Synthesis and discovery of novel 1,2,3-triazole based cabotegravir derivatives with potent anticancer activity

A series of 28 novel cabotegravir derivatives, incorporating the 1,2,3-triazole moiety, were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against four different human cancer cell lines: HuH-7 (hepatocellular), MCF-7 (breast), SKOV3 (ovarian), and HCT-116 (colon). Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds KJ9 and KJ23 demonstrated the most pronounced effects, with IC50 values of 6.59 and 7.83 μM in HuH-7 cells, 27.24 and 8.59 μM in MCF-7 cells, 4.46 and 6.30 μM in SKOV3 cells, 23.90 and 17.00 μM in HCT-116 cells, respectively. Further investigations demonstrated that compound KJ9 and KJ23 induced cell apoptosis, elevated reactive oxygen species (ROS) levels, and ultimately led to cell death. Additionally, western blot analysis revealed altered expressions of proteins involved in autophagy and DNA damage following treatment with compound KJ9 and KJ23. Molecular structure analysis found that the novel compounds tend towards a planar conformation which contained multiple rigid planar structures. This planar structure makes it possible for the compounds to intercalate into DNA and causing DNA damage. These findings suggested that cabotegravir-1,2,3-triazole derivatives possess potential antitumor abilities and warrant further investigations for the development of novel anticancer drugs.