Design and Synthesis of Cabotegravir Derivatives Bearing 1,2,3-triazole and Evaluation of Anti-liver Cancer Activity

Overview

Journal Front Pharmacol

Date 2023 Oct 23

PMID 37869757

Authors

Huaxia Xie

Longfei Mao

Gaolu Fan

Ziyuan Wu

Yimian Wang

Xixi Hou

JianGang Wang

Huili Wang

Ling Liu

Sanqiang Li

Affiliations

Soon will be listed here.

Abstract

Based on the structure of the anti-HIV drug cabotegravir, we introduced 1,2,3-triazole groups with different substituents to obtain 19 cabotegravir derivatives and tested their activity against HepG2 cells. The proliferation of HepG2 cells was examined following treatment with derivatives. Most of the compounds demonstrated significant inhibitory effects, particularly compounds KJ-5 and KJ-12 with IC values of 4.29 ± 0.10 and 4.07 ± 0.09 μM, respectively. Furthermore, both compounds 5 and 12 significantly caused cell apoptosis, G2/M arrest, and DNA damage, and suppressed invasion and migration in a concentration-dependent manner. In addition, KJ-5 and KJ-12 could trigger apoptosis via the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating cleaved caspase-9, cleaved caspase-3, and cleaved PARP.

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References

Chen H, Ji P, Qi Y, Chen S, Wang C, Yang Y . Inactivation of biofilms by thymoquinone in combination with nisin. Front Microbiol. 2023; 13:1029412. PMC: 9893119. DOI: 10.3389/fmicb.2022.1029412. View

Andrews C, Heneine W . Cabotegravir long-acting for HIV-1 prevention. Curr Opin HIV AIDS. 2015; 10(4):258-63. DOI: 10.1097/COH.0000000000000161. View

Hu J, Ludgate L . HIV-HBV and HIV-HCV coinfection and liver cancer development. Cancer Treat Res. 2007; 133:241-52. View

Queiroz T, Orozco E, Silva V, Santos L, Soares M, Bezerra D . Semi-synthesis of β-keto-1,2,3-triazole derivatives from ethinylestradiol and evaluation of the cytotoxic activity. Heliyon. 2019; 5(9):e02408. PMC: 6734327. DOI: 10.1016/j.heliyon.2019.e02408. View

Wang L, Liu X, Duan Y, Li X, Zhao B, Wang C . Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors. Chem Biol Drug Des. 2018; 92(1):1301-1314. DOI: 10.1111/cbdd.13192. View

Wu C, Eck B, Zhang S, Zhu J, Tiwari A, Zhang Y . Discovery of 1,2,3-Triazole Derivatives for Multimodality PET/CT/Cryoimaging of Myelination in the Central Nervous System. J Med Chem. 2017; 60(3):987-999. DOI: 10.1021/acs.jmedchem.6b01328. View

Johns B, Kawasuji T, Weatherhead J, Taishi T, Temelkoff D, Yoshida H . Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J Med Chem. 2013; 56(14):5901-16. DOI: 10.1021/jm400645w. View

Bertrand H, Schaap M, Baird L, Georgakopoulos N, Fowkes A, Thiollier C . Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1-Nrf2 Protein-Protein Interaction. J Med Chem. 2015; 58(18):7186-94. DOI: 10.1021/acs.jmedchem.5b00602. View

Mao L, Sun G, Zhao J, Xu G, Yuan M, Li Y . Design, synthesis and antitumor activity of icotinib derivatives. Bioorg Chem. 2020; 105:104421. DOI: 10.1016/j.bioorg.2020.104421. View

10.

Engelman K, Engelman A . Long-Acting Cabotegravir for HIV/AIDS Prophylaxis. Biochemistry. 2021; 60(22):1731-1740. PMC: 8515172. DOI: 10.1021/acs.biochem.1c00157. View

11.

Oekchuae S, Sirirak J, Charoensuksai P, Wongprayoon P, Chuaypen N, Boonsombat J . The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2. Pharmaceuticals (Basel). 2022; 15(5). PMC: 9147274. DOI: 10.3390/ph15050504. View

12.

Mao L, Wang Z, Wu Q, Chen X, Yang J, Wang X . Design, Synthesis, and Antitumor Activity of Erlotinib Derivatives. Front Pharmacol. 2022; 13:849364. PMC: 9065260. DOI: 10.3389/fphar.2022.849364. View

13.

Chen H, Guan X, Liu Q, Yang L, Guo J, Gao F . Co-assembled Nanocarriers of Thiol-Activated Hydrogen Sulfide Donors with an RGDFF Pentapeptide for Targeted Therapy of Non-Small-Cell Lung Cancer. ACS Appl Mater Interfaces. 2022; 14(48):53475-53490. DOI: 10.1021/acsami.2c14570. View

14.

Mao L, Wang Y, Zhao J, Xu G, Yao X, Li Y . Discovery of Icotinib-1,2,3-Triazole Derivatives as IDO1 Inhibitors. Front Pharmacol. 2020; 11:579024. PMC: 7555427. DOI: 10.3389/fphar.2020.579024. View

15.

Fu D, Li P, Wu B, Cui X, Zhao C, Zhang S . Molecular diversity of trimethoxyphenyl-1,2,3-triazole hybrids as novel colchicine site tubulin polymerization inhibitors. Eur J Med Chem. 2019; 165:309-322. DOI: 10.1016/j.ejmech.2019.01.033. View

16.

Rohrig U, Reynaud A, Majjigapu S, Vogel P, Pojer F, Zoete V . Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1). J Med Chem. 2019; 62(19):8784-8795. DOI: 10.1021/acs.jmedchem.9b00942. View

17.

Qi Z, Hao S, Tian H, Bian H, Hui L, Chen S . Synthesis and biological evaluation of 1-(benzofuran-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole derivatives as tubulin polymerization inhibitors. Bioorg Chem. 2019; 94:103392. DOI: 10.1016/j.bioorg.2019.103392. View

18.

Thacker P, Goud N, Argulwar O, Soman J, Angeli A, Alvala M . Synthesis and biological evaluation of some coumarin hybrids as selective carbonic anhydrase IX and XII inhibitors. Bioorg Chem. 2020; 104:104272. DOI: 10.1016/j.bioorg.2020.104272. View

19.

Wang B, Zhao B, Chen Z, Pang L, Zhao Y, Guo Q . Exploration of 1,2,3-triazole-pyrimidine hybrids as potent reversal agents against ABCB1-mediated multidrug resistance. Eur J Med Chem. 2017; 143:1535-1542. DOI: 10.1016/j.ejmech.2017.10.041. View