s t u d i e s i s t h e im p o r t a n c e o f an u n s u b s t i t u t e d double bond and a C-7 a l k o x y s u b s t i t u e n t i n t h e chromene s t r u c t u r e t o e l i c i t AJH a c t i v i t y . However, r e s u l t s o f p r e c o c e n e metabolism i n d i f f e r e n t i n s e c t s p e c i e s r e v e a l e d t h a t c l e a vage a t t h i s s u b s t i t u e n t i s one o f t h e main d e t o x i f i c a t i o n mechanisms o b s e r v e d . A c c o r d i n g l y , we e x p e c t e d t h a t an i n c r e a s e o f s t e r i c h i n drance a t t h i s s i t e might p r e v e n t t h e o c c u r r e n c e o f such a c l e a v a g e and, i n t h i s way, enhance t h e AJH a c t i v i t y . T h i s r e q u i r e m e n t was f u l f i l l e d by p r e p a r a t i o n o f d i h y d r o b e n z o d i p y r a n d e r i v a t i v e s V and VI, i n which a b u l k y p s e u d o t e r b u t o x y s u b s t i t u e n t i s p r e s e n t a t C-7 o f t h e chromene s t r u c t u r e , as p a r t o f a 2,2-dimethylchroman r i n g , l i n k i n g t h i s s i t e and C-6 o r C-8, r e s p e c t i v e l y i n l i n e a r i s o m e r s V o r a n g u l a r d e r i v a t i v e s VI ( 7 ) .

VI

V

P r e l i m i n a r y r e s u l t s o f a n t i j u v e n i l e hormone b i o a s s a y s f o r p r e c o c i o u s metamorphosis i n immature s t a g e s o f O n c o p e l t u s f a s c i a t u s r e v e a l ed t h a t some o f t h e n o n - l i n e a r d e r i v a t i v e s (VI) showed h i g h e r a c t i v i t i e s and lower t o x i c i t i e s t h a t t h o s e e x h i b i t e d by n a t u r a l p r e c o c e n e s o r 7-ethoxy-6-methoxy-2,2-dimethylchromene, one o f t h e most a c t i v e s y n t h e t i c a n a l o g s known. I n a d d i t i o n , some o f t h e s e compounds were unexpectedly i n a c t i v e i n the s t e r i l i z a t i o n bioassay with adults o f the same s p e c i e s ( 8 ) . F u r t h e r i n v e s t i g a t i o n o f a n t i j u v e n i l e hormone a c t i v i t i e s o f s e l e c t e d compounds o f t h i s s e r i e s i n o t h e r i n s e c t s i s now i n p r o g r e s s . Modification o f transport

properties

A l t h o u g h t h e d i f f e r e n t i a l s e n s i t i v i t y o f hemi- and h o l o m e t a b o l o u s l a r v a e t o t h e p r e c o c e n e s remains u n e x p l a i n e d , i t has been shown t h a t the c o r p o r a a l l a t a o f h o l o m e t a b o l o u s s p e c i e s a r e s e n s i t i v e t o t h e p r e cocenes i n v i t r o ( 9 ) . L i k e w i s e , i t has been demonstrated t h a t p r e c o c e nes a r e r a p i d l y s e q u e s t e r e d by hemolymph p r o t e i n s i n s e v e r a l i n s e c t s p r e v e n t i n g an e f f e c t i v e amount o f the p r e c o c e n e s from ever r e a c h i n g the c o r p o r a a l l a t a ( 1 0 ) . C o n s e q u e n t l y , we a n t i c i p a t e d t h a t t o overcome t h e s e problems i t might be i m p o r t a n t t o i n c o r p o r a t e m o i e t i e s i n t h e p r e c o c e n e s t r u c t u r e t o a l t e r t h e t r a n s p o r t p r o p e r t i e s o f t h e n a t u r a l compounds. F o r t h i s aim, we s y n t h e s i z e d crown e t h e r p r e c o c e n e s V I I (11), i n which C-6 and C-7 o f t h e chromene s k e l e t o n were i n c o r p o r a t e d i n t o a 15-crown-5 o r 18-crown-6 e t h e r r i n g . We a l s o p r e p a r e d s e v e r a l chromene d e r i v a t i v e s VIII bearing polyoxyethylenated groups and s u g a r r e s i d u e s a t t h e C-8 p o s i t i o n (12).


240

BIOREGULATORS F O RPEST C O N T R O L

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n= 3,4

CH

VIII

VII

So f a r a l l t h e s e compounds were i n a c t i v e i n t h e s t a n d a r d c o n t a c t t e s t b u t f u r t h e r i n v e s t i g a t i o n under i n v i t r o c o n d i t i o n s w i l l be c a r r i e d o u t i n t h e near f u t u r e . Another s t r a t e g y used t o modify t h e t r a n s p o r t p r o p e r t i e s o f n a t u r a l p r e c o c e n e s was t o p r e p a r e analogues i n which t h e double bond was masked i n such a way t h a t might be l i b e r a t e d under m i l d o x i d a t i v e c o n d i t i o n s ( 1 3 ) . I t was thought t h a t by an a p p r o p r i a t e c h o i c e o f t h e s e p r o t e c t i v e groups, t h e AJH a c t i v i t y might be enhanced i f t h e p r o a l l a t o c i d i n s t r u c t u r e c o u l d be l i b e r a t e d c l o s e t o t h e c o r p o r a a l a t a . F o r t h i s aim we have p r e p a r e d i n o u r l a b o r a t o r y (14) p r e c o s y l t h i o p h e n y l e t h e r s IX, i n view o f t h e u s e f u l n e s s o f t h i s p r o t e c t i v e group i n o r g a n i c s y n t h e s i s , a l l o w i n g t h e easy r e g e n e r a t i o n o f t h e double bond by o x i d a t i o n t o t h e c o r r e s p o n d i n g s u l f o x i d e s and s u l f o n e s f o l l o w e d by

IX e l i m i n a t i o n under v e r y m i l d c o n d i t i o n s ( 1 5 ) . B i o l o g i c a l s t u d i e s o f t h e s e compounds a r e under way w i t h d i f f e r e n t i n s e c t s . C h e m i c a l S t u d i e s o f 3,4-epoxyprecocenes I n v e s t i g a t i o n s o f t h e i n v i v o and i n v i t r o metabolism o f t h e p r e c o c e nes d i s c l o s e d t h a t 3 , 4 - d i h y d r o x y p r e c o c e n e s were t h e most common me t a b o l i t e s . The abundance o f t h e s e d i o l s s u g g e s t e d t h a t p r e c o c e n e must have undergone e p o x i d a t i o n f o l l o w e d by h y d r a t i o n , l e a d i n g t o a c o n s t a n t isomer r a t i o o f 70:30 t r a n s c i s i s o m e r s , (2,16). R e c e n t l y , i t was demonstrated by i n c u b a t i o n i n v i t r o w i t h L o c u s t a m i g r a t o r i a c o r p o r a a l l a t a t h a t 4 - ^ H - p r e c o c e n e ~ was m e t a b o l i z e d s t e r e o s p e c i f i c a l l y t o (-)-trans-(3R,4S) and (+)-cis-(3R,4R) d i o l s ( 1 7 ) . To prove t h e above h y p o t h e s i s o f precocene mode o f a c t i o n , i t was r e q u i r e d t o s y n t h e s i z e t h e c o r r e s p o n d i n g 3,4-epoxyprecocenes and t o s t u d y i t s c h e m i c a l r e a c t i v i t y . When t h i s was a c c o m p l i s h e d i n two d i f f e r e n t l a b o r a t o r i e s (16,18) t h e l a b i l i t y o f t h e s e e p o x i d e s towards n u c l e o p h i l i c o r e l e c t r o p h i l i c a t t a c k was c o n f i r m e d . I n each case t h e c h e m i c a l h y d r o l y s i s o f t h e s e compounds gave t h e same isomer r a t i o o f d i o l s o b s e r v e d i n t h e enzymatic m e t a b o l i c p r o c e s s . We a n t i c i p a t e d t h a t s t a b i l i z a t i o n o f t h e s e type o f e p o x i d e s might be a c h i e v e d by r e p l a c e m e n t o f 7-alkoxy s u b s t i t u e n t by a f l u o r o a l k o x y group. I n f a c t , t h i s was t h e case and 7 - t r i f l u o r o e t h o x y - 3 , 4 -


16.

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241


epoxy precocene d e r i v a t i v e s X e x h i b i t e d h i g h e r s t a b i l i t i e s than t h e c o r r e s p o n d i n g n o n - f l u o r i n a t e d a n a l o g s ( 1 9 ) , w h i t h o u t l o s s o f AJH a c t i v i t y i n the o l e f i n i c precursors.

In s e a r c h i n g f o r a r e l a t i o n s h i p between a n t i j u v e n i l e hormone a c t i v i t i e s and epoxide c h e m i c a l r e a c t i v i t y , we attempted t o a p p l y as a c h e m i c a l probe t h e m - c h l o r o p e r o x y b e n z o i c - a l k a l i n e f l u o r i d e system, a reagent developed i n t h i s l a b o r a t o r y f o r p r e p a r a t i o n o f a c i d l a b i l e epoxides ( 2 0 ) . However, f o r m a t i o n o f h e m i e s t e r s o f 3,4-dihydroxy p r e cocene , was t h e predominant r e a c t i o n i n t h e case o f a c t i v a t e d c h r o mene s t r u c t u r e s . L i k e w i s e , as i t has been s t u d i e d i n t h e chromenes ( 2 1 ) , we exa mined t h e p o s s i b l e r e l a t i o n s h i p between p r e c o c e n e - l i k e a c t i v i t y and C c h e m i c a l s h i f t s o f C-3 and C-4 i n s e v e r a l 3,4-epoxides o f a c t i v e and i n a c t i v e chromenes. I n a l l c a s e s o b s e r v e d , t h e s e c h e m i c a l s h i f t s d i f f e r e d t o o s l i g h t l y , w i t h i n t h e range o f 0.5 ppm f o r C-3 and 0.7 ppm f o r C-4, t o be o f any d i a g n o s t i c v a l u e . R e c e n t l y , s e v e r a l n u c l e o p h i l i c r e a g e n t s have been used t o e s t a b l i s h t h e mode o f a c t i o n o f t h e m e t a b o l i t e s o f p o l y c y c l i c a r o m a t i c hydrocarbons (PAH). Among them, s e v e r a l p h o s p h o d i e s t e r s have been examined t o c l a r i f y t h e p o s s i b i l i t y o f r e a c t i o n o f PAH e p o x i d e s w i t h the phosphate groups ( P - a l k y l a t i o n ) o f n u c l e i c a c i d s ( 2 2 ) . I n t h i s c o n t e x t we have s t u d i e d t h e r e a c t i o n o f 3,4-epoxyprecocene I I w i t h d i b e n z y l phosphate under a v a r i e t y o f c o n d i t i o n s . I n a l l c a s e s , i n s t e a d o f t h e f o r m a t i o n o f phenol o r p h o s p h o t r i e s t e r s o b s e r v e d w i t h PAH e p o x i d e s , we o b t a i n e d p r e d o m i n a n t l y dimer X I . T h i s compound was a l s o t h e main component o f t h e m i x t u r e s o b t a i n e d by r e a c t i o n o f t h e above precocene epoxide w i t h o t h e r a c i d c a t a l y s t s , a l o n g w i t h dimers X I I and X I I . Dimer X I I was formed almost e x c l u s i v e l y by t h e r m a l t r e a t ment. The s t r u c t u r e and c o n f i g u r a t i o n f o r compound X I I has been e s t a b l i s h e d by s p e c t r a l and X-ray d i f f r a c t i o n a n a l y s e s ( 2 3 ) . 1 3


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R

R

R

R

XIII I t i s worth o f note t h a t t h e f o r m a t i o n o f a dimer, w i t h d i f f e r e n t dioxane s t r u c t u r e , i n t h e t r e a t m e n t o f 3,4-dihydroxyprecocene I with p - t o l u e n s u l f o n i c a c i d has been r e c e n t l y r e p o r t e d ( 1 3 ) . F u r t h e r work, t o s t u d y t h e r e a c t i v i t y o f precocene e p o x i d e s w i t h s e l e c t e d n u c l e o p h i l e s , which c a n shed l i g h t on t h e mode o f a c t i o n o f t h e s e compounds, i s i n progress. As a complement t o t h e s t u d y o f t h e c h e m i s t r y o f 3,4-epoxypreco cenes, we have a l s o p r e p a r e d t h e c o r r e s p o n d i n g 2 , 2 - d i m e t h y l - 3 - c h r o manones by p y r o l y s i s o f h e m i e s t e r s o f 3 , 4 - d i h y d r o x y p r e c o c e n e s . These chromanones might a f f o r d by e n o l i z a t i o n 3-hydroxyprecocenes, tautomers o f t h e 3,4-epoxyprecocenes, w i t h an enhanced r e a c t i v i t y towards n u c l e o p h i l e s a t C-4. However, p r e l i m i n a r y r e s u l t s o f a n t i j u v e n i l e

>H

hormone a c t i v i t y o f t h e s e chromanones were n e g a t i v e . In s h o r t , although precocenes are a very v a l u a b l e t o o l f o r c a r r y i n g out chemical allatectomy i n i n s e c t physiology s t u d i e s , the f u t u r e a p p l i c a t i o n o f agents o f t h e p r e c o c e n e type i n i n s e c t c o n t r o l depends on overcoming two main problems o f t h e n a t u r a l p r e c o c e n e s , namely, i t s r e p o r t e d t o x i c i t y i n v e r t e b r a t e s (24,25) and i t s i n s e n s i t i v i t y t o holometabolous i n s e c t s . Acknowledgments F i n a n c i a l s u p p o r t from C o m i s i o n A s e s o r a de I n v e s t i g a c i o n C i e n t i f i c a y Técnica (Grant 1664-82) and J o i n t American-Spanish Committee f o r S c i e n t i f i c and T e c h n o l o g i c a l C o o p e r a t i o n (Grant 0394-11) i s g r a t e f u l l y acknowledged.


16.

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Literature

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cited

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