Repurposing of Indomethacin and Naproxen as anticancer agents: progress from 2017 to present

Abstract

Inflammation is strongly linked to cancer and is essential for the growth and development of tumors. Targeting inflammation and the mediators involved in the inflammatory process could therefore provide a suitable method for cancer prevention and therapy. Numerous studies have shown that inflammation can predispose tumors. Non-steroidal anti-inflammatory drugs (NSAIDs) can affect the tumor microenvironment through increasing apoptosis and chemo-sensitivity while decreasing cell migration. Since the development of novel drugs requires a significant amount of money and time and poses a significant challenge for drug discovery, there has been a recent increase in interest in drug repositioning or repurposing. The growing body of research suggests that drug repurposing is essential for the quicker and less expensive development of anticancer therapies. In order to set the course for potential future repositioning of NSAIDs for clinical deployment in the treatment of cancer, the antiproliferative activity of derivatives of Indomethacin and Naproxen as well as their mechanism of action and structural activity relationships (SARs) published in the time frame from 2017 to 2024 are summarized in this review.

Fig. 1. The structure of Indomethacin–Pt(iv) prodrug 1.

Fig. 2. The structure of Indomethacin–methotrexate hybrid 2.

Fig. 3. The structure of Indomethacin derivatives 3a,b.

Fig. 4. The structure of Indomethacin podophyllotoxin conjugate 4.

Fig. 5. The structure of Indomethacin nitroxide hybrid 5.

Fig. 6. The structure of zinc(ii)–phenanthroline–Indomethacin complexes 6a–d.

Fig. 7. The structure of Indomethacin-Se derivatives 7a,b.

Fig. 8. The structure of Indomethacin thioesters 8a,b.

Fig. 9. The structure of Indomethacin derivatives 9a–f.

Fig. 10. The structure of metalloporphyrin–Indomethacin conjugates PtPor, PdPor, and ZnPor.

Fig. 11. The structure of OAO-Indomethacin conjugates 10a,b.

Fig. 12. The structure of coumarin–Indomethacin hybrid 11.

Fig. 13. The structure of Indomethacin derivatives 12a,b.

Fig. 14. The structure of Indomethacin derivative 13.

Fig. 15. The structure of Indomethacin–porphyrin and –chlorin conjugates (P2-Ind and C2-Ind).

Fig. 16. The structure of Indomethacin derivative 14.

Fig. 17. The structure of Se-Indomethacin analogs 15a,b.

Fig. 18. The structure of triarylphosphonium–Indomethacin derivatives 16a–d.

Fig. 19. The structure of Indomethacin derivative 17.

Fig. 20. The structure of Indomethacin derivatives 18a–c.

Fig. 21. The structure of Indomethacin derivative 19.

Fig. 22. The structure of copper(ii)–Naproxen complexes 20a–d.

Fig. 23. The structure Naproxen derivatives 21a–e.

Fig. 24. The structure of Naproxen derivatives 22–29.

Fig. 25. The structure Naproxen derivatives 30a–f.

Fig. 26. The structure Naproxen organometallic derivative 31.

Fig. 27. The structure of Naproxen-HBTA (32).

Fig. 28. The structure of Naproxen triazole–thioether hybrids 33a–g.

Fig. 29. The structure of Naproxen organoselenium compounds 34a,b.

Fig. 30. The structure of tryptophan-1,2,3-triazole Naproxen derivative 35.

Fig. 31. The structure of Naproxen selenocyanate and diselenide compounds 36 and 37.

Fig. 32. The structure of tryptophan-Naproxen-triazole hybrids 38a,b.

Fig. 33. The structure of Naproxen derivative 39.

Fig. 34. The structure of Naproxen-1,3,4-oxadiazole derivatives 40a,b.

Fig. 35. The structure of Naproxen organoselenium derivatives 41a,b.

Fig. 36. The structure of Naproxen-1,2,4-triazole hybrid 42.

Fig. 37. The structure of bifunctional Ibuprofen and Naproxen dendrimers 43 and 44.

Fig. 38. The structure of Naproxen-1,2,4-triazole hybrid 45a–c.

Fig. 39. The structure of Naproxen-1,2,4-triazole-Schiff base derivatives 46a,b.

Fig. 40. The structure of Naproxen thiourea derivatives 47a–d.

Fig. 41. The structure of Naproxen hydroxamic acid derivative 48.

Fig. 42. The structure of Naproxen–phosphane gold(i) complexes 49a,b.

Fig. 43. The summary of SARs of Indomethacin and Naproxen derivatives as antiproliferative agents.