Design, structure-activity relationship study and biological evaluation of the thieno[3,2-c]isoquinoline scaffold as a potential anti-cancer agent

Thieno[2,3‐c]isoquinolines: A novel chemotype of antiproliferative agents inducing cellular apoptosis while targeting the G2/M phase and Tubulin

“…Another access to target thieno[2,3‐c]isoquinoline scaffold was gained from the isosteric replacement of (tetrahydro)quinoline motif in compound III (a potent antimitotic KSP inhibitor, Tagat, Guzi, Labroli, Poker, Kerekes, Yu, Paliwal, et al, 2006; Tagat, Guzi, Labroli, Poker, Kerekes, Yu, Tsui, et al, 2006) with isoquinoline (Figure 2). Additionally, a third design strategy of the target thieno[2,3‐c]isoquinoline scaffold was to modify the heterocyclic ring fusion pattern in compound IV (a promising thieno[3,2‐c]isoquinoline derivative causing cancer cell mitotic arrest [Liu et al, 2021]), see Figure 2.…”

“…Accordingly, this work has been devoted to expanding the scope of our successful design of thieno[2,3‐c]isoquinoline scaffold (Sayed et al, 2022) with special attention being payed to the following concerns. Namely, SAR studies, extending the in vitro screening to include HepG2 cell line hopefully of successful intervention in HCC, safety profile study (by using Vero cells as control) as well as further computational, and biological investigations of possible mechanisms of cytotoxicity while giving special focus on the potential antimitotic activities of the designed derivatives (inspired from compounds III [Tagat, Guzi, Labroli, Poker, Kerekes, Yu, Paliwal, et al, 2006; Tagat, Guzi, Labroli, Poker, Kerekes, Yu, Tsui, et al, 2006] and IV [Liu et al, 2021] as mentioned earlier).…”

“…Given the moderate antiproliferative activities displayed by the top three compounds 4b , 5b , and 7a and the cell growth arrest at the G2/M phase, a cell division interference mechanism of action was expected. Additionally, the reported potential antimitotic effects of very close compounds IIIa,b (Tagat, Guzi, Labroli, Poker, Kerekes, Yu, Paliwal, et al, 2006; Tagat, Guzi, Labroli, Poker, Kerekes, Yu, Tsui, et al, 2006) and IV (Liu et al, 2021) (as outlined in Section 1 and Figure 2) have created a motivation for selecting a mitosis‐related target. Tubulin protein is considered an ideal one, and antiagents have got a well‐established mechanism of cancer cell cytotoxicity, which is mainly attributed to interference with the G2/M phase of the cancer cell cycle (Aly et al, 2014; Cheng et al, 2020; Maklad, 2017).…”

“…Given the moderate antiproliferative activities displayed by the top three compounds 4b, 5b, and 7a and the cell growth arrest at the G2/M phase, a cell division interference mechanism of action was expected. Additionally, the reported potential antimitotic effects of very close compounds IIIa,b and IV (Liu et al, 2021) (as outlined in Section 1 and…”

“…On the other hand, if the quinoline moiety in thieno[2,3‐b]quinolines IIIa and IIIb (Figure 1) is completely replaced with its isostere “isoquinoline,” the resulting scaffold (thieno[3,2‐c]isoquinoline) will retain both antiproliferative and antimitotic activities (Liu et al, 2021). Lead optimization of such a new scaffold was reported to finally afford thieno[3,2‐c]isoquinoline derivative IV (Figure 1) as a potent antiproliferative agent causing spindle phenotypes and mitotic arrest of the A549 (lung cancer) cell line (Liu et al, 2021). Again, partial saturation of the isoquinoline derivatives ( IV ) was crucial for preserving high potency (as discussed earlier in IIIa and IIIb ).…”