Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance

Farhat Firdous, Sharon Riaz, Muhammad Furqan, Salman Fozail, Khushboo Fatima, Sebastian Öther Gee Pohl, Nora Julia Doleschall, Kevin B. Myant, Jordan Kahfi, Abdul Hamid Emwas, Mariusz Jaremko, Ghayoor Abbas Chotana, Rahman Shah Zaib Saleem*, Amir Faisal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Microtubules are dynamic structures that form spindle fibers during cell division; pharmacological inhibition of microtubule dynamics arrests cells in mitosis, leading to apoptosis, and they have been extensively used to treat various cancers. However, the efficacy of such drugs is often limited by multidrug resistance. This study synthesized and evaluated 30 novel derivatives of podophyllotoxin, a natural antimitotic compound, for their antiproliferative activities. Compound SSE1806 exhibited the most potent antiproliferative activity with GI50 values ranging from 1.29 ± 0.01 to 21.15 ± 2.1 μM in cancer cell lines of different origins; it directly inhibited microtubule polymerization, causing aberrant mitosis and G2/M arrest. Prolonged treatment with SSE1806 increased p53 expression, induced cell death in monolayer cultures, and reduced the growth of mouse- and patient-derived human colon cancer organoids. Importantly, SSE1806 overcame multidrug resistance in a cell line overexpressing MDR-1. Thus, SSE1806 represents a potential anticancer agent that can overcome multidrug resistance.

Original languageEnglish (US)
Pages (from-to)1369-1377
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume14
Issue number10
DOIs
StatePublished - Oct 12 2023

Keywords

  • Apoptosis
  • Cell cycle arrest
  • Microtubule assembly
  • Multidrug resistance
  • Podophyllotoxin
  • Tubulin polymerization

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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