Biological activity alteration

There is also a crucial problem of stereochemistry in the synthesis of polypeptides. Natural proteins consist of L-amino acids, and any racemization at the chiral centers has a profound effect on the structure and biological activity. Altered stereochemistry drastically changes the three-dimensional shape of a polypeptide chain, and this three-dimensional structure is normally essential for the biological function of the polypeptide. 

Through combined effects of noncovalent forces, proteins fold into secondary stmctures, and hence a tertiary stmcture that defines the native state or conformation of a protein. The native state is then that three-dimensional arrangement of the polypeptide chain and amino acid side chains that best facihtates the biological activity of a protein, at the same time providing stmctural stabiUty. Through protein engineering subde adjustments in the stmcture of the protein can be made that can dramatically alter its function or stabiUty. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

Modem Methods for the Introduction of Fluonne into Organic Molecules An Approach to Compounds with Altered Chemical and Biological Activities... 

The low structural requirements for local anesthetic activity do not maintain in all classes of drugs. Structural requirements for biologic activity in fact follow a full continuum from those cases in which addition of a single carbon atom serves to abolish activity to the case of the local anesthetics that tolerate quite drastic alterations. 

Performance of an imaginary 1,2-shift on the benzhydrol antihistamines, that is, attachment of the side chain directly to the benzhydryl carbon while leaving the hydroxyl group intact, affords a series of molecules with markedly altered biologic activities. 

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

Changing the substitution pattern on the benzimidazole greatly alters the biologic activity. Thus, inclusion of a thia-zole ring affords thiabendazole (70), a drug used for the treatment of helminthiasis. 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

These tests demonstrate that rhizomes of johnsongrass have biological activity and that the activity is residual. The allelochemic usually associated with Sorghum species in general, and with johnsongrass in particular, is the cyanogenic glucoside dhurrin (3) or its decomposition product (p-hydroxybenzaldehyde). Whether these compounds act as allelochemics in field situations is unknown and somewhat suspect, since they would surely be immobilized or altered in most soil situations, as was shown for... 

The fluorescent labelling of heparin with F-D by this technique did not observably alter the biologic activity of the heparin as regards to its binding to antithrombin and catalysis of antithrombin s neutralization of activated coagulation factors. F-D labelled heparins also bound to other known heparin-binding proteins in a saturable and reversible manner, as demonstrated by the dot-blot assay technique (Figure 6). 

Aggregation of proteins is a microscopic process of protein molecule association. The aggregates may be dimers or larger oligomers that remain in solution, yet may alfect the observed biological activity. Precipitation refers to the formation of visible proteinaceous particles, which may reduce potency in addition to altering the appearance of a formulation and its performance in various infusion devices. 

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