Low-Molecular-Weight Organosulfur Compounds in Nature: The

1 Low-Molecular-Weight Organosulfur Compounds in Nature: The Search for New Pesticides ERIC BLOCK

Downloaded by 128.122.230.148 on September 2, 2016 | http://pubs.acs.org Publication Date: June 11, 1981 | doi: 10.1021/bk-1981-0158.ch001

Department of Chemistry, University of Missouri, St. Louis, MO

63121

A rich variety of organosulfur compounds are found in living systems. A list of biochemically notable organosulfur compounds would include, among others, the essential amino acids cysteine and methionine, peptides such as glutathione, and the recently characterized biologically extremely potent glutathione deriva tive leukotriene C-1 (1)(1)(Fig. 1) (the "slow reacting substance" of anaphylaxis (SRS) which is known for its role in the lungs during asthma attacks), polycyclic peptide antibiotics such as bacitracin, gliotoxin, cephalosporin, penicillin, and the recently discovered β-lactam antibiotic thienamycin (2)(2), cofactors and vitamins such as thiamine, biotin, coenzyme A and α-lipoic acid, a bio logical alkylating agent, S-adenosylmethionine, the biological redox systems ferredoxin and rubredoxin and sulfur-containing bases found in bacterial transfer-RNA such as 4-thiouracil (3). A remarkable range of simpler organosulfur compounds are known to be widely distributed throughout the plant kingdom (3,4,5,6). These compounds often make important contributions to the odor and flavor of many of the common comestibles. In some instances these sulfur compounds may also serve by their odor and taste to repel predators or to act for the plant as resistance factors against infection by microorganisms (e.g. as natural pest icides). Not to be outdone, some insects such as the onionmaggot, Hylemya antiqua, and t u r n i p (or vegetable) w e e v i l , Listroderes obliquas, have evolved so that some of the same organosulfur compounds a c t as a t t r a c t a n t s and s t i m u l a t e egg l a y i n g and b i t i n g

(Z) A number of i n s e c t s and higher animals have a l s o been found to possess unusual small organosulfur molecules which may serve as defensive s e c r e t i o n s , sex a t t r a c t a n t s , or scent markers · In many cases the low molecular weight organosulfur compounds occur i n p l a n t s (and p o s s i b l y i n animals as w e l l ) i n an odorless com bined form (e.g., as peptides o r g l y c o s i d e s ) and a r e r e l e a s e d enzymatically when the t i s s u e i s i n j u r e d or s t i m u l a t e d , i . e . during a t t a c k by a predator. F i n a l l y i t should be noted that c e r t a i n s u l f u r compounds reported to be of n a t u r a l o r i g i n may 0097-6156/81/015 8-0003$05.00/0 © 1981 American Chemical Society

Rosen et al.; Sulfur in Pesticide Action and Metabolism ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

SULFUR IN PESTICIDE ACTION AND METABOLISM


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be a r t i f a c t s formed during the i s o l a t i o n procedures through r e a c t i o n s of unstable p r e c u r s o r s . In the survey of n a t u r a l organosulfur molecules that follows I have focused on those lower molecular weight compounds known to show b i o l o g i c a l a c t i v i t y (or which might be expected to possess such a c t i v i t y ) , p a r t i c u l a r l y as p e s t i c i d e s and a n t i b i o t i c s , and have emphasized the more current l i t e r a t u r e with coverage through J u l y 1980. There are v a l u a b l e lessons f o r us to l e a r n from a c a r e f u l study of attempts by other species to use chemicals as pest c o n t r o l agents i n t h e i r s t r u g g l e f o r s u r v i v a l . A few i l l u s t r a t i o n s w i l l be given showing how t h i s knowledge has been put i n t o p r a c t i c e i n the design of new p e s t i c i d e s . I t i s convenient to group the compounds according to whether the s u l f u r i s bonded i n an a c y c l i c or h e t e r o c y c l i c manner. The a c y c l i c n a t u r a l l y o c c u r r i n g organosulfur compounds w i l l be discussed f i r s t . A c y c l i c S u l f u r Systems Plant Sources. The t u r n i p (Brassica campestris), rutabaga (Brassica napus), cabbage (Brassica oleracea) r a d i s h (Raphanus sativus) and a number of other p l a n t s contain 2-phenylethylisothiocyanate, PhCH CH NCS, (3), while the r a d i s h , b l a c k mustard (Brassica nigra) and penny~cress (Thlaspi arvense) contain related isothiocyanates which possess sharp i r r i t a t i n g odors and cause b l i s t e r i n g of the s k i n . C e r t a i n of these i s o t h i o c y a n t e s such as 3 are i n s e c t i c i d a l or a n t i b i o t i c p r o t e c t i n g the p l a n t against p a r a s i t e s (6^, 8_). At the same time a l l y l i s o t h i o c y a n a t e , CH2=CHCH2NCS, found i n v a r i o u s Brassica s p e c i e s , has been found to be an a t t r a c t a n t f o r the vegetable w e e v i l , Listroderes efoliquus which feeds on B r a s s i c a species and the f l e a b e t t l e , Phyllotreta cmciferae and to i n i t i a t e b i t i n g by the former harmful pest (7) · The i s o t h i o c y a n a t e s , or mustard o i l s as they are c a l l e d , have been known s i n c e the nineteenth century to be secondary products a r i s i n g from breakdown of mustard o i l glucosides (widely d i s t r i b u t e d i n the C r u c i f e r a e family) when c e l l u l a r s t r u c t u r e i s d i s r u p t e d (6)· The Allium species such as the onion (Allium cepa), g a r l i c (Allium sativum)^ s h a l l o t (Allium ascalonicum), chive (Allium scordoprasum), caucas (Allium victorialis)> and leek (Allium odonon) and other members of the L i l i a c e a e f a m i l y are r i c h n a t u r a l sources of b i o l o g i c a l l y a c t i v e organosulfur compounds. As i n the case of the mustard o i l from B r a s s i c a s p e c i e s , the organosulfur compounds from A l l i u m species are found i n the plant t i s s u e s i n an odorless combined form, e.g. as γ-glutamyl peptides of the S - a l k y l - and S-alkenylcysteine s u l f o x i d e s 4, F i g u r e 2. A l l i i n , (R = H, R = CH =CH) the n a t i v e c o n s t i t u e n t of g a r l i c i s broken down enzymatic a l l y to a l l i c i n , CH =CHCH S(0)SCH CH=CH (6c), when the p l a n t i s crushed. A l l i c i n i s b a c t e r i o c i d a l and along~with t h i o s u l f i n a t e s 5a and 5b from onion or g a r l i c possesses a n t i f u n g a l , a n t i v i r a l and tumor i n h i b i t i n g a c t i v i t y (9). D i a l l y l d i s u l f i d e , (CHf=CHCH S) , and d i a l l y l t r i s u l f i d e , (CH =CHCH S) S, two other components of 3

2

2

Λ

9

>

f

2

2

2

2

2

2

2

2

2


2

1.

BLOCK

5

Low-Molecular-Weight Organosulfur Compounds

H

OH Λ00Η


/

C5H11

If

*CH2CHC0NHCH2C00H NHC0CH2CH2CHC00H NH 2

r^-SCH2CH2NH

2

COOH

Figure 1.

RR'CHS(0)CH 2 CH(NH 2 )COOH

Leukotriene C-l (1) and thienamycin (2)

ALLIINASE PYRIDOXAL

RR'CH-S-O-H

+

CH 2 =C(NH 2 )C00H

PHOSPHATE

R' RR'CHS(0)SCHRR' 6 A

R = R'

Β

R = H,

= H R'

= C2H5

c

R = H,

R'

= CH2=CH

W / Y 7 A

R = C2H5,

R'

= H

(MAJOR) Β

R = H,

R'

= C2H5

(MINOR)

Figure 2. Organosulfur compounds from allium species


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g a r l i c o i l have been found to possess l a r v i c i d a l a c t i v i t y ( f a t a l at 5 ppm t o Culex pipiens, a mosquitoe s p e c i e s ) (10). The i n t e n s e l y lachrymatory p r i n c i p l e of the onion, shown to be a 20:1 mixture of Z- and E - p r o p a n e t h i a l S-oxide, 7a and 7b, (1J., 12, 13) i s d e r i v e d by enzymatic breakdown of trans-(+)-S-(1-propeny1)-Lc y s t e i n e s u l f o x i d e CH CH=CHS(0)CH CH(NH )COOH f o l l o w e d by r e arrangement of the i n t e r m e d i a t e ( E ) - l - p r o p e n e s u l f e n i c a c i d , CH3CH=CHS-0-H (ljL, 13). The onion lachrymator may serve an ecol o g i c a l f u n c t i o n i n r e p e l l i n g some h e r b i v o r e s or p a r a s i t e s . D i n-propyl d i s u l f i d e and other d i s u l f i d e s produced by the onion a c t as powerful a t t r a c t a n t s f o r the onion maggot (Hylemya antiqua), and b l a c k b l o w f l y (Phormia regina)(only the female i s a t t r a c t e d ! ) (_7) and s t i m u l a t e egg l a y i n g by the onion maggot and leek moth (Acrolepiopsis asseotella) (14). Crude onion j u i c e i n h i b i t s the growth of Escherichia coli, Pseudomonas pyocyaneus, Salmonella typhi and Bacillus subtilis (15). R e c e n t l y , the c a u s a t i v e agent of a type of a l l e r g i c c o n t a c t d e r m a t i t i s known as "Dogger Bank i t c h " has b e e n i d e n t i f i e d as the (2-hydroxyethyl)dimethylsulfoxonium i o n , (CH )2S(0)CH2CH20H, produced by the marine bryozoan, Alcyonidium gelatinosvm (16). Related s a l t s are known such as 6-dimethylsulfonium pentanoic a c i d , (CH ) *CH2CH2CH2CH2C02H, from the c o a s t a l dune p l a n t Diplotaxis tenuifolia, and t h e t i n , (CH ) SCH2CH2C02H, a common component of v a r i o u s marine algae (17 ). A v a r i e t y of other compounds c o n t a i n i n g a c y c l i c s u l f u r have r e c e n t l y been i s o l a t e d from p l a n t s although nothing has been reported on t h e i r b i o l o g i c a l a c t i v i t y . These examples would i n c l u d e d i e t h y l t e t r a s u l f i d e , (C2H SS)2, and r e l a t e d p o l y s u l f i d e s and h y d r o s u l f i d e s from the f r u i t of the d u r i a n , Durio zibethinus (a much c h e r i s h e d south-east A s i a n f r u i t ) ( 1 8 ) , germacradienolide t h i o l 8 from Eupatorium mikanioides ( 1 9 ) , sesquiterpene l a c t o n e su I f one g from the r o o t s of Eelenium autvamale ( 2 0 ) , v i n y l s u l f i d e s 10 and 11 ( S - p e t a s i n ) from Petasites japonicus and Petasites nybridus^ r e s p e c t i v e l y (21, 22), t h i o s u l f o n a t e 12, from the mushroom Lentinus edodes, and S-methylthiomethyl 2-methylbutanet h i o a t e , C2H CH(CH )C(0)SCH SCH , from the e s s e n t i a l o i l of hops (23). (See F i g u r e 3.)


3

2

2

+

3

3

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2

5

5

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Animal Sources. The spray of the s t r i p e d skunk (Mephitis mephitis) which i n c l u d e s t r a n s - 2 - b u t e n e t h i o l , CH CH=CHCH SH, 3m e t h y l b u t a n e t h i o l , (CH ) CHCH2CH SH, and c r o t y l methyl d i s u l f i d e , CH CH=CHCH SSCH (24) i s o b v i o u s l y v e r y e f f e c t i v e i n r e p e l l i n g (and making q u i t e m i s e r a b l e ) would-be p r e d a t o r s . As an a s i d e i t may be noted t h a t the s e n s i t i v i t y of the human nose to simple t h i o l s ( c a . 0.02 ppb of methanethiol and 0.0007 ppb of 2-methyl2 - b u t a n e t h i o l can be detected (25)) and other s m a l l s u l f u r molecules as w e l l as to low molecular weight amines coupled w i t h the f a c t t h a t many animals a l s o f i n d t h e i r s m e l l o f f e n s i v e supports s p e c u l a t i o n t h a t n a t u r a l s e l e c t i o n developed t h i s o l f a c t o r y sens i t i v i t y as a form of p r o t e c t i o n f o r the organism a g a i n s t the 3

3

3

2

2

2

2

3



1.

BLOCK

LoW'Molecular-Weight Organosulfur Compounds

CH 3 S(0)2SCH20CH 2 SCH 2 S(0)CH3

12

Figure 3. Compounds containing acyclic sulfur


7


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i n g e s t i o n of decaying food (low molecular weight organosulfur compounds and amines are a l s o products of b i o l o g i c a l decay). A p r a c t i c a l a p p l i c a t i o n of t h i s o b s e r v a t i o n i s the use of d i a l l y l d i s u l f i d e , (CH =CHCH S) , as a r e p e l l e n t f o r i n j u r i o u s b i r d s (26)» The occurrence of Δ -isopentenyl methyl s u l f i d e , CH =C(CH )CH CH SCH , and 2-phenylethyl m e t h y l s u l f i d e , PhCH CH SCH3, as components of the u r i n e scent mark of the red fox (Vulpes vulpes) (27), of 5-methylthio-2,3-pentanedione, CH C(0)C(0)CH CH SCH , as a v o l a t i l e s e c r e t i o n from the a n a l scent gland of the s t r i p e d hyena (Hyaena hyaena) (28), of d i ( 3 - m e t h y l b u t y l ) s u l f i d e , ((CH ) CHCH CH ) S, from the polecat (Mustela putovius) (29), and of dimethyl d i s u l f i d e , CH SSCH , as an a t t r a c t a n t pheromone i n the v a g i n a l s e c r e t i o n of the hamster (Cricetus cricetus) (30) provide examples of organosulfur compounds i n v o l v e d i n chemical i n t e r a c t i o n s between animals. 2

2

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3

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H e t e r o c y c l i c S u l f u r Systems P l a n t Sources, F i g . 4 d i s p l a y s a broad range of organo s u l f u r compounds found i n p l a n t s or animals i n which the s u l f u r atom(s) i s p a r t of a r i n g . Many of these compounds show sub s t a n t i a l b i o l o g i c a l a c t i v i t y . Thus, v a r i o u s s p e c i e s of marigold (Tagetes) and other members of the Compositae f a m i l y c o n t a i n a - t e r t h i e n y l , 21, and 5 - ( 3 - b u t e n - l - y n y l ) - 2 , 2 ' - b i t h i e n y l , 20, which are l e t h a l to b a c t e r i a , yeasts and other f u n g i , nematodes and f i s h i n near-UV l i g h t (31,32,33). In the o r i g i n a l study i n t h i s a r e a , 24 kg of marigold r o o t s were processed to u l t i m a t e l y a f f o r d 200 mg of 21 which proved to be n e m a t i c i d a l against Heterodera rostochiensis l a r v a e , Pratylenohus penetrans, Ditylenchus dipsaci and other species of nematodes (34). Other n a t u r a l t h i o phene r i n g c o n t a i n i n g nematicides i n c l u d e 2-phenyl-5-(l -propynyl)thiophene 19 from Coreopsis lanceolata (35) and r e l a t e d compounds from ChrystTumthenum vulgare (36) and other species (37). A second group of b i o l o g i c a l l y a c t i v e molecules i s o l a t e d from n a t u r a l sources are 1 , 2 - d i t h i o l a n e d e r i v a t i v e s 22-25 which are s t r u c t u r a l l y r e l a t e d to the c o f a c t o r , α-lipoic a c i d . Asparagusic a c i d , 22, present to the extent of about 35 ppm i n the r o o t s of asparagus (Asparagus officinalis) i s a c t i v e against the p l a n t p a r a s i t i c nematodes Paratylenchus penetrana and P. eurvitatus, Eeterodera rostochiensis and #. glycines, and Meloidogyne hapla, and i s considered t o be a major f a c t o r i n n a t u r a l r e s i s t ance of asparagus (38). Asparagusic a c i d , i t s syn and a n t i Soxide (39) and some r e l a t e d a c y c l i c d e r i v a t i v e s are a l s o very e f f e c t i v e p l a n t growth i n h i b i t o r s . Compounds 23 (4-methylthio1 , 2 - d i t h i o l a n e ) and 32 ( 5 - m e t h y l t h i o - l , 2 , 3 - t r i t h i o l a n e ) are r e s p o n s i b l e f o r the rank, pungent s m e l l a s s o c i a t e d w i t h the stonewort (Chara globularis). Whenever t h i s green a l g a occurs i n a pond i t dominates the a l g a l f l o r a of the ecosystem, apparently because 23 and 32 act as extremely a c t i v e i n h i b i t o r s of photosyn t h e s i s , thus eliminating'would-be competitive species (40). The f


BLOCK

Low-Molecular-Weight Organosulfur Compounds


1.

Figure 4.

Naturally occurring thiaheterocycles


9



10

p r o p e r t i e s of 1,2-dithiolanes 24 and 25 w i l l be discussed below. A number of unusual c y c l i c p o l y s u l f i d e s showing a n t i b i o t i c a c t i v i t y against b a c t e r i a and fungi have been i s o l a t e d from the red alga Chondria oalifomica (41) and from the mushroom Lentinus edodes (42). Both 34 (1,2,4,6-tetrathiepane) and 35 (1,2,3,5,6pentathiepane or l e n t h i o n i n e ) have been i s o l a t e d from both sources, while 1,2,3,4,5,6 -hexathiepane, 36, was obtained from the mushroom and 27 ( 1 , 2 , 4 - t r i t h i o l a n e ) , 2g ( 1 , 2 , 4 - t r i t h i o l a n e 4-oxide), 30 ( 1 , 2 , 4 - t r i t h i o l a n e 1-oxide), 37 (1,2,4,6-tetrathiepane 4,4dioxide) and 40 (1,2,4,5,7,8,10,11-octathiacyclododecane) were obtained from the alga ( f o r a synthesis of 29, see (43); f o r s t u dies on precursors to 35, see (44)). T r i t h i o l a n e s r e l a t e d to 27, 2g, and 30 have been i s o l a t e d from steam v o l a t i l e o i l of onion (e.g. 28) (45) and root m a t e r i a l of Petivevia alliaoeae (46). Other b i o l o g i c a l l y a c t i v e n a t u r a l l y derived t h i a h e t e r o c y c l e s include ôjô'-dihydroxythiobinupharidine, 17, a fungicide from the spatterdock or yellow pond l i l y (Nuphar luteum)(47,48), griseov i r i d i n , 39, an a n t i o b i o t i c from Streptomyces griseus (49) and the a n t i b i o t i c u r e o t h r i c i n 26 (50). Other n a t u r a l t h i a h e t e r o c y c l e s whose b i o l o g i c a l a c t i v i t i e s have not yet been reported include l-cyano-2,3-epithiopropane, 13, from cabbage, (51) the isomeric 2-methyl-4-propyl-l,3-oxathianes, 31, from the Hawaiian yellow passion f r u i t (Passiflora edulis) (52), the sesquiterpene m i n t s u l f i d e , 18, from o i l of peppermint (Mentha piperita) (53), the d i t e r p e n o i d , p h a r b i t i c a c i d , 16, from the seeds of the Japanese morning-glory (Pharbitis niV) (thought to be a g i b b e r e l l i n A r e g u l a t o r ) (54), t r a n s - 3 , 4 - d i e t h y l - l , 2 - d i t h i e t a n e 1,1-dioxide, 15, formed by d i m e r i z a t i o n of the lachrymatory f a c t o r of the onion, Z- and E-propanethial S-oxide 7a,b (5J5), and d i s u l f i d e 33 from two brown algae of the genus Diotyopteris (56,57). Animal Sources. The marine a n n e l i d worm Lumbrineris heteropoda produces an i n s e c t t o x i n n e r e i s t o x i n , 24, 4-N,N-dimethy1amino-l,2-dithiolane (5

Low-Molecular-Weight Organosulfur Compounds in Nature: The

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