R. D. HOTCHKISS 



successes in chemotherapy have come through such substances as 

 thiouracil, stilbestrol, sulfonamides, and penicillin, all more or less 

 specific agents which are by no means merely carriers of potent, widely 

 active groups. These particular substances were probably first hit 

 upon somewhat accidentally, but the approach through metabolite 

 inhibition would seem to provide a means of arriving at such com- 

 binations rationally. 



Second, let us turn to some considerations which may suggest 

 directions to take in the synthesis of future chemotherapeutic agents. 

 One of the main desiderata, we have agreed, is selectivity for a given 

 type of cell. Comparative biochemistry seems to reveal that different 

 cells are very much alike in the way they break down and oxidize 

 substrates; so agents which inhibit catabolic enzymes are likely to 

 have broad activity. On the other hand, since different cells appear 

 to have developed somewhat different proteins and other macro- 

 molecules in their protoplasm, it is to be hoped that agents which can 

 inhibit synthetic processes will display greater cell specificity. Further- 

 more, in designing modifications in chemical structure which will 

 deceive the enzyme proteins, it should be helpful to look at some of 

 the data from immunochemistry. In his book, The Specificity of Ser- 

 ological Reactions, Landsteiner describes a large number of modifica- 

 tions in chemical structure which greatly alter the reactivity of an 

 antigen toward its antibody, and in addition, many examples of over- 

 lapping specificity, that is, of different chemical groups which to a 

 considerable extent look alike to an antibody protein. These relation- 

 ships, arrived at by trial and error after innumerable painstaking 

 syntheses, may to some degree decrease the number of errors per trial 

 in the synthesis of pharmaceuticals. 



The isolation and characterization a few years ago of two 

 crystalline polypeptides derived from tyrothricin, an antibacterial 

 product extracted from cultures of Bacillus brevis, seemed to offer an 

 opportunity of studying some of the factors which are involved in 

 combating bacterial infections. One of these antibacterial poly- 

 peptides is basic, the other is neutral. Both appear to have molecular 

 weights of about 2500 and contain enough aromatic and higher ali- 

 phatic amino acids to be alcohol-soluble and rather insoluble in water. 

 Both substances markedly depress the surface tension of aqueous 

 solutions. A number of the amino acid residues in each substance 



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