Lower Toxic Derivatives of Antibiotics. V Effects of Substituents on the Toxicity of a N-Methanesulfonate Derivative

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It has previously been reported¹⁾ that although kanamycin-N-methanesulfonates show less toxicity, no lowering of toxicity is exhibited in case of the compounds of NH·CHX·SO₃^- where X is replaced by alkyl or aryl group. The significant differentation has appeared to be related to the hydrolytic mechanisms of N-methanesulfonic groups. Alternative mechanisms of hydrolysis of N-methanesulfonates have thus been presented to explain the dissimilarity in toxicity beween substituted and unsubstituted N-methanesulfonates. In the present paper we wish to call further attention on the effect of substituents on the toxicity of N-methanesulfonate derivative.

Studies have been made to prepare derivatives of a type K(NH₂)₂(NH·CHCH₂X·SO₃H)₂, wherein X represents an electronegative atom or group and K represents the residual part resulted from removing of (NH₂)₁ from kanamycin molecule. It seemed likely that the system -NH·CHCH₂X>·SO₃^- would have a possibility to form a somewhat stabilized chelate ring and therefore, C-S fission would proceed in preference to N-C fission; this corresponds to the mechanism (I) in a previous paper¹⁾, lowering of toxicity being expected. It has been found that the results are in agreement with the above speculation as shown in Table 1

These derivatives except the promo derivative (III) showed significant lowering of toxicity. This is probably due to the fact that the promine atom generally fails to form hydrogen bond.