Streptomyces sp. KY40-1, a strain isolated from the Kentucky Appalachian foothills, is the producer of moromycins A (18) and B (19). Further investigations of this strain led to the isolation and structure elucidation of the five new saquayamycins G-K (1-5), along with known compounds. Two of the new compounds bear the unusual aminosugar rednose, which was found here for the first time in angucyclines. The different attachment positions of this aminosugar in these two compounds indicate a high acceptor substrate flexibility of the responsible glycosyl transferase or alternatively the involvement of multiple glycosyl transferases. The cytotoxic activity of the isolated compounds was determined using human prostate cancer (PC-3) and non-small-cell lung cancer (H460) cell lines. Cell viability assays showed that saquayamycins J (4), K (5), A (7), and B (8) were most active in PC3 cells, with saquayamycin B (8) showing the highest activity (GI(50) = 0.0075 μM). The aminosugar-containing saquayamycins H (2) and saquayamycin B (8) showed the highest activity against H460 cells, with a GI(50) of 3.3 and 3.9 μM, respectively. The results presented here provide more insights into the structure-activity relationship of saquayamycins with respect to the nature, number, and linkage of sugar residues.