Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018-2021)

Abstract

Cancer, which is the uncontrolled growth of cells, is the second leading cause of death after heart disease. Targeting drugs, especially to specific genes and proteins involved in growth and survival of cancer cells, is the prime need of research world-wide. Indole moiety, which is a combination of aromatic-heterocyclic compounds, is a constructive scaffold for the development of novel leads. Owing to its bioavailability, high unique chemical properties and significant pharmacological behaviours, indole is considered as the most inquisitive scaffold for anticancer drug research. This is illustrated by the fact that the U.S. Food and Drug Administration (FDA) has recently approved several indole-based anticancer agents such as panobinostat, alectinib, sunitinib, osimertinib, anlotinib and nintedanib for clinical use. Furthermore, hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years. Taking into account the facts stated above, we have presented the most recent advances in medicinal chemistry of indole derivatives, encompassing hot articles published between 2018 and 2021 in anticancer drug research. The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act via various targets such as topoisomerase, tubulin, apoptosis, aromatase, kinases, etc., have been discussed. This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018-2021. The review also covers the synthesis, structure‒activity relationship, and mechanism by which these leads have demonstrated improved and promising anticancer activity. Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form, along with their mechanism of action. The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.

Keywords: Anticancer; Apoptosis; Aromatase inhibitors; Indole; Structure‒activity relationship; Synthesis; Topoisomerase; Tubulin inhibitors.

Graphical abstract

Figure 1

Synthetic diagram for synthesis of indole derivatives by new green chemical methods.

Figure 2

Design and development of indole based combretastatin and isocombretastatin derivatives.

Figure 3

Chemical structures and SAR of trimethoxy phenyl-based indole derivatives 1–9.

Figure 4

Chemical structure and SAR of indole linked aryl hetero derivatives 10–14.

Figure 5

Phenastatin based indole derivatives 15 and 16.

Figure 6

Design and structures of cyclic bridge analogues 17–21.

Figure 7

Chemical structures and SAR of miscellaneous derivatives 22–28.

Figure 8

Chemical structure and SAR of indole-based topoisomerase inhibitors 29–38.

Figure 9

Chemical structures and SAR of indole-based apoptosis inducers 39–46.

Figure 10

Chemical structures and SAR of aryl sulphonamide-based indole derivatives 47–49.

Figure 11

Chemical structures and SAR of indole-based kinase inhibitors 50–58.

Figure 12

Chemical structures and SAR of indole drugs acting on miscellaneous targets 59–64.

Figure 13

Mechanistic pathways depicting the anticancer mechanism of indole drugs under clinical trial. Protein kinases enzymes driven by tyrosine and serine-threonine kinases phosphorylate protein and modulate various cellular functions by activating various signalling pathways. Ligand (growth factors) binding induces the activation of PI3K through the generation of PIP3 in the membrane. It induces the central signalling chain resulting in cell growth, proliferation and angiogenesis. PI3-Kinase related protein kinases-ATM, ATR, and DNA-PKc act via its downstream targets to induce cell cycle arrest and promote DNA repair. All protein kinase inhibitors drugs act as anticancer agents by blocking tyrosine kinase, EGFR, VEGFR, ATM, ATR, etc., thereby inhibiting cell proliferation and DNA repair. Apoptosis inducers promote apoptosis by a number of methods, including DNA cross-linking and antiapoptotic protein inhibition (Bcl-2, Mcl-1, Bcl-x) and activation of caspases (P53). Apoptosis inducers enhance apoptotic cell death by acting on numerous apoptosis-related proteins. Tubulin inhibitors act by destabilizing microtubule assembly by binding to tubulin binding sites during spindle formation thereby inhibiting cell proliferation and growth. Inhibiting aromatase enzymes and epigenetic regulators (HDAC and EZH2) are other mechanism by which indole derivatives are acting as anticancer agents.