Synthesis,enzyme inhibition,and antitumor activity of new 1,4-benzoquinone analogs of coenzyme Q10

A rationale based upon coenzyme Q₁₀ (CoQ₁₀, ubiquinone) for the synthesis of potential antitumor agents constitutes a new approach in the search toward chemotherapy of cancer. The antitumor activities of 38 alkyl-1,4-benzoquinones, analogs of coenzyme Q, 24 of which are new compounds, are described. The 10 best antitumor analogs of CoQ all showed long-term cures of Walker carcinosarcoma 256 in rats. Particularly impressive were the 6-n-octylmercapto-5-chloro-2,3-dimethoxy-1,4-benzoquinone (NSC 252188), which cured six out of six rats with $\text{\%}\text{T}\text{C}\text{= 584 at 3.13 mg/kg}$, 6-phytyl-5-hydroxy-2,3-dimethoxy-1,4-benzoquinone (NSC 277818) (four out of four cures, $\text{\%}\text{T}\text{C}\text{= 923 at 50 mg/kg}$), and 5-phytyl-2,3-dimethoxy-1,4-benzoquinone (NSC 276371) (three out of six cures, $\text{\%}\text{T}\text{C}\text{= 789 at 0.78 mg/kg}$). In general, a 5-chloro or 5-hydroxy group on the quinone nucleus or a side chain with unsaturation and branching, such as the phytyl side chain of NSC 277818 and NSC 276371, seemed to increase antitumor activity. Although a perfect correlation was not to be expected, many of the most potent antitumor analogs were also among the best in vitro inhibitors of the mitochondrial CoQ₁₀-enzymes, succinoxidase, and NAD oxidase.