Design, Synthesis and Biological Activity Evaluation of β-Carboline Derivatives Containing Nitrogen Heterocycles

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Nov 9

PMID 39519796

Authors

Guiyun Wu

Wenhang Wang

Fulian Li

Chenlu Xu

Yue Zhou

Zhurui Li

Bingqian Liu

Lihui Shao

Danping Chen

Song Bai

Zhenchao Wang

Affiliations

Soon will be listed here.

Abstract

A series of β-carboline derivatives containing nitrogen heterocycles were designed and synthesized. All compounds were screened for their antitumor activity against four human tumor cell lines (A549, K562, PC-3, T47D). Notably, compound -(4-(morpholinomethyl)phenyl)-2-((5-(1-(3,4,5-trimethoxyphenyl)-9-pyrido[3,4-b]indol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide () exhibited significant inhibitory activity against PC-3 cells with an IC value of 9.86 µM. Importantly, compound effectively suppressed both the proliferation and migration of PC-3 cells. Mechanistic studies revealed that compound induced cell apoptosis and caused the accumulation of reactive oxygen species (ROS), leading to cell cycle arrest in the G0/G1 phase in PC-3 cells.

References

Yang Y, Huang Y, Song H, Liu Y, Wang L, Wang Q . Skeletal modifications of β-carboline alkaloids and their antiviral activity profile. Mol Divers. 2016; 20(4):829-835. DOI: 10.1007/s11030-016-9669-8. View

Komulainen H, Tuomisto J, Airaksinen M, Kari I, Peura P, Pollari L . Tetrahydro-beta-carbolines and corresponding tryptamines: In vitro inhibition of serotonin, dopamine and noradrenaline uptake in rat brain synaptosomes. Acta Pharmacol Toxicol (Copenh). 1980; 46(4):299-307. DOI: 10.1111/j.1600-0773.1980.tb02458.x. View

Xu Z, Zhao H, Zhu J, Qian J, Tao W, Xie X . Rational design of β-carboline as an efficient type I/II photosensitizer to enable hypoxia-tolerant chemo-photodynamic therapy. Bioorg Chem. 2023; 141:106875. DOI: 10.1016/j.bioorg.2023.106875. View

Benassi A, Doria F, Pirota V . Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds. Int J Mol Sci. 2020; 21(22). PMC: 7698752. DOI: 10.3390/ijms21228692. View

Atanasov A, Zotchev S, Dirsch V, Supuran C . Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021; 20(3):200-216. PMC: 7841765. DOI: 10.1038/s41573-020-00114-z. View

Patel N, Purohit A, Rajani D, Moo-Puc R, Rivera G . New 2-benzylsulfanyl-nicotinic acid based 1,3,4-oxadiazoles: their synthesis and biological evaluation. Eur J Med Chem. 2013; 62:677-87. DOI: 10.1016/j.ejmech.2012.12.055. View

Kumar S, Wang Y, Chen P, Chang Y, Kashyap H, Shen Y . Design and synthesis of β-carboline and combretastatin derivatives as anti-neutrophilic inflammatory agents. Bioorg Chem. 2021; 111:104846. DOI: 10.1016/j.bioorg.2021.104846. View

Wang W, Qin J, Voruganti S, Srivenugopal K, Nag S, Patil S . The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun. 2014; 5:5086. PMC: 6774205. DOI: 10.1038/ncomms6086. View

Zaidieh T, Smith J, Ball K, An Q . ROS as a novel indicator to predict anticancer drug efficacy. BMC Cancer. 2019; 19(1):1224. PMC: 6916036. DOI: 10.1186/s12885-019-6438-y. View

10.

Xiao D, Lu L, Liang B, Xiong Z, Xu X, Chen W . Identification of 1,3,4-oxadiazolyl-containing β-carboline derivatives as novel α-glucosidase inhibitors with antidiabetic activity. Eur J Med Chem. 2023; 261:115795. DOI: 10.1016/j.ejmech.2023.115795. View

11.

Asati V, Mahapatra D, Bharti S . Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: Potential anticancer agents. Eur J Med Chem. 2014; 87:814-33. DOI: 10.1016/j.ejmech.2014.10.025. View

12.

Han X, Zhang J, Guo L, Cao R, Li Y, Li N . A series of beta-carboline derivatives inhibit the kinase activity of PLKs. PLoS One. 2012; 7(10):e46546. PMC: 3463587. DOI: 10.1371/journal.pone.0046546. View

13.

Meanwell N, Loiseleur O . Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 2. J Agric Food Chem. 2022; 70(36):10972-11004. DOI: 10.1021/acs.jafc.2c00729. View

14.

Giulietti J, Tate P, Cai A, Cho B, Mulcahy S . DNA-binding studies of the natural β-carboline eudistomin U. Bioorg Med Chem Lett. 2016; 26(19):4705-4708. PMC: 5018459. DOI: 10.1016/j.bmcl.2016.08.047. View

15.

Zhang G, Tang Z, Fan S, Li C, Li Y, Liu W . Synthesis and biological assessment of indole derivatives containing penta-heterocycles scaffold as novel anticancer agents towards A549 and K562 cells. J Enzyme Inhib Med Chem. 2023; 38(1):2163393. PMC: 9848270. DOI: 10.1080/14756366.2022.2163393. View

16.

Zou Y, Zhang G, Li C, Long H, Chen D, Li Z . Discovery of Tryptanthrin and Its Derivatives and Its Activities against NSCLC In Vitro via Both Apoptosis and Autophagy Pathways. Int J Mol Sci. 2023; 24(2). PMC: 9861433. DOI: 10.3390/ijms24021450. View

17.

Sathish M, Dushantrao S, Nekkanti S, Tokala R, Thatikonda S, Tangella Y . Synthesis of DNA interactive C3-trans-cinnamide linked β-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors. Bioorg Med Chem. 2018; 26(17):4916-4929. DOI: 10.1016/j.bmc.2018.08.031. View

18.

Zhang Z, Zeng Y, Jiang Z, Shu B, Sethuraman V, Zhong G . Design, synthesis, fungicidal property and QSAR studies of novel β-carbolines containing urea, benzoylthiourea and benzoylurea for the control of rice sheath blight. Pest Manag Sci. 2018; 74(7):1736-1746. DOI: 10.1002/ps.4873. View

19.

Nafisi S, Bonsaii M, Maali P, Khalilzadeh M, Manouchehri F . Beta-carboline alkaloids bind DNA. J Photochem Photobiol B. 2010; 100(2):84-91. DOI: 10.1016/j.jphotobiol.2010.05.005. View

20.

Szabo T, Volk B, Milen M . Recent Advances in the Synthesis of β-Carboline Alkaloids. Molecules. 2021; 26(3). PMC: 7866041. DOI: 10.3390/molecules26030663. View