Sustainable Synthesis of Indole-Based Heterocycles as Anticancer Agents via Green Nanocatalysis

Abstract

Indole is an extremely privileged N-heterocycle which is the structural framework of many clinically active anticancer drugs. Alternate methods for the construction of indole-based heterocycles, on the other hand, are heavily dependent on toxic solvents, stoichiometric reagents, and energy-intensive reaction conditions, which are not desirable according to sustainable chemistry principles. The application of biosynthesized or engineered nanocatalytic materials obtained from renewable and environmentally friendly precursors (green nanocatalysis) is a promising approach to achieve a balance between synthetic efficiency and environmental friendliness. A recent literature survey (2023-2026) of the design, characterization and catalytic applications of various types of metal, metal-oxide and magnetically recoverable nanocatalysts for the synthesis of indole-containing heterocyclic scaffolds has been undertaken, along with a study of the anticancer activity of the resulting compounds on representative cell lines (MCF-7, HeLa, A549, MDA-MB-231 and others). Special focus is given to green chemistry indicators (atom economy, E-factor, recyclability of the catalysts), nanocatalyzed multicomponent reactions for indole derivatives, and the main molecular mechanisms (tubulin destabilization, inhibition of kinases and topoisomerases, interaction with DNA/HDAC, mitochondrial apoptosis) contributing to the cytotoxic effect of these molecules. The representative synthetic protocols of the ZnO, CuO, Fe3O4, Ag and Au nanocatalysts are compared in terms of yield, reaction time and reusability, while recent in vitro and in silico anticancer data are tabulated and graphically summarized. The review shows that, to date, green nanocatalysis provides a platform that is scaled-up and low-waste for anticancer drug discovery, and that standardization, toxicological profiling and scale-up to the clinic are the major challenges that are yet to be overcome..