PREFACE Τ η the last d e c a d e the costs of i n t r o d u c i n g a n e w b i o l o g i c a l -*· ( d r u g or p e s t i c i d e )
to m a r k e t h a v e n e a r l y d o u b l e d .
chemical
Current intro
d u c t o r y costs are o n the order of seven to 10 m i l l i o n dollars. A s a result, f e w e r n e w drugs a n d pesticides are b e i n g m a r k e t e d e a c h year.
Concur
r e n t l y , m a n y large i n d u s t r i a l concerns have c l o s e d out t h e i r a g r i c u l t u r a l Downloaded by 80.82.77.83 on March 12, 2018 | https://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.pr001
research, a n d p h a r m a c e u t i c a l houses h a v e l i k e w i s e decreased t h e i r s y n thesis a n d screening
operations.
F o r those research organizations that c o n t i n u e i n t h e quest for n e w c o m p o u n d s w i t h i m p r o v e d b i o l o g i c a l a c t i v i t y or that f u l f i l l a m a r k e t n e e d , the r i s k is h i g h , b u t the r e w a r d s are h i g h also. It is l i t t l e w o n d e r that i n a n effort to decrease this risk, these concerns are d e v o t i n g
increasing
attention to n e w tools that a i d i n the selection of c o m p o u n d s for f u r t h e r development. T h e i d e a of c o r r e l a t i n g b i o l o g i c a l a c t i v i t y w i t h c h e m i c a l
structure
a n d p h y s i c a l properties of c o m p o u n d s is not n e w . I n d e e d , the b e g i n n i n g s m a y b e t r a c e d b a c k to the famous M e y e r - O v e r t o n theory (1,2)
w h e r e the
b i o a c t i v i t y of anesthetics w a s c o r r e l a t e d w i t h l i p i d / w a t e r p a r t i t i o n co efficients. I n 1935 M e y e r a n d H e m m i ( 3 ) disclosed t h a t b i o l o g i c a l a c t i v i t y was a g a i n r e l a t e d to a p a r t i t i o n coefficient.
I n 1962 H a n s e n (4)
strated the r e l a t i o n s h i p b e t w e e n b i o l o g i c a l a c t i v i t y a n d the s i g m a constant.
demon Hammett
E a c h one of these approaches was a p p l i c a b l e w i t h i n a
n a r r o w area of s t r u c t u r e a n d a c t i v i t y . I n 1964 H a n s c h a n d F u j i t a
(5)
c o n s i d e r a b l y b r o a d e n e d the scope a n d u t i l i t y of s t r u c t u r e - a c t i v i t y c o r r e lations w i t h their i n t r o d u c t i o n of a n a c t i v i t y m o d e l a n d a
two-parameter
e q u a t i o n b a s e d o n H a m m e t t s i g m a constants a n d s o l u b i l i t y parameters. T h e H a n s c h - F u j i t a m e t h o d , the F r e e - W i l s o n t h e o r y
(described by
C r a i g i n C h a p t e r 8 ), a n d the m o l e c u l a r o r b i t a l theory ( d e s c r i b e d b y K i e r , C h a p t e r 15) h a v e greatly i n c r e a s e d o u r u n d e r s t a n d i n g of the m o d e of a c t i o n of m a n y b i o l o g i c a l c h e m i c a l s .
It has also i m p r o v e d o u r a b i l i t y to
p r e d i c t the a c t i v i t y of a v a r i e t y of c h e m i c a l s against p l a n t a n d pests a n d c e r t a i n p a t h o g e n i c
insect
organisms.
O n e w a y to i l l u s t r a t e s t r u c t u r e - a c t i v i t y correlations is to p l o t a c t i v i t y as a l o g a r i t h m i c f u n c t i o n of a p h y s i c a l parameter.
T h e resulting plot
y i e l d s a c u r v e w h e r e o p t i m u m a c t i v i t y lies at the s u m m i t of a h i l l .
By
k n o w i n g the effects of a p p r o p r i a t e d e p e n d e n t variables o n a c t i v i t y , one c a n l e a r n h o w to r e a c h the s u m m i t i n the most efficient m a n n e r . vii
Van Valkenburg; Biological Correlations—The Hansch Approach Advances in Chemistry; American Chemical Society: Washington, DC, 1974.
A d v e r s e b i o l o g i c a l a c t i v i t y , s u c h as toxicology, c a n also b e c o r r e l a t e d w i t h p h y s i c a l a n d c h e m i c a l parameters.
Imagine
such activity for a
chosen f a m i l y of c o m p o u n d s as b e i n g r e p r e s e n t e d b y a b l a c k h i l l . I f the d e s i r e d b i o l o g i c a l a c t i v i t y is c o r r e s p o n d i n g l y represented as a w h i t e h i l l , the peaks of the w h i t e a n d b l a c k h i l l s w i l l g e n e r a l l y b e d i s p l a c e d f r o m e a c h other.
H e n c e , o n e m a y a d v a n t a g e o u s l y use c o r r e l a t i o n studies t o
a p p r o a c h as close t o the top of the w h i t e h i l l as possible w h i l e s t i l l b e i n g as far r e m o v e d f r o m s u m m i t of the b l a c k h i l l as is feasible. T h i s c o n c e p t is d e p i c t e d o n the cover a n d jacket of this book. Acknowledgment
Downloaded by 80.82.77.83 on March 12, 2018 | https://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.pr001
I extend m y sincere a p p r e c i a t i o n t o C o r w i n H a n s c h of P o m o n a C o l lege for his p a r t i c u l a r l y enthusiastic assistance i n o r g a n i z i n g this s y m p o s i u m . M y thanks also goes t o W . P . P u r c e l l a n d T . R . F u k u t o f o r their h e l p a n d p a r t i c i p a t i o n i n the s y m p o s i u m . I also extend a p p r e c i a t i o n to J . E . J o h n s o n a n d W . B r o c k N e e l y of the D o w C h e m i c a l C o . f o r s t i m u l a t i n g a n d m a i n t a i n i n g m y interest i n this area of a c t i v i t y f o r m a n y years. A n d last b u t not least, m y sincere thanks go t o A . F . Y a p e l here at 3 M for his e n t h u s i a s m , d r i v e , a n d h a r d w o r k that m a d e o u r p a r t i c i p a t i o n i n this s y m p o s i u m possible.
Literature Cited 1. Meyer, H. H., Arch. Exptl. Pathol. Pharmakol. Naunyn-Schmiedeberg's (1899) 42, 109. 2. Overton, E., "Studienüberdie Narkose," Jena, Germany, 1901. 3. Meyer, K. H., Hemmi, H., Biochem. Z. (1935) 227, 39. 4. Hansen, O., Rosenlund, Acta Chem. Scand. (1962) 16, 1593. 5. Hansch, C., Fujita, T., J. Amer. Chem. Soc. (1964) 86, 1616. St. Paul, Minn. September 1972
J. W. VAN VALKENBURG
viii
Van Valkenburg; Biological Correlations—The Hansch Approach Advances in Chemistry; American Chemical Society: Washington, DC, 1974.
