**10. Conclusion**

thiourea linker, yielding two metabolites that were also detected *in vivo* [58]. The proposed

Given that ShetA2 has several mechanisms of action involving various cellular targets, these findings suggest the possibility for SHetA2 to be metabolized into several active metabolites, each targeting a different molecular pathway. This is further supported by a recent *in vivo* study where the monohydroxy SHetA2 (**25**) was found to be the major metabolite of SHetA2 in rat plasma, and it was detected at a much higher concentration than the parent compound after

Pharmacokinetic studies using HPLC/UV of SHetA2 in mice(**Table 5**) have shown that

pharmacokinetic profile of this compound is favorable for future development [59].

 **PK SHetA2**  1 Oral bioavailability at 20 mg/kg 15% Oral bioavailability at 60 mg/kg 19%

2 Urinary excretion (%) Not reported 3 Bound to mouse and human plasma proteins at μM concentrations 99.3–99.5%

Half-life in the mouse Detectable after 60 h after IV

SHetA2 is now in Phase-0 clinical trial for ovarian cancer chemoprevention. However, since it inhibits growth of most cancers *in vitro* and *in vivo*, it may potentially be used for the prevention

8 Peak concentration (IV 20 mg/kg dose of SHetA2 to mice) 10 μM after 5 min Maxima mean plasma concentration in the mouse (PO) 0.79 μM at 2 h 2.35 μM at 3 h

administration

4 Total body clearance (L/h/kg) 1.8 5 Volume distribution (L/kg) at steady state (*V*dss) 20.8 6 Half-life in mouse plasma 12.7 h

 Half-life in human plasma (once a day dosing proposed) 12 h 7 Peak time (plasma concentrations of 10 μM following i.v. bolus dose) 5 min

and treatment of other cancers which are listed in **Table 6**.

**Table 5.** Pharmacokinetic data of SHetA2 [59].

**9. Possible clinical applications**

mechanism for the formation of these metabolites is shown in **Figure 11**.

oral and intravenous administration [13].

86 Anti-cancer Drugs - Nature, Synthesis and Cell

**8. Pharmacokinetics**

SHetA2 has exhibited anticancer activity in 60 NCI cancer cells and has shown favorable results in inhibiting various types of cancer growth *in vivo*, particularly ovarian cancer. It exerts various chemopreventive and chemotherapeutic activities through its ability to induce apoptosis and Differentiation, and inhibit angiogenesis and cell growth. It promotes mitochondrial swelling and mitophagy leading to apoptosis of cancer cells, while sparing normal cells. Once the targets are validated, tweaking of existing Flex-Hets or synthesis of newer related analogs may offer greater specificity and improved anticancer activity. Preclinical studies in animals have shown that SHetA2 has high efficacy with minimal toxicity and has a good pharmacokinetic profile. This provides the foundation for developing a novel class of more effective, chemo-preventive and anticancer drugs with a better therapeutic window.
