Chemical structure and biological activity 



almost complete loss of activity, both in mono and in poly-substituted 

 compounds. Matell (1953) has also reported that the activity of (4-)-a-(2- 

 naphthyloxy) propionic acid in the flax root growth test is lowered about 

 600 times when chlorinated in position 1. He also makes the significant 

 comment that the strong antagonistic action of the ( — ) form is very little 

 affected by chlorination. Positions 6, 7, and 8 are also important for activity, 

 though blocking of these points with chlorine causes a reduction but not 

 complete loss of activity. It is interesting to note that replacement of the 

 chlorine in position 8 by a nitro-group causes a further ten-fold reduction in 

 activity. In the first results of substitution in the 3-position which we now 

 report, it is seen that a chlorine atom here has no detrimental effect on the 

 activity in the acetic acid series, though some reduction in the a-propionic 

 acid series takes place, being part of the gradual decrease in the activity of 

 a-substituted acids already mentioned. 



An examination of Fischer-Hirschfelder molecular models of chlorinated 

 2-naphthyloxyacetic acids shows that chlorine atoms in positions 1 and 3 

 interfere to some extent with the free rotation of the — O • CHgCOOH side- 

 chain, and thus influence the final spatial arrangement of atoms. Although 

 the naphthalene nucleus is planar, large substituent groups such as chlorine 

 may cause a buckling effect to relieve strain, which would destroy planarity, 

 and in certain cases possibly affect the compactness of the molecule. It is 

 unfortunate that the models give little help on this point. Jonsson (1955) 

 does however stress that a planar structure is not the only requirement for 

 bicyclic molecules to possess high activity. 



The electronic effects of nuclear chlorine atoms may also be important. 

 Reaction with other molecules such as coenzyme A forming an acetyl-thiol 

 ester as has been suggested by Leopold and Guernsey (1953) would appear to 

 be encouraged by chlorine atoms in positions 1, 3, 6, and 8 but not in 

 positions 4, 5, and 7 as shown in the following diagrams: 



/V V-O • CH2 • COOH 



y\XV%LO . CH2 • COOH 



CI 



. CHo • COOH 



(fS^O . CH. • COOH 



The inactivity of the 1 -chloro-compound would then have to be explained 

 by a superimposed steric effect involving the side-chain (Jonsson's activity 

 requirements (iv) and (v)). 



Two other hypotheses concerning mode of action have suggested inter- 

 action of growth substances with a hypothetical plant protein. The papers of 



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