**2.2. Arotinoids**

Recognizing the potential chemopreventive and chemotherapeutic effects of retinoids, chemists have tried to design and synthesize new retinoid derivatives that express high cytotoxic potential with lower toxicity. The rationale is that by developing compounds that selectively activate only one retinoid receptor subtype, the associated toxicities could be reduced. For example, RXR-selective compounds were thought to have great potential for pharmacological use against tumors and other diseases due to a large number of ligand activated receptors whose activities involve dimerization with RXR receptors [19]. Bexarotene (Targretin®, with a one-carbon linker), is a selective RXR agonist and the first synthetic arotinoid approved for the treatment of all stages of cutaneous T-cell lymphoma [27]. RARγ, selectively expressed at high levels in the skin, has been shown to be the mediator of retinoid activity [28]. Early efforts to increase the therapeutic ratio of retinoids included increasing the structure rigidity by incorporating a double-bond between the two aromatic rings, leading to the development of arotinoids with two atom linker. For example, TTNPB (**Figure 1**, **5**), an arotinoid with significant anti-tumor activity [29] was found to be selective for RAR receptors [30]. Unfortunately, intolerable toxicities observed in animal models limited its clinical utility [29].

## **2.3. Heteroarotinoids**

Subsequent structural modifications involved the addition of one heteroatom (O, N, and S) in the cyclic ring of the arotinoids to block its oxidation into toxic metabolites. This resulted in the development of a new class of compounds called the heteroarotinoids (Hets, **Figure 1**, **6**– **12**). These Hets exhibited similar biological activities to retinoids, but with significantly reduced toxicities [29, 31].
