Synthesis and biological evaluation of SHetA2 (NSC-721689) analogs against the ovarian cancer cell line A2780

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 μM and 85.6–95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 μM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells. [Display omitted] •Thirty-seven new SHetA2 derivatives have been prepared and tested.•A synthesis of isothiocyanate 13 paved the way to 3 new families of compounds.•Ureas, thioureas, hydrazines and hydrazides have been evaluated.•SAR studies were inconclusive, but several potent new compounds were prepared.•Compound 2c is the most potent compound prepared to date.