Phenoxyalkanoic Acid Sweetness Inhibitors - ACS Symposium Series

Lintech, P.O. Box 68, Whiteknights, Reading, England. Sweeteners ... DOI: 10.1021/bk-1991-0450.ch019 ... Publication Date (Print): December 31, 1991...
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Chapter 19

Phenoxyalkanoic Acid Sweetness Inhibitors Michael G . Lindley

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Lintech, P.O. Box 68, Whiteknights, Reading, England

Substituted phenoxyalkanoic acids are potent inhibitors of the sweetness response. The degree of inhibition of sweetness is dependent on the concentration of substituted phenoxyalkanoic acid in a sweetener-inhibitor mixture. In contrast to some other sweetness inhibitors, pre-treatment of the tongue is not necessary and the inhibitory effect is immediate and rapidly reversible. The acidic group, or its salt, is necessary, and the nature, position and degree of substitution on the phenyl moiety influences potency. The results of sensory studies designed to determine the possible mechanism of action are described, and the implications for our understanding of the mechanism whereby sweeteners induce their effects are discussed. The existence of c o m p o u n d s capable of i n h i b i t i n g t h e perception of sweetness have been k n o w n for m a n y years, b u t they have not been the subject of intense study. Nonetheless, the mechanisms w h e r e b y k n o w n i n h i b i t o r s exert t h e i r effects h a v e , t o s o m e degree, been examined a n d a variety of mechanisms s h o w n to be operating. F o r example, N-ethylmaleimide, iodoacetic acid, a n d p - c h l o r o mercuribenzoate (J) p r o b a b l y i n h i b i t s w e e t n e s s p e r c e p t i o n b y c o v a l e n t i n t e r a c t i o n a t t h e t a s t e c e l l m e m b r a n e (2). Gymnemic acid a n d t h e more recently discovered ziziphins are believed to i n h i b i t sweetness t h r o u g h their surface active, detergent like p r o p e r t i e s (3). S i m i l a r l y , s o d i u m d o d e c y l s u l p h a t e i s c a p a b l e o f penetrating and disrupting the phospholipid membranes that are b e l i e v e d t o b e c o m p o n e n t s o f s w e e t n e s s r e c e p t o r s (4). M e t h y l - 4 , 6 dichloro-4,6-dideoxy-a-D-galactopyranoside i n h i b i t s sweet taste N O T E : The work described in this paper was carried out in the Tate and Lyle Research and Development Laboratories, Whiteknights, Reading, England.

0097-6156/91/0450-0251$06.00/0 © 1991 American Chemical Society

Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

Downloaded by IOWA STATE UNIV on April 19, 2017 | http://pubs.acs.org Publication Date: December 31, 1991 | doi: 10.1021/bk-1991-0450.ch019

252

SWEETENERS:

DISCOVERY, M O L E C U L A R

DESIGN, A N D

CHEMORECEPTION

r e s p o n s e s i n g e r b i l s , a n d there i s s o m e evidence to s u g g e s t t h a t t h e m e c h a n i s m o f i n h i b i t i o n m a y b e c o m p e t i t i v e (5). Finally, the d i u r e t i c a m i l o r i d e is reportedly a n i n h i b i t o r of sweetness, a l t h o u g h there are conflicting results using conventional sensory methodology. Its m e c h a n i s m of a c t i o n h a s b e e n s u g g e s t e d a s t h a t o f a n i n h i b i t o r o f i o n t r a n s p o r t m e c h a n i s m s (6). R e c e n t l y , a n u m b e r of other c l a s s e s of c h e m i c a l s h a v e b e e n d i s c o v e r e d to have s w e e t n e s s i n h i b i t i n g p r o p e r t i e s (7-9). In c o m m o n with other sweetness inhibitors, these substituted phenylalkanoic acids, phenoxyalkanoic acids, and benzoylalkanoic a c i d s i n h i b i t t h e p e r c e p t i o n of s w e e t n e s s of d i f f e r i n g c h e m i c a l s t r u c t u r e s . However, they e x h i b i t n o evidence of d i s r u p t i n g taste c e l l m e m b r a n e s , a n d t h e i r effects are i m m e d i a t e l y reversible. T h e r e f o r e , t h e y are p o t e n t i a l l y v a l u a b l e t o o l s to i n c r e a s e o u r u n d e r s t a n d i n g of the c h e m i c a l s t r i c t u r e s of s w e e t n e s s p e r c e p t i o n . Structure-Activity

Relationships

The initial observation that these phenoxyalkanoic acids c a n i n h i b i t t h e p e r c e p t i o n of s w e e t n e s s w a s m a d e o n t a s t i n g a s o l u t i o n of s u c r o s e a t 5 % (w/v) c o n c e n t r a t i o n w h i c h c o n t a i n e d 0 . 0 5 % (w/v) 4-hydroxy-3-methoxy-phenylpropanoic acid. The mixture was p e r c e i v e d a s b e i n g e q u i - s w e e t t o a 3 % (w/v) s u c r o s e s o l u t i o n , t h u s , the degree of i n h i b i t i o n w a s a p p r o x i m a t e l y 4 0 % . This initial o b s e r v a t i o n l e d to w h a t w a s m e r e l y a s t a n d a r d s t r u c t u r e - a c t i v i t y relationship program. Derivatives were prepared synthetically a n d their inhibitory action assessed u s i n g either the methodology d e s c r i b e d o r o n e i n w h i c h s u c r o s e w a s a t 1 0 % (w/v) a n d t h e i n h i b i t o r u n d e r t e s t a t 0 . 0 0 5 % (w/v). S y n t h e t i c procedures followed general p u b l i s h e d guidelines (10-12). In outline, p h e n y l p r o p a n o i c acid derivatives were p r e p a r e d b y r e d u c t i o n of the c o r r e s p o n d i n g c i n n a m i c a c i d derivative, itself o b t a i n e d b y a P e r k i n c o n d e n s a t i o n of the a p p r o p r i a t e b e n z a l d e h y d e w i t h acetic a n h y d r i d e i n the p r e s e n c e of s o d i u m acetate. P h e n o x y a l k a n o i c acid derivatives were p r e p a r e d b y r e d u c t i o n of the a p p r o p r i a t e p h e n o l w i t h a h a l o a l k a n o i c a c i d or a n ester of a h a l o a l k a n o i c a c i d . It w a s u n f o r t u n a t e t h a t t h e s c o p e o f t h i s p r o g r a m m e w a s l i m i t e d b y its objective. It w a s n o t d e s i g n e d e i t h e r t o u n r a v e l t h e c o m p r e h e n s i v e r e l a t i o n s h i p s p r e s u m e d to e x i s t b e t w e e n s t r u c t u r e a n d effect, o r t o d e v e l o p s t r u c t u r a l c o r r e l a t i o n s b e t w e e n s w e e t n e s s inhibitors a n d k n o w n sweeteners. T h e o b j e c t i v e s w e r e to i d e n t i f y t h e o p t i m u m c o m p o u n d to d e v e l o p c o m m e r c i a l l y . Nonetheless, there were m a n y interesting observations arising from the limited s t r u c t u r e - a c t i v i t y p r o g r a m , s o m e of w h i c h are s e e m i n g l y c o n f l i c t i n g a n d have not yet been rationalised. F o r example, w i t h i n the phenylpropanoic acid series, the p o s i t i o n of a m e t h o x y - s u b s t i t u e n t h a s n o i n f l u e n c e o n the effectiveness of the r e s u l t i n g c o m p o u n d as a n i n h i b i t o r of

Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

19. LINDLEY

Phenoxyalkanoic Acid Sweetness Inhibitors

253

s w e e t n e s s ( T a b l e I). H o w e v e r , w i t h i n t h e 2 - p h e n o x y p r o p a n o i c a c i d series, positioning of a methoxy-substituent h a s a major i m p a c t o n i n h i b i t o r y p o w e r ( T a b l e II) a n d i t i s n o t i m m e d i a t e l y o b v i o u s w h y t h i s difference exists. T a b l e I.

Effect of S u b s t i t u e n t P o s i t i o n o n I n h i b i t i o n b y Phenylpropanoic acids.

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Position/Substituent

Inhibition (%) (0.05% Inhibitor i n 5 % Sucrose)

2-Methoxy

40

3-Methoxy

40

4-Methoxy

40

3-Ethoxy

60

4-Ethoxy

60

T a b l e II. E f f e c t o f S u b s t i t u e n t P o s i t i o n o n I n h i b i t i o n b y Phenoxypropanoic Acids Position/Substituent 2- Methoxy

I n h i b i t i o n (%) (0.05% Inhibitor i n 1 0 % Sucrose) 15

3-Methoxy

30

4- M e t h o x y

50

S i m i l a r l y , α-naphthyl p h o s p h a t e does n o t i n h i b i t sweetness, w h e r e a s t h e c o r r e s p o n d i n g s u l p h a t e (α-naphthyl s u l p h a t e ) d o e s . In contrast, α-hydroxy b e n z y l p h o s p h i n i c acid does inhibit s w e e t n e s s , b u t α-hydroxy-a-toluene s u l p h o n i c a c i d d o e s n o t (Figure 1). O t h e r structure-activity relationships developed follow a m o r e consistent pattern. Increasing the lipophilicity of s u b s t i t u e n t s o n the p h e n y l o r p h e n o x y moiety increases the effectiveness u p to a m a x i m u m , when, w i t h further increases i n lipophilicity, there is a d r o p i n i n h i b i t o r y efficiency. A s long ago as 1 9 6 6 , s i m i l a r observations h a d been m a d e o n the relative sweetness of derivatives of 2 - a m i n o - 4 - n i t r o b e n z e n e s . D e u t s c h a n d H a n s c h h a d observed that relative sweetness w a s highly dependent o n the h y d r o p h o b i c b i n d i n g c o n s t a n t (13). Here, the i n h i b i t o r y effectiveness of c o m p o u n d s w a s f o u n d to correlate w i t h t h e i r c a l c u l a t e d l o g Ρ v a l u e s i n a s i m i l a r w a y to t h a t observed b y D e u t s c h a n d H a n s c h for sweeteners. A s the lipophilicity of a s u b s t i t u e n t increases, so does the c o m p o u n d ' s m e a s u r e d "biological response", u p to a m a x i m u m , f o l l o w i n g w h i c h t h e r e i s a s t e a d y f a l l i n e f f e c t i v e n e s s ( T a b l e s III a n d IV). I n t e r e s t i n g l y , e v e n t h i s r e l a t i o n s h i p o n l y h o l d s w i t h i n t h e a l k y l

Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

254

SWEETENERS:

DISCOVERY, M O L E C U L A R

DESIGN, A N D

CHEMORECEPTION

s u b s t i t u e n t or a l k o x y s u b s t i t u e n t series, not across those s t r u c t u r a l boundaries. T a b l e III. C o r r e l a t i o n o f t h e N a t u r e o f t h e S u b s t i t u e n t w i t h t h e B i o l o g i c a l R e s p o n s e of P h e n o x y p r o p a n o i c A c i d s . R

Log Peak

H

1.60

11

3

2.16

41

C H

2.62

63

3.13

45

3.58

33

CH 2

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Inhibition (%) (0.005% Inhibitor i n 1 0 %

5

iC3H

7

tC4H

9

Sucrose)

T a b l e IV. C o r r e l a t i o n of the N a t u r e of t h e S u b s t i t u e n t w i t h t h e B i o l o g i c a l R e s p o n s e of P h e n o x y p r o p a n o i c A c i d s . R

Log Peak

Inhibition (%) (0.005% Inhibitor i n 1 0 %

OH

0.93

0

OCH3

1.58

48

OC2H5

1.98

34

OC3H7

2.65

13

OC4H9

3.14