Design and synthesis of cabotegravir derivatives bearing 1,2,3-triazole and evaluation of anti-liver cancer activity

Xie, Huaxia; Mao, Longfei; Fan, Gaolu; Wu, Ziyuan; Wang, Yimian; Hou, Xixi; Wang, Jiangang; Wang, Huili; Liu, Ling; Li, Sanqiang

doi:10.3389/fphar.2023.1265289

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…Its high efficacy at low doses and the high satisfaction reported by individuals living with HIV make it a very promising drug for long-term treatment [60]. Interestingly, some triazole analogues of cabotegravir were recently synthesized and tested in vitro for their antitumor activity against non-small-cell lung cancer cells [61] and a hepatocellular carcinoma cell line [62]. These results, along with our findings, suggest that the potential of cabotegravir in melanoma therapy deserves organoids and/or in vivo investigations.…”

Section: Discussionmentioning

confidence: 99%

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

Zanrè,

Bellinato,

Cardile

et al. 2024

IJMS

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This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals—lamivudine, doravirine, and cabotegravir—in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells. The antiretroviral drugs also demonstrate selectivity against malignant cells, sparing normal human epithelial melanocytes. The study reveals that the integrase inhibitor cabotegravir is particularly effective in inhibiting cell growth and invasion across different cell lines in comparison with lamivudine and doravirine, which are inhibitors of the viral reverse transcriptase enzyme. The investigation further delves into the molecular mechanisms underlying the observed effects, highlighting the potential induction of ferroptosis, apoptosis, and alterations in cell cycle regulatory proteins. Our findings showed cytostatic effects principally revealed in A375, and SK-Mel-28 cell lines through a downregulation of retinoblastoma protein phosphorylation and/or cyclin D1 expression. Signs of ferroptosis were detected in both A375 cells and FO-1 cells by a decrease in glutathione peroxidase 4 and ferritin expression, as well as by an increase in transferrin protein levels. Apoptosis was also detected in FO-1 and SK-Mel-28, but only with cabotegravir treatment. Moreover, we explored the expression and activity of the stimulator of interferon genes (STING) protein and its correlation with programmed death-ligand 1 (PD-L1) expression. Both the STING activity and PD-L1 expression were decreased, suggesting that the antiretroviral treatments may counteract the detrimental effects of PD-L1 expression activation through the STING/interferon pathway triggered by HERV-K. Finally, this study underscores the potential therapeutic significance of cabotegravir in melanoma treatment. The findings also raise the prospect of using antiretroviral drugs to downregulate PD-L1 expression, potentially enhancing the therapeutic responses of immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

Zanrè,

Bellinato,

Cardile

et al. 2024

IJMS

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“…Furthermore, both KJ-5 and KJ-12 were found to induce apoptosis via the mitochondrial pathway and inhibit the invasion and migration of cancer cells. [ 19 ]. By utilizing the structural features of the EGFR inhibitor erlotinib, compounds a1–a22 with erlotinib-1,2,3-triazole derivatives were obtained through click reactions [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Vitro Antitumor Activity Evaluation of Gefitinib-1,2,3-Triazole Derivatives

Liu,

Gao

et al. 2024

Molecules

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In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 μM (NCI-H1299), 3.94 ± 0.01 μM (A549) and 1.56 ± 0.06 μM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 μM (A549) and 3.51 ± 0.05 μM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment.

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Synthesis and Activity Study of Gefitinib Derivatives Inducing Mitochondrial Apoptosis in Hela Cells

Li,

Hou,

Liu

et al. 2024

Chem Biol Drug Des

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Cervical cancer is the fourth most common cancer among women globally. Its development is closely linked to accelerated cell cycle progression and the inhibition of apoptosis in cervical cancer tissues. Gefitinib has demonstrated efficacy in inhibiting cervical cancer cells, and the 1,2,3‐triazole structure is widely recognized for its role in inducing mitochondrial apoptosis in tumor cells. In this study, we employed click chemistry to modify the structure of gefitinib, leading to the synthesis of 16 derivatives containing the 1,2,3‐triazole moiety. These compounds were evaluated for their in vitro activity against Hela cells. Among them, compound 3p exhibited the most promising anticancer activity, with an IC50 value of 4.09 ± 0.54 μM. Compound 3p significantly inhibited Hela cell colony formation in a dose‐dependent manner, accompanied by noticeable morphological changes. Further investigations revealed that 3p induced apoptosis and caused G2/M phase cell cycle arrest in Hela cells. Western blot analysis showed that 3p increased the Bax/Bcl‐2 ratio and elevated the levels of cleaved caspase‐3 and PARP1, indicating that apoptosis was mediated through the mitochondrial pathway. Additionally, 3p inhibited indoleamine 2,3‐dioxygenase 1 (IDO1) enzymatic activity, and molecular docking studies revealed a strong interaction between 3p and the IDO1 active site, suggesting that IDO1 may be a potential target. In conclusion, compound 3p shows promise as a potential therapeutic agent for cervical cancer.

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Design and synthesis of cabotegravir derivatives bearing 1,2,3-triazole and evaluation of anti-liver cancer activity

Cited by 4 publications

References 19 publications

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

Synthesis and In Vitro Antitumor Activity Evaluation of Gefitinib-1,2,3-Triazole Derivatives

Synthesis and Activity Study of Gefitinib Derivatives Inducing Mitochondrial Apoptosis in Hela Cells

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