## 6 Novel Tanshinones and Chemical Modifications  
More recently identified novel tanshinones-related compounds by [PERSON] and associates [293; 294; 295; 296] have not been studied beyond their initial discovery work. Many of these novel compounds, including neo-tanshinlactone (Figure 1), appear to have greater cytotoxic potency against select cancer cells and better selectivity compared to those reviewed above [297]. Readers should follow up on the research progress dealing with these new entities.  
Because of the high hydrophobicity of tanshinones, poor solubility in aqueous medium and poor bioavailability through oral or _i.p._ route of delivery have been the major challenges for pharmaceutical development. Early effort in China with structural modification led to the development of a water-soluble sodium tanshinone IIA sulfonate (STS) (See Figure 3). This TIIA derivative drug has been widely used for patients with cardiovascular disorders in China [298; 299; 300]. However, this compound had little apoptosis-inducing ability when tested in six cancer cell lines [301; 302]. For this reason, investigators synthesized a novel TIIA compound, acetyltanshinone IIA (ATA) (Figure 3) [116]. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed higher growth inhibition ability on breast cancer especially ErbB-2/HER2/Neu positive cancer cells than normal cells and it inhibited MDA-MB-435 (now a confirmed melanoma cell line) xenograft growth in mice at a dose of 30 mg per kg by _i.p._ injection, three times per week. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death (Figure 3). The ATA-induced ROS production and its downstream apoptotic events could be blocked by propyl gallate, an antioxidant agent, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein decreased ATA-induced cell death. The authors concluded that ATA was a novel agent with potent _in vitro_ and _in vivo_ anti-cancer ability and ROS-mediated Bax activation as a mechanism by which ATA induced apoptosis and inhibited cancer cell growth (Figure 3).  
[PERSON] and colleagues synthesized a new sodium derivative of CT which they named PTS33 (Figure 3) and tested its effect on androgen receptor (AR) pathway [263]. Their data showed that PTS33 selectively inhibited AR activities, but did not repress the activities of other nuclear receptors, including ER\(\alpha\), GR, and PR. At a concentration of 2 \(\upmu\)M PTS33 effectively suppressed the growth of AR-positive prostate cancer (PCA) cells, and had little effect on AR-negative PCa cells. Furthermore, their data indicated that PTS33 could modulate AR transactivation and suppress the AR target genes (PSA, TMPRSS2 and TMEPA1) expression in both androgen responsive LNCaP cells and castration-resistant C4-2 cells. In addition, PTS33 inhibited estrogen/\(\Delta\)5-androstenediol induced AR activities. Further mechanistic studies indicated that PTS33 inhibited AR function by suppression of AR protein expression, AR N-C interaction and AR co-regulator interaction. The structure of PTS33 could be used as a prototype for development of novel AR signaling inhibitors to treat PCa. So far, the _in vivo_ bioavailability and efficacy of PTS33 has not been reported.