Effects of Imidazopyridine Derivatives on Cancer Cell Signaling

Abstract

The limited effectiveness of conventional chemotherapeutics used in cancer treatment requires the discovery of new agents. Compounds with imidazopyridine scaffolds have promising potential for the development of new agents because they are open to various chemical modifications. Intracellular signaling pathways are essential in normal cell physiology, and their defects play a role in the pathogenesis of many diseases, including cancer. Although numerous studies have demonstrated the cytotoxic and apoptotic properties of imidazopyridines on cancer cells, a limited number of studies have aimed to investigate the effects of these compounds on signaling pathways. Obtained data show that this group of compounds is effective on signaling pathways.

Keywords

• Cancer
• imidazopyridine
• signaling

İMİDAZOPİRİDİN TÜREVLERİNİN KANSER HÜCRE SİNYALİNDEKİ ETKİLERİ

Abstract

Kanser tedavisinde kullanılan konvansiyonel etkinliklerinin sınırlı olması yeni ajanların keşfini gerektirmektedir. İmidazopiridin iskelesine sahip bileşikler çeşitli kimyasal modifikasyonlara açık olması sebebiyle yeni ajanların geliştirilmesi için umut verici potansiyele sahiptir. Hücre içi sinyal yolakları normal hücre fizyolojisinde gerekli olup bozuklukları kanser dahil çok sayıda hastalığın patogenezinde rol oynar. Çok sayıda çalışma ile imidazopiridinlerin kanser hücreleri üzerinde sitotoksik ve apoptotik özellikleri gösterilmiş olsa da sınırlı sayıda çalışma bu bileşiklerin sinyal yolakları üzerindeki etkilerini araştırmayı hedeflemiştir. Elde edilen veriler bu grup bileşiklerin sinyal yolları üzerinde etkili olduğunu göstermektedir.

Keywords

• Kanser
• imidazopiridin
• sinyal

References

1. Ding H, Yu X, Hang C, et al. Ailanthone: A novel potential drug for treating human cancer. Oncol Lett. 2020;1;20(2):1489-1503.
2. Talib WH, Alsayed AR, Barakat M, Abu-Taha MI, Mahmod AI. Targeting drug chemo-resistance in cancer using natural products. Biomedicines. 2021;29;9(10):1353.
3. Majumder A, Gupta R, Jain A. Microwave-assisted synthesis of nitrogen-containing heterocycles. Green Chem Lett Rev. 2013;1;6(2):151-182.
4. Arellano AR, Garcia OG, Jaramillo JT. Synthesis of azolines and ımidazoles and their use in drug design. Med Chem (Los Angeles) 2016;6(9):561-570.
5. Ravi C, Adimurthy S. Synthesis of Imidazo[1,2-a]pyridines: C-H functionalization in the direction of C-S bond formation. Chem Rec. 2017;17(10):1019-138.
6. Bagdi AK, Santra S, Monir K, Hajra A. Synthesis of imidazo[1,2-a]pyridines: A decade update. Chem Commun. 2015;15;51(9):1555-1575.
7. Yang MH, Sethi G, Ravish A, et al. Discovery of imidazopyridine-pyrazoline-hybrid structure as SHP-1 agonist that suppresses phospho-STAT3 signaling in human breast cancer cells. Chemico-Biol Interact. 2023;1;386:110780.
8. Al-Muntaser SM, Al-Karmalawy AA, El-Naggar, et al. Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, and in silico studies. RSC Adv. 2023;17;13(18):12184-12203.

9. Aliwaini S, Awadallah AM, Morjan RY, et al. Novel imidazo[1,2‑a]pyridine inhibits AKT/mTOR pathway and induces cell cycle arrest and apoptosis in melanoma and cervical cancer cells. Oncol Lett. 2019;1;18(1):830-837.
10. Yang WC, Li J, Li J, Chen Q, Yang GF. Novel synthetic methods for N-cyano-1H-imidazole-4-carboxamides and their fungicidal activity. Bioorg Med Chem Lett. 2012;1;22(3):1455-1458.
11. Feng S, Hong D, Wang B, et al. Discovery of imidazopyridine derivatives as highly potent respiratory syncytial virus fusion inhibitors. ACS Med Chem Lett. 2015;25;6(3):359-362.
12. Padmavathi V, Prema kumari C, Venkatesh BC, Padmaja A. Synthesis and antimicrobial activity of amido linked pyrrolyl and pyrazolyl-oxazoles, thiazoles and imidazoles. Eur J Med Chem. 2011;1;46(11):5317-5326.
13. Pandey J, Tiwari VK, Verma SS, et al. Synthesis and antitubercular screening of imidazole derivatives. Eur J Med Chem. 2009;1;44(8):3350-3355.
14. Tatipaka HB, Gillespie JR, Chatterjee AK, et al. Substituted 2-phenyl-ımidazopyridines: A new class of drug leads for human african trypanosomiasis. J Med Chem. 2014;13;57(3):828-835.
15. Kankala S, Kankala RK, Gundepaka P, et al. Regioselective synthesis of isoxazole–mercaptobenzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies. Bioorg Med Chem Lett. 2013;1;23(5):1306-1309.
16. Chen X, Cao D, Liu C, et al. Discovery of 1H-Imidazo[4,5- b]pyridine derivatives as potent and selective bet inhibitors for the management of neuropathic pain. J Med Chem. 2023;13;66(13):8725-8744.
17. Igawa H, Takahashi M, Kakegawa K, et al. Melanin- concentrating hormone receptor 1 antagonists lacking an aliphatic amine: Synthesis and structure–activity relationships of Novel 1-(Imidazo[1,2-a]pyridin-6- yl)pyridin-2(1H)-one derivatives. J Med Chem. 2016;59;(3): 1116-1139.
18. Vakalopoulos A, Wunder F, Hartung IV, et al. New Generation of sGC Stimulators: Discovery of Imidazo[1,2- a]pyridine Carboxamide BAY 1165747 (BAY-747), a long- acting soluble guanylate cyclase stimulator for the treatment of resistant hypertension. J Med Chem. 2023;8;66(11):7280- 7303.
19. Khatun S, Singh A, Bader GN, Sofi FA. Imidazopyridine, a promising scaffold with potential medicinal applications and structural activity relationship (SAR): Recent advances. J Biomol Struct Dynamics. 2022;26;40(24):14279-14302.
20. Krause M, Foks H, Gobis K. Pharmacological potential and synthetic approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine derivatives. Molecules. 2017;22(3):399.
21. Kuş C, Özer E, Korkmaz Y, Yurtcu E, Dağalp R. Benzamide and benzamidine compounds as new inhibitors of urokinase type plasminogen activators. Mini Rev Med Chem. 2018;18(20):1753-1758.
22. Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2010;277(2):301-308.
23. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers. 2017;9(5):52.
24. Shaban N, Kamashev D, Emelianova A, Buzdin A. Targeted inhibitors of EGFR: Structure, biology, biomarkers, and clinical applications. Cells. 2024;13(1):47.
25. Gharwan H, Groninger H. Kinase inhibitors and monoclonal antibodies in oncology: Clinical implications. Nat Rev Clin Oncol. 2016;13(4):209-227.
26. Lee HK, Noh MH, Hong SW, et al. Erlotinib activates different cell death pathways in EGFR-mutant lung cancer cells grown in 3D versus 2D culture systems. Anticanc Res. 2021;1;41(3):1261-1269.
27. Rini BI. Sorafenib. Exp Opin Pharmacother. 2006;1;7(4):453-461.
28. Fakhry MM, Mattar AA, Alsulaimany M, et al. New thiazolyl-pyrazoline derivatives as potential dual EGFR/HER2 inhibitors: Design, synthesis, anticancer activity evaluation and ın silico study. Molecules. 2023;6;28(21):7455.
29. Bhavya K, Mantipally M, Roy S, et al. Novel imidazo[1,2- a]pyridine derivatives induce apoptosis and cell cycle arrest in non-small cell lung cancer by activating NADPH oxidase mediated oxidative stress. Life Sci. 2022;1;294:120334.
30. He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;16;6:425.
31. Wang Y, Zhang T, He X. Advances in the role of microRNAs associated with the PI3K/AKT signaling pathway in lung cancer. Front Oncol. 2023 19;13:1279822.
32. Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Ann Rev Med. 2016;67(1):11-28.
33. Da Costa Machado AK, Machado Cezerra, De Pinho Pessoa FMC, et al. Development and clinical applications of PI3K/AKT/mTOR pathway iınhibitors as a therapeutic option for leukemias. Cancer Diagn Progn. 2024;3;4(1):9- 24.
34. Wen T, Thapa N, Cryns VL, Anderson RA. Regulation of phosphoinositide signaling by scaffolds at cytoplasmic membranes. Biomolecules. 2023;13(9):1297.
35. Wu Y, Xu X, Liu M, et al. DZW-310, a novel phosphoinositide 3-kinase inhibitor, attenuates the angiogenesis and growth of hepatocellular carcinoma cells via PI3K/AKT/mTOR axis. Biochem Pharmacol. 2022;1;201:115093.
36. Gandin V, Khalkar P, Braude J, Fernandes AP. Organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment. Free Rad Biol Med. 2018;1;127:80-97.
37. dos Santos DC, Rafique J, Saba S, et al. IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, modulates ıntracellular redox state and causes Akt/mTOR/HIF-1α and MAPK signaling inhibition, promoting antiproliferative effect and apoptosis in glioblastoma Cells. Oxid Med Cell Longev. 2022;22;2022:e3710449.
38. dos Santos DC, Rafique J, Saba S, et al. Apoptosis oxidative damage-mediated and antiproliferative effect of selenylated imidazo[1,2-a]pyridines on hepatocellular carcinoma HepG2 cells and in vivo. J Biochem Mol Toxicol. 2021;35(3):e22663.
39. Chen R, Wang Z, Sima L, et al. Design, synthesis and evaluation of 2, 6, 8-substituted imidazopyridine derivatives as potent PI3Kα inhibitors. J Enzyme Inhib Med Chem. 2023;31;38(1):2155638.
40. Kim OH, Lee JH, Mah S, et al. HS‑146, a novel phosphoinositide 3‑kinase α inhibitor, induces the apoptosis and inhibits the metastatic ability of human breast cancer cells. Int J Oncol. 2020;1;56(6):1509-1520.
41. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: From bench to clinic. Sig Transduct Target Ther. 2021;26;6(1):1-33.
42. Garrido-Trigo A, Salas A. Molecular structure and function of Janus kinases: Implications for the development of inhibitors. J Crohn’s Colitis. 2020;1;14(S_2):S713-24.
43. Kohal R, Bisht P, Gupta GD, Verma SK. Targeting JAK2/STAT3 for the treatment of cancer: A review on recent advancements in molecular development using structural analysis and SAR investigations. Bioorg Chem. 2024;1;143:107095.
44. Xue C, Yao Q, Gu X, et al. Evolving cognition of the JAK- STAT signaling pathway: Autoimmune disorders and cancer. Sig Transduct Target Ther. 2023;19;8(1):1-24.
45. Ravish A, Shivakumar R, Xi Z, et al. De Novo design of imidazopyridine-tethered pyrazolines that target phosphorylation of STAT3 in human breast cancer cells. Bioengineering. 2023;10(2):159.
46. Huang Q, Zhong Y, Li B, et al. Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3). Eur J Med Chem. 2021;5;221:113525.
47. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13(1):11-26.
48. Rahmani F, Avan A, Hashemy SI, Hassanian SM. Role of Wnt/β-catenin signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J Cell Physiol. 2018;233(2):811-817.
49. He LJ, Yang DL, Chen HY, et al. A novel imidazopyridine derivative exhibits anticancer activity in breast cancer by inhibiting Wnt/β‑catenin signaling. OncoTargets Therapy. 2020;9;13:10111-1021.
50. Kim HM, Kim CS, Lee JH, et al. CG0009, a novel glycogen synthase kinase 3 inhibitor, induces cell death through Cyclin D1 depletion in breast cancer cells. PLoS ONE. 2013;8(4):614906.