**2. History of retinoid development**

#### **2.1. Retinoids**

Retinoids, including natural retinoic acid (RA) and its synthetic derivatives, are a group of promising anticancer agents that have shown both chemotherapeutic and chemopreventive potential in both animals and humans [15–17]. They exhibit therapeutic properties by activating the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) [18]. Each receptor has three subtypes (-α, -β, -γ), and they belong to a family of proteins that regulate the transcription of genes responsible for a variety of metabolic, developmental, and differentiation pathways in cells and tissues [19]. Retinoids have been shown to inhibit growth, and induce differentiation and apoptosis of cancer cells both *in vitro* and *in vivo* [20, 21]. Naturally occurring retinoids, all-*trans*-retinoic acid (ATRA, **Figure 1**, **1**), 9-*cis*-retinoic acid (**Figure 1**, **2**), and 13-*cis*-retinoic acid (**Figure 1**, **3**) have been shown to display significant anticancer activities [22]. Synthetic retinoids, such as *N*-(4-hydroxyphenyl) retinamide (4HPR, fenretinide, **Figure 1**, **4**), are also effective inducers of apoptosis [23]. However, the use of retinoids as chemotherapeutics has been hampered by their local and systemic toxicities and side effects. Chronic retinoid treatment can lead to teratogenicity and toxicities to the skin, mucus membranes, hair, eyes, gastrointestinal system, liver, endocrine system, kidneys, and bone [24]. These toxicities are found to be associated with the activation of the nuclear retinoid receptors [25, 26].

and isothiocyanates), minerals (calcium and selenium), phytoestrogens (resveratrol), flavonoids (genistein and quercetin), synthetic compounds (retinoids, sulforamate, and prenylated flavonoid analogs) [2], and marketed drugs (tamoxifen, raloxifene, finasteride, aspirin, sulindac, difluoromethylornithine, and metformin) [3]. Drug development for cancer prevention imposes distinct challenges beyond those associated with drug development for cancer therapy. One of the challenges is that cancer preventive agents must have higher therapeutic index. Nevertheless, the potential to intervene prior to the cancer developing is

A novel class of anticancer agents that has demonstrated such qualities is the flexible heteroarotinoids (Flex-Hets). Flex-Hets, derived from the retinoids, have exhibited potential anticancer activities in various cancer cell lines, while displaying minimal toxicity to normal cells. Among these compounds, SHetA2 [(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl]amino]methane-thione) exhibited the greatest growth inhibitory efficacy and potency against various cancer cell lines and was chosen as a lead compound for further development [5–7]. SHetA2 has been shown to interfere with mortalin binding to p53 and p66 Src homologous-collagen homologue (p66shc) leading to apoptosis in cancer cells [8]. Furthermore, it has been shown to induce both intrinsic [9] and extrinsic apoptotic pathway [10], cause cell cycle arrest [11], induce differentiation [7], and inhibit angiogenesis [12] in cancer cells, while displaying negligible toxicity in animal models [13]. Hence, SHetA2 was regarded as a novel class of promising anticancer agent that selectively targeted the cancer cells. Consequently, it was evaluated in preclinical development for cancer prevention through the National Cancer Institute (NCI) Rapid Access to Intervention Development (RAID) and Rapid Access to Preventive Intervention Development (RAPID) program [6]. Studies in rats and dogs showed that no toxicity was observed in any of the tested dosage groups. The no-observed-adverse-effect-level (NOAEL) for SHetA2 was not established and was considered to be above 1500 mg/kg/day in dogs [13]. The therapeutic window for administrative safety with SHetA2 was determined to be 25- to 150-folds above *in vivo* effective doses. As a result, it is currently undergoing Phase-0 clinical trials through RAID [14]. This chapter will provide a comprehensive review of SHetA2, including its design and development, and possible molecular targets and mechanisms of action and its potential

Retinoids, including natural retinoic acid (RA) and its synthetic derivatives, are a group of promising anticancer agents that have shown both chemotherapeutic and chemopreventive potential in both animals and humans [15–17]. They exhibit therapeutic properties by activating the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) [18]. Each receptor has three subtypes (-α, -β, -γ), and they belong to a family of proteins that regulate the transcription of genes responsible for a variety of metabolic, developmental, and differentia-

an attractive strategy to fight cancers [4].

68 Anti-cancer Drugs - Nature, Synthesis and Cell

clinical applications, based on the literature published thus far.

**2. History of retinoid development**

**2.1. Retinoids**

**Figure 1.** Chemical structures of retinoids, heteroarotinoids, and flexible-heteroarotinoids.
