Fluorination-toxicity relationship

A few other fluorinated kanamycins, including 5-deoxy-5-epi-fluoroamikacin, 5-deoxy-5-ep(-fluoroarbekacin, and their related analogs, have been prepared to study the fluorination-toxicity relationship. In contrast to the low toxicities of the 5-fluoro derivatives [121], these epi-fluoro compounds showed acute toxicity values identical to those of arbekacin and amikacin [122]. This indicates the importance of stereo-electronic effects of the fluoro group at position 5 of the 2-deoxystreptomine moiety in toxicity of aminoglycoside antibiotics. 

In a study on the fluorination-toxicity relationship, investigators prepared 1-A-acylamido derivatives of kanamycins, including (2R,3R)- and (27 ,35)-4-amino-3-fluoro-2-hydroxybutanoylkanamycins A and B (compounds 262-265 ). The l-N-[(2/ ,3i )-4-amino-3-fluoro-2-hydroxybutanoyl] derivatives 262-264 showed activity similar to that of the related compoimds [amikacin (2), arbekacin (260), and l-N-[(5)-4-amino-2-hydroxybutanoyl]-3 -deoxykanamycin B 261], whereas the (2R,3S)-derivative 265 (compounds 260 65) showed decreased activity relative to 260. In toxicity, these compounds were similar to the parent antibiotics, and fluorination did not show any influence in the toxicity of the antibiotics [137]. 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

In general, the chlorinated and the mixed analogs are more toxic than those containing only fluorine as a halogen.6,204 Further, there exists a direct relationship between toxicity and reactivity towards nucleophilic agents. -Isomers are, in general, more toxic than Z-isomers. 

The Aape values did not exhibit a good linear relationship with LDso-Dexamethasone valerate, betamethasone valerate, dexamethasone acetate and triamcinolone acetonide were approximately one-fold more toxic and difluoro-substituted steroids were approximately one-fold less toxic than that estimated from the ape Specifically, steroids with a fluorine at the C6 position were less toxic. The correlation coefficient between LD50 and Aape was calculated without these positively and negatively affected compounds. The correlation coefficient was not satisfactory. The analysis of a molecule... 

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