*1.3. Comparison of Main Components of Tanshinone*

Tanshinones are uniquely characterized by the presence of 14,16-ether D rings, such as CYT and DHTI, but this heterocycle is usually further converted to furan, as in TsI and TsIIA [14,15]. Tanshinone generally consists of four rings, including naphthalene or tetrahydronaphthalene rings A and B, a normal or paraquinone or lactone ring C, and a furan or dihydrofuran ring D [15,16]. Just as A, B, C, and D rings as shown in the above figure (Figure 1). Obviously, although the molecular skeleton of the four main components of Tanshinone is similar, the groups, group positions, and double bond positions are slightly different.

Secondly, there are some differences in the pharmacokinetics of Tanshinone in vivo, but generally speaking, all Tanshinones, whether oral administration, intravenous administration, subcutaneous injection, or conventional delivery, all have the characteristics of short half-life and low bioavailability [17,18]. Interestingly, there seems to be a certain synergistic effect among the components of Tanshinone. Multiple components of Tanshinone given together can improve the bioavailability of some components, such as Tanshinone IIA and Tanshinone I, which indicates that drug interactions occur among the components of Tanshinone [19]. Tanshinone pharmacokinetics have been well summarized in previous work [20,21]. In addition, the metabolism of different types of Tanshinone in vivo is also different. It is reported that the metabolism of Tanshinones mainly depends on their saturation and substituents in their skeletons. For example, the main metabolic pathway of CYT with saturated A and D rings is dehydrogenation; DHTI with saturated D rings is mainly metabolized by D ring hydrolysis; and hydroxylation is the main metabolic pathway of TsIIA with saturated A rings [22].

In addition, there are differences among Tanshinone components in terms of antitumor pharmacological characteristics, and the conformational relationships show that the pharmacological effects of Tanshinone depend mainly on its D-ring (furan/dihydrofuran) and steroidal structure [14,23], and it has been reported that during the antitumor response, DNA molecules bind to the phenanthrene ring structure of Tanshinone, which in turn affects the synthesis of tumor DNA, while the furan ring and steroidal structure also generate free radicals, which in turn impede DNA synthesis in tumor cells [24,25]. In addition, the antioxidant effect of Tanshinone is also dependent on the D-ring, and changes in the structure of the D-ring can often affect the antioxidant capacity of Tanshinone. For example, Tanshinone containing the dihydrofuran D-ring has a stronger antioxidant capacity than those containing the furan D-ring [26], which is also reflected in the antitumor pharmacological effect. TsIIA's tumor suppressive effect, for example, is primarily dependent on the PI3K/AKT/mTOR signaling pathway and the JNK pathway, whereas CYT is more dependent on State3-mediated anti-tumor effects and has stronger immunomodulatory effects than the other three components [27–29].

In addition, the antitumor potency of Tanshinone components differed among them, and the potency (either induction of apoptosis, inhibition of invasion, or inhibition of proliferation) among the components of Tanshinone was reported to be TsI > TsIIA > CYT in all three prostate cancer cell lines, whether DU145, PC3, or LNCaP [30], which may be partly due to the stronger anti-vascular activity of TsI. In addition, CYT appears to have a stronger anti-androgenic effect, but interestingly, the toxic effect of CYT on DU145 is more enhanced than that of LNCaP [31], suggesting that CYT may be more dependent on other pathways in prostate cancer.
