Specific RITA modification produces hyperselective cytotoxicity while maintaining in vivo antitumor efficacy

The preclinical antitumor agent RITA (2,5-bis[5-hydroxymethyl-2-thienyl] furan, NSC 652287), an analog of the natural product α-terthiophene, failed during the development phase due to acute pulmonary toxicity in animal models. A series of synthetic modifications to RITA9s heterocyclic scaffold resulted in activity ranging from broadly cytotoxic to highly selective. In the National Cancer Institute 60-cell line screen, these "hyperselective" agents (e.g., imatinib) are rare. A Selectivity Index (SI) was developed to quantify this desirable feature, which is 20 for imatinib, while RITA9s SI is only 0.10. One of the described hyperselective RITA analogs (SI = 7.9) completely lost activity in the presence of a known SULT1A1 inhibitor. This result, coupled with previous evidence that RITA is a SULT1A1 substrate, suggests that carbinol modification by a sulfate leaving group and subsequent formation of a reactive carbocation may explain RITA9s broad cytotoxicity. While SULT1A1 expression is required for susceptibility, hyperselective analogs exhibited reduced association of activity with SULT1A1 mRNA expression compared to RITA, apparently requiring some additional target(s). In support of this hypothesis, there is a strong correlation (P