STERIMOL

The Kd(X) values thus obtained (Table 3) were analyzed by the multivariant technique using such parameters as n, a0, Bt, Ibmch, and Ihb, where Bj is a STERIMOL parameter showing the minimum width of substituents from an axis connecting the a-atom of the substituents and the rest of molecule, and Ibrnch, an indicator variable representing the number of branches in a substituent. 

In these equations, Dmax is the larger of the summed values of STERIMOL parameters, Bj, for the opposite pair 68). It expresses the maximum total width of substituents. The coefficients of the ct° terms in Eqs. 37 to 39 were virtually equal to that in Eq. 40. This means that the a° terms essentially represent the hydrolytic reactivity of an ester itself and are virtually independent of cyclodextrin catalysis. The catalytic effect of cyclodextrin is only involved in the Dmax term. Interestingly, the coefficient of Draax was negative in Eq. 37 and positive in Eq. 38. This fact indicates that bulky substituents at the meta position are favorable, while those at the para position unfavorable, for the rate acceleration in the (S-cyclodextrin catalysis. Similar results have been obtained for a-cyclodextrin catalysis, but not for (S-cyclodextrin catalysis, by Silipo and Hansch described above. Equation 39 suggests the existence of an optimum diameter for the proper fit of m-substituents in the cavity of a-cyclodextrin. The optimum Dmax value was estimated from Eq. 39 as 4.4 A, which is approximately equivalent to the diameter of the a-cyclodextrin cavity. The situation is shown in Fig. 8. A similar parabolic relationship would be obtained for (5-cyclodextrin catalysis, too, if the correlation analysis involved phenyl acetates with such bulky substituents that they cannot be included within the (5-cyclodextrin cavity. 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

Verloop A (1987) The sterimol approach to drug design. Marcel Dekker, New York... 

A. Verloop, The STERIMOL Approach to Drug Design. Marcel Dekker, New York, 1987. L.B. Kier and L.H. Hall, Molecular Connectivity in Structure-Activity Analysis. Wiley, New York, 1986. 

Use of STERIMOL, MTD, and MTD Steric Parameters in Quantitative Structure-Activity Relationships... 

STERIMOL and MTD (Minimum Topological Difference) steric parameters to account for steric influences in QSAR of pesticides have been described and applied in the literature. We have recently developed an improved version of the Simon MTD method, i.e. MTD parameters. The MTD and MTD methods will be described. The scope and limitations of the STERIMOL,... 

TIPKER VERLOOP STERIMOL MTD Steric Parameters in QSAR 281... 

The results of the studies will be summarized. Details of the QSAR analyses are or will be published elsewhere, including intercorrelation matrices of the steric parameters mentioned. But relevant conclusions from e.g. intercorrelations will be dicussed. At this moment the STERIMOL method has been applied successfully in about 50 publications often with better results than other steric approaches, including MTD and MTD, especially in series with few substituent positions. A recent example is our study of DDT analogs. Brown et al. (9J analysed a series of 21 derivatives using the van de Waals (Vw) volumes as steric parameters. In Table I the equations are given in which the steric parameters are compared. 

The MSD approach gave no significant results. Addition of a to Equation 1-3 did not improve the correlation significantly. STERIMOL gave the best results and MTD and MTD were comparable with Vw. The obtained optimal standard from the procedure that gave Equation 4 is shown in Figure 4, and it indicates that di-substituted carbon atoms gave the best fit. 

Table I. Comparison of Vw, MSD, MTD, MTD and STERIMOL parameters in a series of 21 DDT analogs with activity against Culex fatigans. ...

Another example of the use of the MTD and MTD approaches can be found in a series of optically active o-phenoxypropionic acids with auxin-like activity, partly published in ( ). The R-stereo isomers are much more active than the S-analoges. Both series were analyzed by Lien et al. (10) and a correlation with ir, a and the Van der Waals volume was found. The Pfeiffer rule is explained in terms of different structural requirements for the substituents as measured by and van der Waals volume. Analysing the series using STERIMOL delivered equations containing too many parameters. In Table III the equations are given as a result of... 

When less substituent positions are present STERIMOL can be used but in those cases there is often hardly any difference in results if compared with the MTD method. This is illustrated by our version of the QSAR of the insecticidal activity against American cockroaches of 36 substituted benzyl chrysanthemates. 

In a series of 28 compounds with 3 substitution positions, MTD MTD and STERIMOL were compared [5). The biological values were taken from the work of Trebst and Draber (1 ) and the results are summarized in Table V. There is already a significant correlation with ir alone, as can be seen from Equation 21, but it can be improved by adding 81 terms for both ortho substituents. 

These results give some insight in the scope and limitations of the MTD, MTD and STERIMOL parameters. Let us first compare the MTD and MTD methods. In the example of the benzyl chrysanthemates the regression equations have only steric terms, sothat there is no difference between the two methods in principle. In the case of the benzoylphenyl ureas the intercorrelation between the MTD values and the other parameters is very low, so it is understandable that there is hardly any difference. But in the four other studies there was much more intercorrelation between the MTD values on the one hand and the electronic and/or hydrophobic parameters on the other hand, and in these cases the MTD method gives slightly better results. Our preliminary conclusion from the examples discussed, is that the MTD is the preferable one, both from fundamental and... 

The choice between the STERIMOL and MTD approaches is dependent on some properties of the series studied, e.g. the number of members in relation to the number of substitution positions In those cases where the resulting degrees of freedom are sufficient, the STERIMOL approach gives the most satisfactory results (e.g. in the studies on the DDT analogs and to a lesser extent in benzoylphenylureas Table VII). But in opposite cases,... 

S phenomenon is probably caused by the fact that the STERIMOL... 

STERIMOL approach has the greatest advantages provided that the... 

At this point it was clear that the highest potential for increased activity was by substitution in the 2-position of the biphenyl alcohol. We prepared the sequence of compounds shown in Table 1. Substituents were again chosen to maximize the parameter space covered within the relatively stringent synthetic limitations of the biphenyl substitution pattern. The application of regression analysis to the data for these compounds provided no clear relationship between structure and activity when the parameters in our standard data base were used. The best linear fit was found for B4, the STERIMOL maximum radius. However, the correlation coefficient was only 0.625. 

The 4 -substituted biphenyl compounds were included in this study by subtracting the length of hydrogen (2.06) from the STERIMOL length of benzene (6.28) and adding on the STERIMOL length of the 4 -substituent. 

A. Verloop (1987). The STERIMOL Approach to Drug Design. New York Marcel Dekker. 

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