Divergent Synthesis of Three Classes of Antifungal Amphiphilic Kanamycin Derivatives.

A concise and novel method for site-selective alkylation of 1,3,6',3″-tetraazidokanamycin has been developed that leads to the divergent synthesis of three classes of kanamycin A derivatives. These new amphiphilic kanamycin derivatives bearing alkyl chains length of 4, 6, 7, 8, 9, 10, 12, 14, and 16 have been tested for their antibacterial and antifungal activities. The antibacterial effect of the synthesized kanamycin derivatives declines or disappears as compared to the original kanamycin A. Several compounds, especially those with octyl chain at O-4″ and/or O-6″ positions on the ring III of kanamycin A, show very strong activity as antifungal agents. In addition, these compounds display no toxicity toward mammalian cells. Finally, computational calculation has revealed possible factors that are responsible for the observed regioselectivity. The simplicity in chemical synthesis and the fungal specific property make the lead compounds ideal candidates for the development of novel antifungal agents.