Nogalamycin (NOG), isolated from Streptomyces nogalator, contains a unique D-ring bicyclic amino sugar and an A-ring nogalose sugar, with the overall structure resembling a dumbbell. The tetracyclic core is proposed to intercalate DNA, with the D-ring sugar binding in the major groove and the A-ring sugar in the minor groove. A cocrystal structure of NOG and a DNA hexamer suggest unfolding of the hexamer to bind to NOG, followed by adoption of a distorted helix post-binding. While the exact details of the mechanism-of-action are unclear, it is known that binding of NOG to an up-stream site can induce highly specific topoisomerase I-mediated DNA cleavage. NOG also inhibits Gram-positive bacteria and shows promising cytotoxicity against L1210 and KB cell lines in vitro; however, it shows only weak activity against solid tumors in vivo and high toxicity in mammalian subjects. Menogaril (MEN, Scheme 1A) is a semisynthetic derivative of NOG 10 that lacks the A-ring ester and sugar; the weaker binding of MEN to DNA may be due to the latter circumstance. While NOG and other anthracyclines are type II topoisomerase inhibitors, MEN selectively inhibits type I topoisomerase. MEN successfully entered Phase II clinical trials against non-Hodgkin lymphomas, but no other NOG analogs have been reported in the clinic. We were interested in developing a modular approach to NOG that would enable systematic study of the impact of the identity of A-and Dring sugars on the anti-cancer activity and toxicity of new analogues.