**2.4. Flexible heteroarotinoids**

Different linkers were placed between the two aryl groups of the Hets to increase their rigidity, providing a more specific fit into each receptor's binding pocket. Two-atom linkers, such as amide (**Figure 1**, **8**) and esters (**Figure 1**, **9**–**11**) were synthesized, and they showed varying degree of receptor selectivity. Interestingly, Hets with either the three-atom urea (**Figure 1**, **14**, **17**, **18**) or thiourea (**Figure 1**, **15**, **16**, **19**, **20**) linker demonstrated significant anticancer activity without activating any of the retinoid receptors [6]. These compounds showed significant growth inhibitory activities against the ovarian cancer cell lines: Caov-3, OVCAR-3, and SK-OV-3, while exhibiting low activities against normal and benign cells. Moreover, due to the lack of RAR/RXR activation, these compounds did not exhibit the associated toxicities observed with other retinoids. Among these compounds, SHetA2 (**Figure 1**, **16**) demonstrated the greatest potency against the aforementioned ovarian cancer cell lines at concentrations ranging from 0.2–3.7 μM. Since both urea and thiourea linkers are somewhat flexible in nature, these compounds were termed flexible heteroarotinoids (Flex-Hets). The evolution of SHetA2 is shown in **Figure 2**.

**Figure 2.** The evolution of SHetA2 from all *trans* retinoic acid (ATRA).
