Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties

Abstract

Cancer is one of the most significant health challenges worldwide. Various techniques, tools and therapeutics/materials have been developed in the last few decades for the treatment of cancer, together with great interest, funding and efforts from the scientific society. However, all the reported studies and efforts seem insufficient to combat the various types of cancer, especially the advanced ones. The overexpression of tyrosine kinases is associated with cancer proliferation and/or metastasis. VEGF, an important category of tyrosine kinases, and its receptors (VEGFR) are hyper-activated in different cancers. Accordingly, they are known as important factors in the angiogenesis of different tumors and are considered in the development of effective therapeutic approaches for controlling many types of cancer. In this case, targeted therapeutic approaches are preferable to the traditional non-selective approaches to minimize the side effects and drawbacks associated with treatment. Several indole-containing compounds have been identified as effective agents against VEGFR. Herein, we present a summary of the recent indolyl analogs reported within the last decade (2012-2023) with potential antineoplastic and VEGFR inhibitory properties. The most important drugs, natural products, synthesized potent compounds and promising hits/leads are highlighted. Indoles functionalized and conjugated with various heterocycles beside spiroindoles are also considered.

Fig. 1. Clinically approved indole-containing drugs (1–7) and cipargamin (8).

Fig. 2. Sunitinib (sutent) 9 multi-targeted tyrosine kinase inhibitor, erlotinib 10 (EGFR inhibitor) and celecoxib 11 (COX-inhibitor).

Fig. 3. Nintedanib 12 (multi-targeted) tyrosine kinase inhibitor, docetaxel 13 and cytarabine 14.

Fig. 4. Inhibitory properties of sunitinib and nintedanib against tyrosine kinases (VEGFR-1, -2, -3; PDGFR-α, -β and FGFR-1, -2, -3, -4).

Fig. 5. Anlotinib 15 (a multi-targeted tyrosine kinase inhibitor), oxaliplatin 16 capecitabine 17.

Fig. 6. Chemical structures of surufatinib 18, SU5416 (semaxanib) 19, vorolanib (CM082) 20, everolimus 21, gefitinib (Iressa) 22, famitinib 23, almonertinib (HS-10296) 24, toceranib (Palladia, Zoetis) 25, S49076 26 and SIM010603 27.

Fig. 7. Natural indole-containing compounds 28–38 with potential bio-properties.

Fig. 8. Chemical structures of vincristine 39, vinblastine 40, vindesine 41, 3-indole acetic acid 42 and 3-indole pyruvic acid 43.

Scheme 1. Synthesis of indole-2-carboxamides 49.

Scheme 2. Synthesis of 5-indolecarboxamides 53.

Scheme 3. Synthesis of indolyl Schiff bases 55, 57–59, 61, 63, 65, 67 and 68.

Scheme 4. Synthesis of indolyl Schiff bases 73.

Scheme 5. Synthesis of indolyl Schiff bases 76.

Scheme 6. Synthesis of mono- 78 and bis-alkylated isatins 79.

Scheme 7. Synthesis of indolyl Schiff bases 82.

Scheme 8. Synthesis of indolyl Schiff bases 83.

Scheme 9. Synthesis of indolyl Schiff bases 88.

Scheme 10. Synthesis of hydrazone derivative 95.

Scheme 11. Synthesis of hydrazones 102.

Fig. 9. Antiproliferation (in μM ± SD) and inhibitory properties against VEGFR-2 (in μM ± SD) of the tested hydrazones 102 and standard references (5-fluorouracil and sorafenib), respectively.

Scheme 12. Synthesis of hydrazones 106.

Scheme 13. Synthesis of indolyl hydrazones 113.

Scheme 14. Synthesis of 2-oxoindolin-3-ylidenes 118.

Scheme 15. Synthesis of 2-oxoindolin-3-ylidenes 121.

Scheme 16. Synthesis of 2-oxoindolin-3-ylidenes 124.

Fig. 10. Antiproliferation and tyrosine kinase (VEGFR-2, c-kir) inhibitory properties of 118a–c, 121a–c and sunitinib.

Scheme 17. Synthesis of 2-oxoindolin-3-ylidenes 130.

Scheme 18. Synthesis of 2-oxoindolin-3-ylidenes 135 and 137.

Fig. 11. Antiproliferation and receptor inhibitory properties of 138 and sunitinib.

Scheme 19. Synthesis of 2-oxoindolin-3-ylidenes 146.

Scheme 20. Synthesis of 2-oxoindolin-3-ylidenes 149, 151 and 153.

Scheme 21. Synthesis of 2-oxoindolin-3-ylidenes 161.

Fig. 12. Antiproliferation and enzymatic inhibitory properties of 161a–e and sunitinib.

Scheme 22. Synthesis of 2-oxoindolin-3-ylidenes 168.

Scheme 23. Synthesis of 2-oxoindolin-3-ylidenes 172 and 173.

Scheme 24. Synthesis of indole triazole conjugates 179 and 181.

Scheme 25. Synthesis of indole triazole conjugates 182–186.

Scheme 26. Synthesis of indole benzimidazole conjugates 191.

Scheme 27. Synthesis of indole benzimidazole conjugates 197.

Scheme 28. Synthesis of indole benzothiazole conjugates 202.

Fig. 13. % Inhibitory properties of VEGFR-2 by indole benzothiazole conjugates 202 at 10 μM.

Fig. 14. Pazopanib VEGFR-2 inhibitor FDA approved for treatment of advanced renal cell cancer and soft tissue sarcoma.

Scheme 29. Synthesis of indole-pyrimidine conjugates 211.

Scheme 30. Synthesis of indole-pyrimidine conjugates 221.

Scheme 31. Synthesis of indole chromene conjugates 225.

Fig. 15. Antiproliferation properties of indole chromene conjugates 225 and doxorubicin (standard reference).

Scheme 32. Synthesis of spiroindoles 230.

Dalia R. Aboshouk

M. Adel Youssef

Mohamed S. Bekheit

Ahmed R. Hamed

Adel S. Girgis