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Comparative Biological Activity of Nogalamycin and Its Analogs¹

The Upjohn Company, Kalamazoo, Michigan 49001

Nogalamycin, a cytotoxic antibiotic, inhibited DNA-directed RNA synthesis by binding to adenine or thymine of the DNA primer. Partial structures of nogalamycin and its derivatives are shown. All compounds were highly cytotoxic to KB and L1210 cells in culture; all, except nogalarene, inhibited uridine incorporation into RNA more than thymidine or valine incorporation into DNA or protein, respectively. However, nogalarene inhibited all three macromolecule syntheses equally. All the derivatives bound to DNA with resulting increase in the T_m (T_m) of DNA. At equimolar concentrations of the compounds, the T_m with nogalamycin was twice that obtained with the other compounds. The base specificity of the compounds in binding to DNA is reported. The results indicate that: (a) the absence of the nogalose side chain markedly affected binding of the compounds to DNA and also their cytotoxicity, and (b) the oxygen attached to carbon 7 was involved in determining the specificity of binding to bases in DNA. The antileukemic activity in vivo of these compounds is reported.

¹ Supported in part by Contract PH43-68-1023 with Chemotherapy, National Cancer Institute, NIH, Bethesda, Md.

Received 7/ 3/69. Accepted 9/26/69.