Restriction conformational

Ikegashira et al. reported another recent example of the successful exploitation of conformational locks. They describe the discovery of a novel class of hepatitis C virus NS5B RNA polymerase inhibitors [42]. By designing and synthesizing conformationally constrained analogs of 40 (see Fig. 8.9), they obtained a series of novel compounds with significantly improved potency. Compound 41 was, for example, shown to be 7-fold more potent, see Fig. 8.9. 

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Several hundred analogues to TRF have been synthesized. Some of them, like l-CH2-S-Dio-His-Pro-NH2 are more potent than TRF (116) others are conformationally restricted and equally as potent as TRF (117). 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

There is also a category of intramolecular reactions/transforms which involves total mechanistic stereocontrol with conformationally restricted structures, for example the halolactonization transform 149 150 and the internal cycloaddition 151 152. These... 

Melting points of the polymers from bicyclic lactams are expected to be appreciably high because of some conformational restriction of the main chain due to the ring structural unit, as seen from the examples54 presented on page 25. 

Acid catalyzed intramolecular Diels-Alder reactions in lithium perchlorate-diethyl ether acid promoted migration of terminal dienes prior to [4 + 2] cycioaddition in conformationally restricted substrates [101]... 

Ultraviolet Spectra. The UV and fluorescence spectra for 2-tran -styrylquinoxa-line (132, R = H) and 2-methyl-3-tran -styrylquinoxaline (132, R = Me) indicate considerable conformational restriction in the latter. 

Probing the Active Sites of Enzymes with Conformationally Restricted Substrate Analogs. BY G. L. KENYON AND J. A. FEE, Department of Chemistry, University of California, Berkeley, California. 381... 

Probing the Active Sites of Enzymes With Conformationally Restricted Sutetrate Analogs... 

VI. Conformationally Restricted Active-Site-Directed Enzyme Inhibitors... 

Substrate analogs which promise to be particularly good active-site probes are those which are conformationally restricted. One key feature of enzymatic processes is that when a substrate is bound to an enzyme, probably only one of the many possible conformations of the substrate molecule is assumed. Consequently, before a detailed mechanism for an enzymatic process can be formulated, the preferred conformations of each of the enzyme-bound substrates must be known. ... 

There are some problems involved in the use of conformationally restricted analogs. For example, some enzymes appear to be so highly specific... 

Besides this problem of designing conformationally restricted analogs for highly specific enzymes, there are Other problems to be considered in dealing with less specific enzymes. These are discussed later in the section on locked a-chymotrypsin substrates. 

Despite these problems, the potential of research with conformationally restricted substrate analogs appears to be great. As yet, the use of these analogs with tools other than steady-state kinetics has been little explored. 

Five conformationally restricted analogs of creatine now have been prepared. These are D-N-amidinoproUne, 19 LN-amidinoproline, 20 l-carboxymethyl-2-iminoimidazolidine, 21 l-carboxymethyl-2-iminohexa-hydropyrimidine, 22 and D,L3-methyl-4-carboxy-2-iminoimidazolidine (the L enantiomer is depicted in structure 23). 

In this case, the conformational restriction serves to differentiate between two otherwise equivalent portions of a substrate so that the product specificity of the enzyme can be investigated. 

Use of conformationally restricted substrate analogs for investigating the substrate specificity of a-chymotrypsin provides an instructive example of the difficulties encountered in interpreting the results of such experiments, difficulties which, as we shall see, are especially severe for relatively nonspecific enzymes. 

In conclusion, one must be aware of these limitations on the use of locked substrate analogs. The problems encountered in the study of a-chymotrypsin are perhaps more severe than for most other enzymes, since a-chymotrypsin normally acts on large, polymeric substrates and is relatively nonspecific. The active site of a-chymotrypsin therefore potentially can bind small substrates such as D24 in a variety of ways. Ideally, larger conformationally restricted substrates should give more information about the active site of a-chymotrypsin. However, besides the increased problems involved in synthesizing these larger substrates, there is the problem of increased possibility of uncertainty in their conformations. 

VI. CONFORMATIONALLY RESTRICTED ACTIVE-SITE-DIRECTED ENZYME INHIBITORS... 

Studies on the mode of action of the penicillins in inhibiting bacterial cell-wall biosynthesis suggest that the members of this class of antibiotics (including the closely related cephalosporins) are conformationally restricted substrate analogs... 

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