# Synthesis, Biological Evaluation, and Theoretical Study of Indenoquinolinylphosphine Oxide Derivatives as Topoisomerase 1 Inhibitors and Antiproliferative Agents

## TL;DR

This paper reports the synthesis and testing of new phosphine oxide compounds that inhibit topoisomerase 1 and show selective anticancer activity.

## Contribution

The study introduces novel indenoquinolinylphosphine oxide derivatives with promising TOP1 inhibition and selective antiproliferative effects.

## Key findings

- Some synthesized derivatives (9f, 9g, 9l, and 11m) showed better or similar TOP1 inhibition compared to the reference compound CPT.
- The compounds exhibited higher cytotoxicity in human lung adenocarcinoma cells (A549) than in other cancer cell lines.
- Phosphine oxide-substituted quinoline derivatives show potential as selective anticancer agents with minimal toxicity to nonmalignant cells.

## Abstract

The topoisomerase 1 (TOP1) enzymatic inhibition and antiproliferative activity of phosphorated indenoquinoline derivatives were investigated. First, the preparation of new hybrid quinoline and tetrahydroquinoline structures with a phosphine oxide group was performed by a two‐step Povarov type [4 + 2]‐cycloaddition reaction between the corresponding phosphorated aldimines with indene in the presence of BF3·Et2O, affording corresponding 1,2,3,4‐tetrahydroindeno[2,1‐c]quinolinylphosphine oxides 9, 7H‐indeno[2,1‐c]quinolinylphosphine oxides 10 and 7‐oxoindeno[2,1‐c]quinolinylphosphine oxides 11 with good yields. The synthesized derivatives were evaluated as TOP1 inhibitors, showing that some derivatives (9f, 9g, 9l, and 11m) show better or similar activity to the reference compound (CPT) at 1 min. The synthesized derivatives were screened for their antiproliferative activity in different cancerous cell lines, and all of them present a higher selective cytotoxicity in the human lung adenocarcinoma cell line (A549), than in the others. In contrast, almost none of the synthesized phosphorated compounds exhibited antiproliferative activity toward nonmalignant lung fibroblasts MCR5. These results suggest that phosphine oxide‐substituted quinoline derivatives have important properties as TOP1 inhibitors and show an interesting cytotoxicity against six different cancerous cell lines.

The topoisomerase I inhibition and antiproliferative activities of phosphorated indenoquinoline derivatives were investigated. The target hybrid quinoline and tetrahydroquinoline compounds were synthesized via a two‐step Povarov‐type cycloaddition. Biological evaluation antiproliferative assays across multiple cancer cell lines, ADME and docking studies concluded that phosphine oxide–substituted indenoquinolines could be a promising topoisomerase 1 inhibitors with selective anticancer potential.© 2026 WILEY‐VCH GmbH