Doxorubicin (DOX) is a potent chemotherapeutic agent that has been used to treat cancer since the 1970’s. Although DOX has shown antitumor activity in a variety of cancer cells including sarcomas, it produces cardiac damage that is both cumulative and irreversible, which limits the lifetime dose that can be used. The serious and often fatal side effects of DOX call for the discovery and production of new drugs with greater effectiveness in the treatment of tumors. Sarcoma cancer is rare, but also one of the most deadly and difficult cancers to treat. Since DOX is one of the primary drugs used to treat sarcomas, it is critical to find an analog that will more effectively inhibit sarcoma tumor growth and can be used at a reduced dose. In this study, DOX analogs synthesized with key structural substitutions have been tested for their anti-proliferative activity against a panel of human sarcoma cell lines. All of the analogs showed improved activity relative to DOX. In addition, two of the DOX analogs showed promising synergistic activity when tested in combination. This suggests that these analogs may be useful in successfully treating human sarcomas at even lower doses that may dramatically reduce the occurrence of unwanted side-effects.