Cotton Dust - American Chemical Society

18 S e c o n d a r y M e t a b o l i t e s of

Gossypium:

A Biogenetic Analysis J. P. McCORMICK

Downloaded by GEORGETOWN UNIV on August 18, 2015 | http://pubs.acs.org Publication Date: July 1, 1982 | doi: 10.1021/bk-1982-0189.ch018

University of Missouri, Department of Chemistry, Columbia, MO 65211 Some 310 secondary metabolites which reportedly have been found from the cotton plant are reviewed according to the biogenetic classifications of acetogenins, shikimates, terpenoids and steroids, nitrogen compounds, monosaccharides, and others which are not classified. Aside from synthesis for structural materials, the cotton plant apparently invests the energy expended on secondary metabolism primarily toward the formation of terpenoids. Of these, the sesquiterpenoids account for the majority and the cadinane group in particular is predominant. Alkaloids are conspicuously absent from the known Gossypium secondary metabolites, perhaps as a result of isolation techniques employed. Relevant to the byssinosis problem, assay of physiological activities might best be focused on the cadinane terpenoids, the flavanoid, coumarin and cinnamic acid phenols, and any alkaloids which may be found by future investigation. Of the p o s s i b l e causes of b y s s i n o s i s , the suggestion t h a t one or more organic substances found i n c o t t o n dust may p l a y a r o l e remains a p l a u s i b l e h y p o t h e s i s . Based on v a r i o u s b i o l o g i c a l assays of e x t r a c t s obtained from c o t t o n t r a s h , much of the work performed t o i d e n t i f y an organic c a u s a t i v e agent has focused on a cadinane sesquiterpene, l a c i n i l e n e C methyl ether (178a) and such r e l a t e d compounds as the parent phenol (1.77) and g l y c o -

177 178a 178b

R

1

= H,

1

R

2

= H

2

R = Me, R = H 1 2 R = Me, R = sugar

l a c i n i l e n e compounds 0097-6156/82/0189-0275$7.50/0 © 1982 American Chemical Society

In Cotton Dust; Montalvo, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


276

COTTON

DUST

s i d e d e r i v a t i v e s (1.78b) (1_, 2_, 3 ) . However, the l i k e l i h o o d of these compounds' involvement i n causing b y s s i n o s i s has been questioned and to date no convincing evidence has been presented i m p l i c a t i n g them i n the development of t h i s d i s e a s e . For t h i s reason, i t i s t i m e l y to consider what other organic substances are known to be i n the c o t t o n p l a n t . As w e l l , i t can be u s e f u l to consider which types of compounds have not been reported and to question whether such compounds r e a l l y are absent or simply have not yet been found, owing to the nature of the methods and o r i e n t a t i o n of previous i n v e s t i g a t i o n s . S t r i c t l y speaking, i t i s the m a t e r i a l i n c o t t o n dust which i s of i n t e r e s t . However, only very s m a l l amounts of such a i r b o r n e , s m a l l p a r t i c u l a t e matter has been a v a i l a b l e f o r examination. Thus, the reasonable assumption has been made that the organic composition of such dust i s s i m i l a r to that of i t s major components, which are derived from the d r i e d , f r i a b l e cotton p l a n t p a r t s : b r a c t and l e a f , p e r i c a r p , stem, and seed fragments ( 4 ) . [Of these, the b r a c t and l e a f are the most abundant i n raw c o t t o n dust and t h e r e f o r e have r e c e i v e d the most a t t e n t i o n regarding composition ( 5 ) . ] Using t h i s r e l a t i v e l y sound j u s t i f i c a t i o n , a number of groups have examined the organic composition of the c o t t o n p l a n t i n v a r y i n g stages of growth and senescence. One must be c a r e f u l about drawing c o n c l u s i o n s regarding the composit i o n of c o t t o n dust from s t u d i e s of m a t e r i a l i n a s t a t e of development u n l i k e that of c o t t o n - d e r i v e d m a t e r i a l when i t i s gene r a l l y processed. However, the focus of the present paper i s on the general secondary metabolism of Gossypium as i t can be surmised from the known organic substances reported to be i n the p l a n t . In t h i s context, i t i s u s e f u l to consider r e s u l t s obtained from s t u d i e s of c o t t o n i n v a r i o u s stages of growth and aging. The purpose of t h i s paper, then, i s to present an organized summary of the known secondary m e t a b o l i t e s of Gossypium, i n order to provide a conceptual p l a t f o r m f o r f u r t h e r work toward i d e n t i f i c a t i o n of organic substances which may play a c a u s a t i v e r o l e i n byssinosis. Historical A few groups have made s u b s t a n t i a l progress toward the i d e n t i f i c a t i o n of Gossypium secondary m e t a b o l i t e s . S t i p a n o v i c , i n c o l l a b o r a t i o n w i t h Wakelyn, B e l l , and o t h e r s , has i d e n t i f i e d seve r a l compounds, p r i m a r i l y cadinane sesquiterpenoids ( 1 7 , 2 1 - 2 8 , 3 1 ) . Hedin's group has used gas chromatography-mass spectrometry to i d e n t i f y a wide v a r i e t y of substances which may be d e r i v e d from the c o t t o n p l a n t ( 8 - 10^ JL2, _13, 1 4 , 2 0 ) . Brzozowska, Hanower, and Tanguy have reported the s t r u c t u r e s of s e v e r a l phenolic compounds ( 1 5 ) . Other i n v e s t i g a t o r s have made more focused, but s i g n i f i c a n t c o n t r i b u t i o n s . Wakelyn, G r e e n b l a t t , Brown and T r i p p have reviewed much of the e a r l y work i n t h i s area ( 1 6 ) .


18.

MCCORMICK

Secondary Metabolites

of

Gossypium

277


Approach In the present d i s c u s s i o n , the general scheme of b i o g e n e s i s w i l l be used as the b a s i s f o r o r g a n i z a t i o n of the compounds r e p o r t e d l y found i n Gossypium. Biogenesis i s a term which r e f e r s to the general b i o l o g i c a l pathway(s) u t i l i z e d by an organism f o r formation of secondary m e t a b o l i t e s , those nonpolymeric substances produced which are not a p a r t of the primary metabolism system. A schematic r e p r e s e n t a t i o n of the major components of such systems i n p l a n t s i s given i n F i g u r e 1. The o r g a n i z a t i o n a l v a l u e of u s i n g such a scheme i s r e a d i l y apparent, s i n c e there are only a few major groups of secondary m e t a b o l i t e s . More i m p o r t a n t l y , the members of a p a r t i c u l a r group share general s t r u c t u r a l f e a t u r e s which may g i v e them common p r o p e r t i e s and perhaps s i m i l a r l o c a tions i n a plant. The weaknesses of t h i s approach a l s o should be pointed out. The c l a s s i f i c a t i o n system g e n e r a l l y ignores s p e c i f i c f u n c t i o n a l i t y found i n the compounds. To c i t e an example of p a r t i c u l a r relevance to Gossypium secondary m e t a b o l i t e s , most of those c l a s s e s l i s t e d i n F i g u r e 1 may c o n t a i n phenolic compounds. As w e l l , although some g e n e r a l i z a t i o n s may be made concerning the common p h y s i o l o g i c a l a c t i v i t i e s of each of the groups of metab o l i t e s , the a c t u a l a c t i v i t i e s of a s p e c i f i c compound must be examined i n d i v i d u a l l y before any statements are made regarding t h a t member of the group. R e l a t i n g t h i s to the goal of i d e n t i f y i n g c a u s a t i v e agents of b y s s i n o s i s , c e r t a i n groups of compounds may be s i n g l e d out as l i k e l y candidates f o r c o n t a i n i n g one or more c u l p r i t s , but nevertheless the p h y s i o l o g i c a l a c t i v i t y of each i s o l a t e d substance must be examined s e p a r a t e l y Most a l l of the organic compounds which have been reported from s t u d i e s of c o t t o n p l a n t p a r t s and c o t t o n t r a s h have been i n cluded i n t h i s review. Only those which seem most u n l i k e l y to be cotton-derived n a t u r a l products have been excluded. For example, the p h t h a l l a t e s reported as " a i r space v o l a t i l e s of the c o t t o n p l a n t " are l i k e l y a r t i f a c t s d e r i v e d from common p l a s t i c s ( 9 ) ; some hydrocarbons found to be i n c o t t o n l i n t and waste probably came from a source obtained from petroleum ( 8 ) ; and a f l a t o x i n i s presumably a mold m e t a b o l i t e (36). A few other compounds have been excluded f o r s i m i l a r reasons. On the other hand, some compounds which are i n c l u d e d may not be t r u e Gossypium secondary m e t a b o l i t e s . Not only are the sources mentioned above p o s s i b l e c o n t r i b u t o r s of exogenous compounds which have been i n c l u d e d i n the accompanying Tables ( I - X ) , but a l s o i t i s q u i t e p o s s i b l e that methods of i s o l a t i o n and a n a l y s i s caused molecular t r a n s f o r m a t i o n which created isomers of t r u e m e t a b o l i t e s or even caused more d r a s t i c a l t e r a t i o n s . The d i v e r s i t y of s t r u c t u r e s which are p l a u s i b l e n a t u r a l products i s so great that i t i s not reasonable to exclude many of those reported simply on the b a s i s of s t r u c t u r e assignment. For t h i s reason, i t can be expected that some e r r o r s of i n c l u s i o n have been made.


In Cotton Dust; Montalvo, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982. Figure 1.

polysaccharides proteins/peptides nucleic acids

v

amino a c i d s other small molecules

shikimate

carbohydrates pyruvate acetate

PRIMARY METABOLISM

Generalized biogenesis scheme for plants.

BIOPOLYMERS

lysine/ornithine tryptophan phenylalanine/ tyrosine " • ' shikimate

aminolevul i n i c acid

mevalonate

i

acetate

KEY SMALL MOLECULES

SECONDARY METABOLISM

Derivatives

1ignins tannins

other aromatic & p r e a r o m a t i c compounds

-• p h e n y l p r o p a n e s

Shikimate

alkaloids

p y r r o l e pigments

Acetogenins fatty acids & derivatives polyketides Terpenoids — • S t e r o i d s N i t r o g e n o u s Compounds


18.

MCCORMICK


of

Gossypium

279

F i n a l l y , i t should be pointed out that i n t h i s review no attempt has been made to separate the r e s u l t s according to p l a n t species or p l a n t p a r t . Both types of d i v i s i o n s would be u s e f u l , but p r a c t i c a l c o n s i d e r a t i o n s have precluded such a d e t a i l e d analys i s . Some r e p o r t s c i t e d , p r i m a r i l y those of S t i p a n o v i c and of Hedin, provide some of t h i s type of i n f o r m a t i o n .


Secondary M e t a b o l i t e s of Gossypium Acetogenins. Consistent w i t h expectations based on the nat u r e of the c o t t o n p l a n t , a number of f a t t y a c i d s and r e l a t e d compounds have been c h a r a c t e r i z e d as components. Table I l i s t s those which have been reported and which c o n t a i n at l e a s t twelve carbon atoms i n the l i n e a r chain. Much of such m a t e r i a l i s found i n the seeds and i n the waxes of the leaves and much i s t i e d up as g l y c e r i d e or as s t e r o l ester ( 6 ) . Of these f a t t y a c i d s , p a l m i t i c

(12), l i n o l e i c ( 2 1 ) , o l e i c (19) and s t e a r i c (18) a c i d s are the predominant ones. F a t t y a c i d substances having an odd number of carbons are g e n e r a l l y l e s s common; s e v e r a l appear i n Gossypium. As w e l l , the unusual cyclopropenoic a c i d s m a l v a l d i c (25) and s t e r c u l i c (26) a c i d s are present and may have s i g n i f i c a n t physiol o g i c a l a c t i v i t y (65). The other acetogenins, shown i n Table I I , are a v a r i e d assortment of s m a l l molecule compounds which as a group c o n t a i n alkene, a l c o h o l , and carbonyl ( a c i d , e s t e r , aldehyde, and ketone) f u n c t i o n a l i t y . They are f a i r l y t y p i c a l substances w i t h common s t r u c t u r a l f e a t u r e s . Again, those compounds possessing an odd number of carbon atoms are l e s s common, and b i o g e n e t i c a l l y may be derived from a propionate s t a r t e r u n i t .


280

COTTON

Table I . F a t t y A c i d s and Related Compounds.


Compound l a u r i c acid methyl l a u r a t e dodecane y-tridecalactone myristic acid methyl m y r i s t a t e tetradecane n-p entad ec ene 3-methyltetradecane pentadecanoic a c i d pentadecenoic a c i d palmitic acid methyl p a l m i t a t e palmitoleic acid margaric a c i d heptadecenoic a c i d heptadecadienoic a c i d stearic acid oleic acid methyl oleate l i n o l e i c acid methyl l i n o l a t e l i n o l e n i c acid octadecatetraenoic acid malvalic acid s t e r c u l i c acid arachidic acid eicosadienoic acid eicosatrienoic acid behenic a c i d dicosadienoic acid tricosane pentacosane heptacosane octacosane octacosanol montanyl a l c o h o l nonacosane triacontane triacontanol untricontane dotriacontane dotriacontanol hexatriacontane

Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

Reference 7 43 8 9 7 43 9 47 10 8 45 8 43 45 8 8 8 6 7 10 8 10 8 45 46 46 45 47 47 47 47 48 48 48 49 49 50 48 49 49 48 49 49 49


DUST

18.

MCCORMICK

Secondary

Metabolites

Table I I . Other


Compound acetic acid ethyl acetate ethylene butyraldehyde y-butyrolactone valeric acid h e x y l crotonate 1-hexanol hexanal 2,4-hexadienal trans-2-hexen-l-ol cis-3-hexen-l-ol 4-hexen-l-ol trans-2-hexenal caproic acid y-caprolactone heptanal 1-octanol 6-octen-4-ol 2-octenal caprylic acid 6-capryllactone 1-nonanol 3-nonanol nonanal 2-nonenal t r a n s , cis-2,6-nonadienal nonanoic a c i d methyl nonanate y-nonalactone 2-methy1-1-nonano1 3-methy1-1-nonanol n-decane n-decene decanal 2-decanone capric acid 6-undecanol undecanoic a c i d y-undecalactone

of Gossypium

281

Acetogenins Number

Reference

45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84

8 12 51 8 8 52 12 8 8 10 13 13 13 8 45 10 8 9 13 8 45 8 14 9 8 8 8 8 43 8 9 9 8 8 9 12 45 12 8 8


282

COTTON

DUST


Shikimates. The f l a v a n o i d s , shown i n Table I I I , have been i n v e s t i g a t e d p r i m a r i l y by a few groups (15, 53 - 58). These s t r u c t u r a l l y complex substances, which c o n t a i n both acetogeninand s k i k i m a t e - d e r i v e d p o r t i o n s , a r e of s i g n i f i c a n t i n t e r e s t r e garding c h a r a c t e r i s t i c p h y s i o l o g i c a l a c t i v i t i e s which make them suspect agents f o r involvement i n b y s s i n o s i s . I n f a c t , q u e r c e t i n (85) has been found t o cause l e u c o c y t e recruitment through airway w a l l s (37) and c a t e c h i n (101) r e p o r t e d l y a f f e c t s c a p i l l a r y f r a g i l -

i t y and p e r m e a b i l i t y (38). Furthermore, these compounds possess c o n s i d e r a b l e water s o l u b i l i t y , a c h a r a c t e r i s t i c r e p o r t e d l y a s s o c i ated w i t h the c a u s a t i v e agent(s) i n c o t t o n dust (42).

COOH

R

1

R

1

= glucosyl, R

111 , R

1

2

109, 110,

= H, R = H, R

2

= OMe = H

112-117 2

= OMe

1

R, R

2

= OH, OMe, o r Osugar

The phenylpropanes (C^Cg compounds) l i s t e d i n Table I I I a r e a r a t h e r common group among p l a n t s . S c o p o l e t i n (109), s c o p o l i n (110), and u m b e l l i f e r o n e (111) are very widespread coumarins. The cinnamic a c i d compounds (112 - 117) a l s o are w e l l known, common p l a n t m e t a b o l i t e s . The remaining shikimates i n Table I I I a l s o a r e r e l a t i v e l y simple, w e l l known compounds. The phenolic s t r u c t u r e s of v a n i l l i n (125) and g a l l i c a c i d (127) and the prephenolic s t r u c t u r e s of the common q u i n i c a c i d (128) and chlorogenic a c i d (129) make them candidates f o r p h y s i o l o g i c a l a c t i v i t y . G a l l i c a c i d i s the monomer f o r t a n n i n s , b i o l o g i c a l polymers found i n the c o t t o n p l a n t (15, 37).


18.

Secondary

MCCORMICK

Table I I I .

Metabolites

283

Shikimate Derived Compounds

Compound


of Gossypium

Flavanoids quercetin q u e r c e t i n rhamnoglucoside q u e r c e t i n glucoside isoquercitrin quercimeritrin rutin kaempferol kaempferol glucoside kaempferol rhamnoglucoside kaempferol r u t i n o s i d e trifolin gossypetin gossypitrin gossypin herbacitin herbacitrin catechin gallocatechin 1-epigallocatechin gallocatechin gallate epigallocatechin gallate cyanidin cyanidin-3-glucoside leucocyanidin

Number

Reference

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108

15 15 53 15 53 15 15 15 15 54 54 15 54 54 55 56 15 57 57 57 57 15 58 15

109 110 111

17 15 15

112 113 114 115 116 117

18 15 15 15 15 15

118 119

10 10

C^C^ Compounds: Coumarins scopoletin scopolin umibelliferone C^C^ Compounds: Cinnamic A c i d s cinnamic a c i d £-coumaric a c i d g l u c o s y l p-coumarate 3-quinoyl p-coumarate caffeic acid f e r u l i c acid Other C^C^ Compounds phenylacetone phenylpropionaldehyde


284

COTTON

Table I I I .

DUST

Shikimate Derived Compounds (Cont'd)

Compound

Number

Reference

C.C Compounds b z 2-phenylethanol phenylacetaldehyde acetophenone

120 121 122

13 10 9

C.C.. Compounds b 1 benzyl alcohol benzaldehyde vanillin s a l i c y l i c acid g a l l i c acid quinic acid chlorogenic acid

123 124 125 126 127 128 129

13 10 8 52 19 15 15


0

C0 H 2

HQ C 0 H /

2

HO'

125

127

128,

R =H

129,

R = caffeoyl


18.


MCCORMICK

Table IV.

285

Hemi t erp eno i d s

Compound 2-methylbutanol 3-methylbutanol 3-methylbutanal


of Gossypium

Number

Reference

130 131 132

13 8 8

Terpenoids and S t e r o i d s . The i n f o r m a t i o n g i v e n i n Tables IV-VII and the b i o g e n e t i c r e l a t i o n s h i p s shown i n F i g u r e s 2 and 3 speak f o r themselves. T h i s c l a s s of compounds accounts f o r more than o n e - t h i r d of the known c o t t o n p l a n t secondary m e t a b o l i t e s . The monoterpenoids l i s t e d i n Table V, many of which have the para-menthane s k e l e t o n , a r e g e n e r a l l y common compounds w i d e l y spread i n the e s s e n t i a l o i l s of p l a n t s . The sesquiterpenes a r e the l a r g e s t group of c o t t o n - d e r i v e d n a t u r a l products which have been c h a r a c t e r i z e d . When the h e l i o cides (239 - 246) are i n c l u d e d , over 50 compounds i n t h i s c l a s s have been r e p o r t e d , 31 of which c o n t a i n the cadinane s k e l e t o n . Importantly, these cadinane compounds i n c l u d e one i m p l i c a t e d i n b y s s i n o s i s , l a c i n i l e n e C methyl ether (178; v i d e supra) and others having s i g n i f i c a n t p h y s i o l o g i c a l a c t i v i t i e s . For example, gossypol (188) i s t o x i c t o humans and i s now known to have male a n t i - f e r t i l i t y a c t i v i t y (39, 40). Gossypol a l s o i s a n a t u r a l i n s e c t i c i d e , as a r e hemigossypolone (185) and i t s methyl ether

188

185

239, R = H 243, R = Me


286

COTTON

Table V.

Monoterpenoids

Compound


Acyclic trans-6 -ocimene myrcene citronellol citronellal geraniol nerol linalool Monocyclic: p-methanes limonene a-terpinene y-terpinene terpinolene a-phellandrene 3- phellandrene a-terpineol carveol isopulegone l-£-menthen-9-al 4- i s o p r o p y l c y c l o h e x - l - e n e 1-carboxaldehyde 4-isopropylcyclohexa-l,3-diene1-carboxaldehyde perilla-aldehyde carvacrol thymol cuminyl a l c o h o l cumic aldehyde Bicyclic thujyl alcohol a-pinene a-pinene oxide 3-pinene isopinocamphene myrtenol myrtenal verbenone borneol isoborneol camphene a-fenchene a-campholene aldehyde

Number

Reference

133 134 135 136 137 138 139

14 20 13 10 13 14 13

140 141 142 143 144 145 146 147 148 149

8 8 14 8 8 8 13 13 10 12

150

10

151 152 153 154 155 156

10 8 10 10 10 10

157 158 159 160 161 162 163 164 165 166 167 168 169

10 14 43 10 10 10 10 10 14 13 14 12 10


DUST

18.

MCCORMICK

Secondary

Metabolites

Table V I .

Sesquiterpene-ids

Compound


287

of Gossypium

6-cadinene y-cadinene y-muurolene copaene a-copaene a l c o h o l 2,7-dihydroxycadalene 2-hydroxy-7-methoxycadalene lacinilene C l a c i n i l e n e C 7-methyl ether hemigossypol 6-methoxyhemigossypol 6-deoxyhemigossypol desoxyhemigossypol 6-methoxydesoxyhemigossypol raimondal hemigossypolone 6-methoxyhemigossypolone gossyrubilone Dimeric Cadinanes gossypol 6-methoxyg os sypo1 6,6 -dimethoxygossypol gossypolone gossypol a l c o h o l T

Bisabolanes a-bisabolene a2~bisabolene cis-y-bisabolene l-methyl-4-(l-methylene-5-methylhexyl)cyclohexa-1,3-diene a-curcumene a-bisabolol 3-bisabolol bisabolene oxide

Number

Reference

170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187

14 43 12 14 12 21 21 22 22 23 23 24 25 25 26 27 27 27

188 189 190 191 192

28 23 23 30 50

193 194 195

8 8 14

196 197 198 199 200

10 10 13 13 14

Continued on next page.


COTTON

288


Table V I . Compound

DUST

Sesquiterpenoids (Cont'd.) Number

Reference

Farnesanes farnesene f a r n e s o l (E,E & Z,E) nerolidol

201 202 203

14 12 13

Germacrane germacrone

204

10

Humulane ot-humulene

205

14

Caryophyllanes caryophyllene 3 - c a r y o p h y l l e n e oxide a-caryophyllene a l c o h o l

206 207 208

14 14 10

Santalanes a-santalene 3-santalene epi-3-santalene

209 210 211

10 10 10

Bergamotane t rans-a-b ergamo t ene

212

14

Guaiane 5-guaiene

213

14

Other abscisin I I

214

44


18.

Secondary

MCCORMICK

Table V I I .


Compound S t e r o l s and S t e r o i d s 3-amyrin 3-amyrin montanate cholesterol campesterol g-sitosterol B-sitostanol campesterol g a l a c t o s i d e stigmasterol galactoside

Metabolites

289

of Gossypium

Other Terpenoids and S t e r o i d s Number

Reference

215 216 217 218 219 220 221 222

47 47 59 59 8 47 59 59

223 224 225 226 227 228 229 230 231 232 233 234

60 60 60 60 60 60 60 60 60 60 60 47

235 236 237 238 239 240 241 242 243 244 245 246

13 61 62 60 27 27 27 27 27 31 31 27

Carotenoids phytoene phytofluene a-carotene B-carotene lutein isolutein flavoxanthin violaxanthin auroxanthin neoxanthin neochrome lycopene Other

Terpenoids

3-ionone strigol s t r i g y l acetate vitamin A heliocide H heliocide H heliocide H heliocide H heliocide B heliocide B heliocide B heliocide B ±

x

2

3

4

1

2

3

4



290 COTTON


DUST

MCCORMICK

Secondary

Metabolites

of Gossypium


18.

239 - 246 Figure 3.

Biogenesis of predominant sesquiterpene and heliocide skeleta.


291

COTTON


292

DUST

as w e l l as the h e l i o c i d e s (239 - 246) (31). These h e l i o c i d e s are most i n t e r e s t i n g compounds, being adducts of the s e s q u i t e r penoid hemigossypolone (185, i t s e l f an i n s e c t i c i d e ) and the common monoterpene hydrocarbons g-ocimene (133) or myrcene (134), which a r e g r a d u a l l y formed during p l a n t aging (very p o s s i b l y by a nonenzymic r e a c t i o n ) . The "B" s e r i e s c o n s i s t s of methyl ether d e r i v a t i v e s of the "H" s e r i e s . As i n d i c a t e d i n F i g u r e 3, the cadinanes (170 - 187) a r e formed from the humulane (205) system, which a l s o i s the prog e n i t o r of the c a r y o p h y l l a n e s (206 - 208). Of these l a s t t h r e e compounds, c a r y o p h y l l e n e (206) i t s e l f i s of p a r t i c u l a r importance, s i n c e i t can account f o r 20 - 25% of the e s s e n t i a l o i l of some samples (14). Other major c o n s t i t u e n t s i n the same sample were copaene (173, another cadinane) and a-humulene (205), each near 15%. I t i s t h e r e f o r e apparent that the pathway i n v o l v i n g i n i t i a l conversion of Z , E - f a r n e s y l pyrophosphate t o the humulane system i s dominant i n Gossypium terpenoid b i o g e n e s i s .

199

193

The b i s a b o l a n e s , of which e i g h t have been reported i n these s t u d i e s , a l s o deserve s p e c i a l mention. Again, Z , E - f a r n e s y l pyrophosphate i s the p u t a t i v e p r o g e n i t o r . One study (13) reported B - b i s a b o l o l (199) t o be about 34% of the v o l a t i l e a l c o h o l f r a c t i o n , making i t about 5% of the t o t a l e s s e n t i a l o i l . a-Bisabolene (193) i s r e p r e s e n t a t i v e of the hydrocarbons of t h i s group.

205

206

173

Studies of Gossypium m e t a b o l i t e s have uncovered the occurrence of a few p l a n t s t e r o l s , i n c l u d i n g the r e p r e s e n t a t i v e gs i t o s t e r o l (219) (8, 18, 47, 59). These w i d e l y o c c u r r i n g phytos t e r o l s a r i s e by e a r l y f o r m a t i o n of c y c l o a r t e n o l (not y e t r e p o r ted) , which i s then s t r u c t u r a l l y m o d i f i e d . Some occur as g l y cosides.



18.

MCCORMICK


293

of Gossypium

cycloartenol Nitrogen Containing Compounds. T h i s remarkably small group contains i n d o l e (247), an unusual d e r i v a t i v e of i n d o l e (249), and the w e l l known d e r i v a t i v e s e r o t o n i n (248), a n e u r o l o g i c a l l y act i v e m a t e r i a l endogenous to the c e n t r a l nervous system.

247

248

249

Expectedly, the p y r r o l e pigments c h l o r o p h y l l , as w e l l as pheophytin a and b, have been c h a r a c t e r i z e d i n Gossypium ( 3 3 , 6 1 ) . Histamine (253), which i s widely regarded as a s s o c i a t e d i n some manner with b y s s i n o s i s ( 4 1 ) , i s present i n r e l a t i v e l y small amounts i n the cotton p l a n t i t s e l f ( 3 4 ) . Apparently much l a r g e r amounts are r e l e a s e d i n lung t i s s u e which i s exposed to b y s s i n o t i c agents.(See Table VIII.)

€1 253

288 , R = H

CHO

Me

287

2 8 9 , R = CHO


COTTON

294

DUST


Monosaccharides. The monomeric carbohydrates which have been found i n the c o t t o n p l a n t appear i n Table IX and have been i n cluded because of an i m p l i c a t i o n by one group t h a t they may act as a c a u s a t i v e agent of b y s s i n o s i s (35). This r e p o r t s t a t e s that a mixture of D-mannose and D-fructose e x h i b i t e d c o n t r a c t o r a c t i v i t y u s i n g the guinea-pig ileum assay. T h e i r r e p o r t on i s o l a t i o n of byssinosan, an aminopolysaccharide, and i t s c a u s a t i v e agent a c t i v i t y has had more impact and some regard t h i s substance to be a l e a d i n g candidate as a s i g n i f i c a n t b y s s i n o t i c agent. (42). B i o g e n e t i c a l l y U n c l a s s i f i e d Compounds. Table X c o n t a i n s the compounds which e i t h e r are not e a s i l y c l a s s i f i e d b i o g e n e t i c a l l y by i n s p e c t i o n of the s t r u c t u r e or which can a r i s e by more than one pathway. In any case, they are g e n e r a l l y s m a l l molecules cont a i n i n g common f u n c t i o n a l groups. Some may w e l l be a r t i f a c t s which have been improperly i n c l u d e d (vide supra). I n any case, none have been s i n g l e d out as p a r t i c u l a r l y strong candidates f o r b y s s i n o t i c a c t i v i t y . On the other hand, compounds such as the dihydropyrans (288 and 289), m e t h y l f u r f u r a l (287) and other a l d e hydes may w e l l possess damaging p h y s i o l o g i c a l a c t i v i t i e s and phenols commonly are t o x i c substances. Discussion General B i o s y n t h e s i s of Gossypium. A s u b s t a n t i a l p o r t i o n of the b i o s y n t h e t i c e f f o r t i n the c o t t o n p l a n t i s i n v e s t e d i n format i o n of s t r u c t u r a l and f u n c t i o n a l substances: c e l l u l o s e , l i g n i n s , t a n n i n s , and waxes, which are d e r i v e d from some of the s m a l l molec u l e m e t a b o l i t e s l i s t e d i n the Tables: monosaccharides, phenylpropanes, f l a v a n o i d s and f a t t y a c i d d e r i v e d substances. Apart from the energy i n v e s t e d i n making these s t r u c t u r a l l y e s s e n t i a l m a t e r i a l s , the v a s t m a j o r i t y of b i o s y n t h e s i s a c t i v i t y charact e r i z e d to date goes toward formation of t e r p e n o i d s . These compounds p u t a t i v e l y p l a y e c o l o g i c a l r o l e s i n many cases and as expected possess s i g n i f i c a n t p h y s i o l o g i c a l a c t i v i t i e s . I t i s c l e a r t h a t the s e s q u i t e r p e n o i d pathway proceeding through Z , E - f a r n e s y l pyrophosphate accounts f o r most of the mevalonate u t i l i z a t i o n . While c y c l i z a t i o n ( F i g u r e 3) of t h i s compound may proceed to g i v e bisabolanes and f u r t h e r d e r i v a t i v e s , i t i s an a l t e r n a t i v e mode of step-wise c y c l i z a t i o n s which forms the cadinanes, those s e s q u i t e r p e n o i d s which appear to be most s i g n i f i cant regarding p o t e n t i a l t o x i c and/or b y s s i n o t i c a c t i v i t i e s of the secondary m e t a b o l i t e s . Only a few s t e r o l s can be found among those compounds c h a r a c t e r i z e d , again emphasizing the s e s q u i t e r p e n o i d , and to a l e s s e r extent the monoterpenoid, o r i e n t a t i o n of the p l a n t ' s biosynthetic industry.


18.

Secondary

MCCORMICK

Table V I I I .

Metabolites

295

N i t r o g e n Containing Compounds

Compound Downloaded by GEORGETOWN UNIV on August 18, 2015 | http://pubs.acs.org Publication Date: July 1, 1982 | doi: 10.1021/bk-1982-0189.ch018

of Gossypium

Number

Reference

Indoles indole serotonin 3-ethyl-5-methoxyindole

247 248 249

8 32 9

P y r r o l e Pigments chlorophyll pheophytin a pheophytin b

250 251 252

33 61 61

Other Compounds histamine n i c o t i n i c acid tetramethylpyrazine

253 254 255

34 47 10

Table IX. Compound 2-acetamido-2-deoxyglucose 2-amino-2-deoxyglucose arabinose fructose galactose glucose mannose rhamnose ribose xylose inositol

Monosaccharides Number

Reference

256 257 258 259 260 261 262 263 264 265 266

35 35 16 35 16 35 35 16 16 16 47


COTTON

296 Table X.

M i s c e l l a n e o u s Compounds


Compound acetone isobutyraldehyde 2-ethyl-l-butanol 2-ethylbutyraldehyde 1-pentanol l-penten-3-ol 4-hydroxy-4-methyl-2-pentanone cyclopentanol cyclohexanol cyclohexanone cycloheptanone 2-cyclohexadienyl-4-methylpentan-l-ol 2,4-dimethyl-2,4-heptadienal 2-methylfuran 2,5-dimethylfuran 2-butyl-4-methylfuran 2-butyl-4-vinylfuran 2-acetylfuran 2-isobutyroylfuran a-furfuryl alcohol 5-methyl-2-furfural dihydropyran 2,3-dihydropyrancarboxaldehyde cyclohexanecarboxaldehyde 5-tert-butyl-3,3-dimethylindanone oxalic acid fumaric a c i d succinic acid malic acid t a r t a r i c acid glutaric acid a-ketoglutaric acid c i t r i c acid phenol o-phenylphenol d i-sec-butylphenol 2-phenoxyethanol m - t o l y l e t h y l ether e thy l b enz a i d ehyd e m-tolualdehyde o-methylacetophenone p-methylacetophenone £-ethylacetophenone 2,4-dimethylacetophenone

Number

Reference

267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310

8 62 9 9 13 13 8 12 13 8 8 10 43 9 10 8 8 10 10 12 8 10 8 8 10 52 52 52 52 52 47 52 52 8 8 8 9 8 9 10 10 12 10 10


DUST

18.

MCCORMICK


of

Gossypium

297


Perhaps most conspicuous by t h e i r absence from the l i s t (c£. Table V I I I ) are the a l k a l o i d s . These substances, g e n e r a l l y def i n e d as n i t r o g e n - c o n t a i n i n g secondary m e t a b o l i t e s , are common p l a n t products and u s u a l l y have d i s t i n c t p h y s i o l o g i c a l a c t i v i t i e s . N e v e r t h e l e s s , to date no r e p o r t s seem to have appeared concerning the presence (or absence) of a l k a l o i d s as Gossypium m e t a b o l i t e s . D i r e c t i o n s f o r Future I n v e s t i g a t i o n . C o n s i d e r a t i o n of the r e s u l t s summarized above permits some suggestions f o r f u r t h e r research concerning Gossypium d e r i v e d b y s s i n o t i c agents. The most obvious area of ignorance concerns the a l k a l o i d s : v i r t u a l l y none have been found. T h i s i s not s u r p r i s i n g when the i s o l a t i o n t e c h niques which have been employed are considered: steam d i s t i l l a tion/gas chromatography, e x t r a c t i o n w i t h water and w i t h low p o l a r i t y s o l v e n t s , guidance of i s o l a t i o n procedures u s i n g s p e c i f i c f u n c t i o n a l group reagents (such as was most e f f e c t i v e l y employed to uncover the terpenoid aldehydes i n S t i p a n o v i c ' s work). While these procedures have been used p r o f i t a b l y to o b t a i n v a l u a b l e r e s u l t s , those r e s u l t s may not be u s e f u l f o r drawing c o n c l u s i o n s about the presence of r a t h e r d i f f e r e n t types of compounds, such as the a l k a l o i d s . T h i s l i m i t a t i o n i s w e l l i l l u s t r a t e d by the f a i l u r e of those methods to uncover the presence of another important group, the f l a v a n o i d , coumarin and cinnamic a c i d phenols (85 - 117). On the other hand, some 32 of these compounds were i d e n t i f i e d when i s o l a t i o n procedures s p e c i f i c f o r these types of compounds were employed. Using i s o l a t i o n and i d e n t i f i c a t i o n techniques which are p a r t i c u l a r l y u s e f u l f o r a l k a l o i d s , i t would be p o s s i b l e to determine whether any r e p r e s e n t a t i v e s of t h i s c l a s s are present and, i f so, to conduct subsequent s t u d i e s f o r s t r u c t u r e d e t e r m i n a t i o n . F i n a l l y , some comments r e g a r d i n g examination of p h y s i o l o g i c a l a c t i v i t y may be made. Using bioassay methods a p p r o p r i a t e f o r det e c t i o n of p o s s i b l e b y s s i n o t i c a c t i v i t y , i t appears reasonable that the p h e n o l i c compounds (85 -117) and the cadinane s e s q u i t e r pene i d s (170 - 192, 239 - 246) should be e s p e c i a l l y s c r u t i n i z e d f o r c a u s a t i v e agent behavior. As w e l l , any a l k a l o i d s found must be c a r e f u l l y examined, i n r e c o g n i t i o n of the f a c t that these compounds g e n e r a l l y have potent p h y s i o l o g i c a l e f f e c t s . Acknowledgment F i n a n c i a l support by Cotton Incorporated- the r e s e a r c h and marketi n g company r e p r e s e n t i n g America's c o t t o n producers- i s g r a t e f u l l y acknowledged.


COTTON

298

DUST

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6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

Lynn, W.S.; Munoz, S.; Campbell, J.A.; Jeffs, P.W. Ann. N.Y. Acad. Sci. 1974, 221, 163-73. Northup, S.; Presant, L.; Kilburn, K.H.; McCormick, J.P.; Pachlatko, J.P. Fed. Proc. 1976, 35, 632. Kilburn, K.H. J . Environ. Pathol. Toxicol. 1979, 2, 350-1. Morey, P.R. Am. Ind. Hyg. Assoc. J . 1979, 40, 702-708. Morey, P.R.; Sasser, P.E.; Beathea, R.M.; Kopetzky, M.T. Am. Ind. Hyg. Assoc. J . 1976, 37, 407-12. Talipova, M.; Glushenkova, A.I.; Umarov, A.U. Khim. Prir. Soedin 1981, 44-7; Chem. Abstr. 1981, 94, 205400t. Ganieva, M.; Badalova, M.; Nasyrova, D. Khlopkovodstro 1981, 36-7; Chem. Abstr. 1981, 94, 153598S. Hedin, P.A.; Thompson, A.C.; Gueldner, R.C. J . Agric. Food Chem. 1975, 23, 698-703. Hedin, P.A.; Thompson, A.C.; Gueldner, R.C. Phytochem. 1975, 14, 2088-90. Hedin, P.A.; Thompson, A.C.; Gueldner, R.C. Ann. N.Y. Acad. Sci. 1974, 221, 174-82. Kajimoto, G.; Tsutsui, Y.; Yoshida, H. Nippon Nogei Kagaku Kaishi 1981, 55, 31-6; Chem. Abstr. 1981, 94, 153532r. Hedin, P.A.; Thompson, A.C.; Gueldner, R.C. Phytochem. 1975, 14, 2087-88. Hedin, P.A.; Thompson, A.C.; Gueldner, R . C ; Minyard, J.P. Phytochem. 1971, 10, 3316-18. Hedin, P.A.; Thompson, A.C.; Gueldner, R . C ; Rizk, A.M.; Salama, H.S. Phytochem. 1972, II, 2356-57. Brzozowska, J.; Hanower, P.; Tanguy, J . Phytochem. 1973, 12, 1253-7. Wakelyn, P.J.; Greenblatt, G.A.; Brown, D.F.; Tripp, V.W. Am. Ind. Hygiene Assoc. J . 1976, 37, 22-31. Wakelyn, P.J.; Stipanovic, R.D.; Bell, A.A. J . Agric. Food Chem. 1974, 22, 567-8. Gilbert, R.D.; Fornes, R.E.; Wang, A . ; Lee, K.S. Textile Res. J.. 1980, 50, 29-33. Robinson, T. "The Organic Constituents of Higher Plants", 2nd ed.; Burgess Pub. Co.: Minneapolis, Minnesota, 1967, p. 72. Minyard, J.P.; Tumlinson, J.H.; Hedin, P.A.; Thompson, A.C. J . Agric. Food Chem. 1965, 13, 599-602. Stipanovic, R.D.; Greenblatt, G.A.; Beier, R.C.; Bell, A.A. Phytochem. 1981, 20, 729-30. Stipanovic, R.D.; Wakelyn, P.J.; Bell, A.A. Phytochem. 1975, 14, 1041-3. Stipanovic, R.D.; Bell, A.A.; Mace, M.E.; Howell, C.R. Phytochem. 1975, 14, 1077-81. Bell, A.A.; Stipanovic, R.D.; Howell, C.R.; Fryxell, P.A. Phytochem. 1975, 14, 225-31. Stipanovic, R.D.; Bell, A.A.; Howell, C.R. Phytochem. 1975, 14, 1809-11.


18.

26. 27. 28. 29.


30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

48. 49. 50. 51.

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299

Stipanovic, R.D.; Bell, A.A.; O'Brien, D.H. Phytochem. 1980, 19, 1735-38. Bell, A.A.; Stipanovic, R.D.; O'Brien, D.H.; Fryxell, P.A. Phytochem. 1978, 17, 1297-1305. Bell, A.A. Phytopathology 1967, 57, 760-64. Adams, R.; Geissman, T.A.; Edwards, J.D. Chem. Rev. 1960, 60, 555-631. Haas, R.H.; Shirley, P.A. J . Org. Chem. 1965, 30, 4111-13. Stipanovic, R.D.; Bell, A.A.; Lukefahr, M.J. "Host Plant Resistance to Pests": Hedin, P.A., Ed.; American Chemical Society: Washington, D.C., 1977; p 197-214. Davenport, A . ; Paton, W.D.M. Brit. J . Ind. Med. 1961, 18, 19-32. Loewenschuss, H.; Wakelyn, P.J. J . Agric. Food Chem. 1973, 21, 319-21. Lloyd, G.R.; Nicholls, P.J. J . Physiol. (London) 1964, 172, 56P-57P. Mohammed, Y . S . ; El-Gazzar, R.M.; Adamyova, K. Carbohyd. Res. 1971, 20, 431-5. Wakelyn, P.J.; O'Brien, C.A.; Loewenschuss, H. Southwest Vet. 1972, 25, 293. Kilburn, K.H.; Lynn, W.S.; Tres, L . L . ; McKenzie, W.N. Lab. Invest. 1973, 28, 55. Hergert, H.L. "The Chemistry of Flavanoid Compounds": Geissman, T.A., Ed.; MacMillan: New York, N.Y., 1962: p 584. Windholz, M. (Ed.) "The Merck Index"; Merck & Co., Inc: Rahway, New Jersey, 1976; p. 588. Maugh, T.H., III Science 1981, 212, 314. Battigelli, M.C.; Craven, P . L . ; Fischer, J.J.; Morey, P.R.; Sasser, P.E. J . Environ. Sci. Health A 1977, 12, 327-39. Cooke, T.F. "Chemical Composition of Cotton Dust and Its Relation to Byssinosis; A Review of the Literature"; Textile Research Institute; Princeton, New Jersey, 1978. Hanny, B.W.; Thompson, A.C.; Gueldner, R.C.; Hedin, P.A. J . Agric. Food Chem. 1973, 21, 1004-6. Ohkuma, K . ; Addicott, F.T.; Smith, O.E.; Thiessen, W.E. Tetrahedron Lett. 1965, 2529-35. Thompson, A.C.; Hedin, P.A. Crop Sci. 1965, 5, 133-5. Shenstone, F.S.; Vickery, J.R. Nature 1961, 190, 168-9. Hedin, P.A.; Thompson, A.C.; Gueldner, R.C. "Recent Advances in Phytochemistry. Vol. 10. Biochemical Interaction Between Plants and Insects": Wallace, J.W.; Mansell, R.L., Eds.; Plenum Press: New York, N.Y., 1976, p. 271-350. Struck, R.F.; Frye, J . L . ; Shealy, Y.F. J . Agric. Food Chem. 1968, 16, 1028-30. Sadykov, A.S.; Isaer, K.I.; Ishmailov, H.I. Uzbeksk. Khim. Zh. 1963, 7, 53-6; Chem. Abstr. 1963, 59, 10473C. Fargher, R.G.; Probert, M.E. J . Textile Institute 1924, 15, T337-46. Guinn, G. Plant Physiol. 1976, 57, 403-5.


COTTON

300

52.

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57. 58. 59. 60. 61. 62. 63. 64. 65.

DUST

Sadykov, A.S.; Pakudina, Z.P.; Buzitskova, E.P.; GuliKevkhyan, A. Sh.; Karimdzhanov, A . ; Isaev, Kh. Uzbek. Khim. Zhur. Akad. Nauk. Uzbek. S.S.R. 1958, 41-8; Chem. Abstr. 1959, 53, 22292b. Hedin, P.A.; Miles, L.R.; Thompson, A.C.; Minyard, J.P. J. Agric. Food Chem. 1968, 16, 505-13. Parks, C.R. Am. J . Batony 1965, 52, 849-56. Grupenberg, J . "The Chemistry of Flavanoid Compounds": Geissman, T.A., Ed.; MacMillan: New York, N.Y., 1962: p. 423. Hattorv, S. "The Chemistry of Flavanoid Compounds": Geissman, T.A., Ed.; MacMillan: New York, 1962: p. 343. Sadykov, A.S.; Karimdzhauov, A.K. Uzbek. Khim. Zhur. 1960, 53-6; Chem. Abstr. 1960, 54, 25083e. Hedin, P.A.; Minyard, J.P.; Thompson, A.C.; Struck, R.F.; Frye, J . Phytochem. 1967, 6, 1165-67. Thompson, A.C.; Henson, R.A.; Gueldner, R.C.; Hedin, P.A. Lipids 1970, 5, 283-4. Thompson, A.C.; Henson, R.D.; Hedin, P.A.; Minyard, J.P. Lipids 1968, 3, 495-7. Temple, C., J r . ; Roberts, E.C.; Frye, J.; Struck, R.F.; Shealy, Y . F . ; Thompson, A.C; Minyard, J.P.; Hedin, P.A. J. Econ. Entomol. 1968, 61, 1388-93. Minyard, J.P.; Tumlinson, J . H . ; Thompson, A.C.; Hedin, P.A. J. Agric. Food Chem. 1967, 15, 517-524. Cook, C.E.; Whichard, L . P . ; Wall, M.E.; Egley, G.H.; Coggen, P.; Luhan, P.A.; McPhail, A.T. J. Am. Chem. Soc. 1972, 94, 6198-99. Cook, C.E.; Whichard, L . P . ; Turner, B.; Wall, M.E.; Egley, G.H. Science 1966, 154, 1189. Hendricks, J.D.; Sinnhuber, R.O.; Loveland, P.M.; Pawlowski, N.E.; Nixon, J.E. Science 1980, 208, 311.

RECEIVED

December 15, 1981.


Cotton Dust - American Chemical Society

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