Development of a novel anti-tumor drug 'amrubicin', a completely synthetic anthracycline

Anthracycline derivatives such as doxorubicin (DXR), daunorubicin (DNR) and epirubicin have been widely used for a variety of carcinomas in the clinical context. In order to discover safer, more effective antitumor derivatives, numerous carbon side chain replacement and amino sugar conversions have been conducted since DNR and DXR were discovered from actinomyces.1) However, despite such attempts many derivatives have not shown better profiles than DXR. Because these anthracycline derivatives are either natural products or semi-synthetic products, they are structurally limited. In order to have more effective derivatives, we have discovered hydrochloric acid amrubicin (AMR, Fig. 1) by screening the derivatives created through total synthesis. It is the world’s first anthracycline anti-cancer agent produced through total chemical synthesis. AMR possesses the amino group instead of the hydroxyl group at the 9-position. The structure of AMR is such that it possesses a simpler carbohydrate part instead of amino sugar.2) AMR demonstrates a higher anti-tumor effect than that of DXR against the human tumor xenografts that have been implanted subcutaneously into nude mice.3) It has been confirmed that its active metabolite amrubicinol (AMR-OH, Fig. 1) plays an important role in its antitumor effect.4) It is a distinctive characteristic of AMR, given that it cannot be seen in any other anthracycline derivative. The major action mechanism of AMR is the Development of a novel anti-tumor drug ‘amrubicin’, a completely synthetic anthracycline