Chemical structure and biological activity 



response they bring about as an end-effect of their actions is clearly percep- 

 tible and measurable. One has to admit, however, that properly speaking we 

 know nothing for certain about what is going on 'in between' (in the cell). 

 This is apparent also from the large number of theories, always inversely 

 proportional to our factual knowledge of the relative problem. By dealing 

 with half of the problem only (the active growth substances) we shall not be 

 able to unravel the secret of auxin action; to achieve that aim we shall have 

 to know more about 'the other side', viz. the receptor(s) in the cell. 



Realizing that the growth response is given by an intact biological system 

 only, it is evident that the primary action cannot be isolated from the cell. 

 In this respect the analysis of localization and mode of action will be even 

 more difficult than it is in enzymatic studies. There, one has the advantage 

 that in several cases free, isolated enzymes are available with which the 

 interaction between agent (substrate or inhibitor) and functioning macro- 

 molecule (viz. the primary action) can be studied uninfluenced by secondary 

 factors. 



However difficult the task may be, in order to get at the final solution of the 

 problem of auxin action, in our opinion the accent of the investigations will 

 have to shift from studies on structure-activity to a biochemical (physical) 

 approach, while looking more inside the cell. For this perhaps new techniques 

 are needed. The way such research will develop will, of course, depend also 

 on the interpretation of knowledge gained previously in physiological and 

 structural chemical investigations. 



From more recent work I have therefore selected a number of experiments 

 which in some respects round off our work on structure-activity relationships, 

 and which in my opinion may guide further analysis in the above-mentioned 

 directions. 



SUBSTITUTED BENZOIC AND NAPHTHOIC ACIDS 



In my opinion there can be no doubt that the activity of the sub- 

 stituted benzoic acids is essentially linked up with the particular spatial 

 Structure, resulting from the steric influence exerted by the dwrtho substitu- 

 tion. The conjugation between the carboxyl group and the ring-system, 

 which normally causes the molecule to occur in the mean in a flat form, is 

 suppressed by the hindering substituents, and the resulting active form is a 

 non-flat one (see Figure 1, also Veldstra, 1952). 



Different opinions have been expressed with respect to the role of the 

 nucleus in the active benzoic acids. Muir and Hansch (1951) and also 

 Thimann (1952) ascribed a special function (according to Muir and Hansch 

 a chemically reactive one) to defined positions in the nucleus (2-6, and 5, 

 respectively) with respect to the primary action. We preferred to consider 

 the whole nucleus as an attaching unit, in which special steric requirements 

 as to size and position of substituents have to be met. 



Our objections to the view of Muir and Hansch have been expounded 

 elsewhere (Veldstra and Westeringh, 1952; Veldstra, 1953) and need not 

 be repeated here. In our opinion, as to the o-substituents it is quite evident 

 that a steric and not a chemically reactive function gives a plausible explana- 

 tion of the observed facts ; however, we desired to know more about the 

 3-, 5-, and 4-positions. 



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