STERIMOL substituents

Size/shape (molecular weight, moments of inertia, shadow descriptors, Verlcmp s STERIMOL substituent constants, etc.)... 

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. 

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. 

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. 

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. 

In the course of developing herbicides possessing N-phenyl tetrahydrophthalimide structure (20), Ohta et al. investigated structural requirements for the activity against sawa millet, Echinochloa utilis, of m- and p-substituted derivatives42 . As shown by Eq. 43, the steric dimensions expressed by the STERIMOL length parameter Lp and maximum width B of p-substituents play a decisive role in determining activity. 

As proposed earlier in this article, the Vw value is the parameter for volume-dependent steric effects such as those on the cavity formation. The Es, E and STERIMOL values are those for the width of substituents. They are supposedly applicable to cases occurring on the broad cleft. The effect on the engulfment within the narrower cleft could be rationalized by either of the volume or the width parameters depending upon the situation. 

While the development of the Taft parameter is similar to that of Hammett and Hansch, / )-val ucs are based on rate constants instead of equilibrium constants. The Taft parameter is a measure of changes in activation energy, not standard free energy. Of the Hammett, Hansch, and Taft parameters, the Taft parameter is utilized the least in QSAR studies. Other steric parameters have been developed over time, and like the Taft parameter, all have shortcomings. One alternative steric parameter was developed by Marvin Charton of Pratt Institute in New York. Charton s parameter is based on the van der Waal radius of a substituent.6 Another alternative steric model is the STERIMOL parameter set developed by Arie Verloop of Philips-Duphar in Holland.7 Unlike Taft and Charton, Verloop... 

To characterize the substituents (the X block) a set common substituent parameters were compiled from the literature. These parameters were as (Taft inductive parameter), trp (Hammett parameter for para substituents), F and R (Swain-Lupton dual substituent parameters), Es and Esc (Taft steric parameters), van der Waals radius, L, Bv B2, B3, (Verloop sterimol parameters), MR (molar refractivity), and n (Hansch lipophilicity parameter). Data are given in Refs. [1,19] and are not reproduced here. 

The most significant term in Eq. 11 is the molar refractivity of the m-substituent at the phenyl ring. Since MR-Ri is primarily a measure of bulk and of polarizabihty of the substituent, the positive coefficients with both terms MR-Ri and CMR suggest that size of Ri-substituent as well as of the whole molecule will be conducive to the activity. The parameter Bs-r is the Sterimol parameter for the maximum-width of the first atom of the group R at the N-heterocyclic ring. This points out a favorable role of the first atom through some steric interaction. 

The major electronic factor influencing the activity has been Hammett s constant a. In some cases, the steric factors were also found to be important, e.g., Bs the Sterimol parameter for the largest width of substituents and L the Sterimol parameter for the length of the substituents. The positive coef-Acients of these parameters give an important positive contribution of width and length of substituents to the inhibition. The values of Taft steric param-... 

Equation 45 contains only molar refractivity terms for Ri and R3 substituents and the Verloop Sterimol parameters L for the length of substituent R4. The negative sign with MR-Ri suggests a steric hindrance directly or through a conformational change. MR-R2 is the most significant parameter. 

Later, a new Sterimol width parameter B5 was introduced to replace the B4 parameter, defined as the maximum width (i.e. the maxmum distance from X axis) of the substituent in the Z-Y plane (perpendicular to the X axis). 

Among the -> shape descriptors, Sterimol shape parameters were proposed as the -> length-to-breadth ratio, defined as L/Bi and B5/B1 (or previously, B4/B1), giving information about the deviations of a substituent from a spherical shape. 

Verloop et al. determined the Sterimol parameters for over 1000 substituent groups. 

Moreover, in spite of their holistic character, several molecular physico-chemical properties have also been calculated for substituents examples are -> molar refractiv-ity, - lipohilicity, and - surface areas size properties of the substituents are often represented by Sterimol parameters. 

MR molar refractivity it hydrophobic substituent constant and Op overall electronic constants for meta- and para-position K and p Swain-Lupton resonance and field constants L Sterimol length parameter B1 and B5 Sterimol B parameters SD Dash-Behera steric density parameter. 

Master Data, now in its third edition, is approaching its final length though a few new substituents may be added each year. However, there is plenty of room for new parameters and we expect to add several new sigmas(JL5), Bondi s volume(l6) and some of the Sterimol constants (17) in the next edition. 

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