Structure-activity relationships steric hindrance

Direct modification has also been applied to the synthesis of fluoro-substituted amikacin (Scheme 4.21). Utilizing the metal-chelating protocol and the steric hindrance of 5-OH, fluorination was carried out selectively at the 5-OH. Two compounds (132 and 133) were found to have similar trends of antibacterial activity (Table 4.11). However, the activities of amikacin, 132 and 133, against E. coli (ANT(2")) were found to be much higher than those reported in Table 4.10 regardless of the sites of deoxygenation. We believe that the results from Table 4.11 may better explain the trend of structure activity relationship... 

The substitution pattern of the 4-aromatic residue is also important for the activity, the ortho-substitution being the best one in terms of potency and selectivity. A Hansch analysis on a series of ortho-derivatives has shown a significant correlation between calcium antagonist activity and steric hindrance of the substituent, while no relationship was found for either electronic or lipophilic parameters [3]. The best SAR correlation was obtained when the B1 steric parameter (the Verloop parameter) was introduced into the analysis [4]. The calcium channel-blocking activity increases as B1 increases, which probably indicates that steric hindrance in the ortho-position is required to fix the dihydropyridine structure into a favorable conformation in which the aromatic group is approximately perpendicular to the dihydropyridine ring (Fig. 7.12). 

Alkoxy(or -aryloxy)halocarbenes are ambiphilic (for selectivity indices, see ref 9), they react at a high rate with electron-rich and electron-poor alkenes, however, they react at a slow rate, with alkenes of intermediate reactivity. Steric hindrance decreases the rate addition of fluoro- and chloro(phenoxy)carbene to 2,3-dimethylbut-2-ene. ° For discussion of structure-activity relationship of carbenes, see ref 9, and Houben-Weyl, Vol. El9b, pp 14-34. 

RDF descriptors can be restricted to specific atom types or distance ranges to represent complete or partial information in a certain chemical environment, for instance, to describe steric hindrance in a reaction or structure-activity relationships of a molecule. 

Biologically active platinum complexes have now been under investigation for nearly two decades. The large data base on structure-activity relationships has revealed a number of principles as well as raised new questions. Mechanistically, the aquation of the compounds and their ability to cause intrastrand cross-links in defined regions of DNA appear to be the chemical events most closely associated with antitumour activity. The reaction kinetics of the compounds in aqueous systems which may be influenced by chelate effects, steric hindrance of bulky ligands or metal oxidation state have been studied for... 

However, has recently been studied the effect of PPG on COX enzymes in two different publications. On one hand, Sahpaz and cols. [21] found that arenarioside, forsythoside, and verbascoside, were the strongest COX-2-inhibitors at 100 pM. Moreover, these compounds did not exhibit any significant inhibition on COX-1 at the same concentration. The authors defended the existence of a structure-activity relationship the possession of two or three sugar units in their structure could contribute to the selective inhibition on COX-2. On the other hand, ballotetroside, with four sugar units, exhibited a weaker activity, and, interestingly is more active over COX-1 than COX-2. They think that the addition of a sugar unit (in this case arabinose on position C-2 of rhamnose) increases the steric hindrance, which prevents the molecule easily getting to the active site of the enzyme. 

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

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