2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance

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

  • ACS Med Chem Lett. 2023 Sep 8;14(10):1369-1377. doi: 10.1021/acsmedchemlett.3c00258.
Farhat Firdous 1 2,  Sharon Riaz 1,  Muhammad Furqan 2,  Salman Fozail 2,  Khushboo Fatima 2,  Sebastian Öther-Gee Pohl 3,  Nora Julia Doleschall 3,  Kevin B Myant 3,  Jordan Kahfi 4,  Abdul-Hamid Emwas 5,  Mariusz Jaremko 4,  Ghayoor Abbas Chotana 1,  Rahman Shah Zaib Saleem 1,  Amir Faisal 2
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
  • 2 Department of Life Sciences, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
  • 3 Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Crewe Road, Edinburgh EH4 2XU, Scotland.
  • 4 Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
  • 5 KAUST Core Laboratories, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia.
PMID: 37849542 DOI: 10.1021/acsmedchemlett.3c00258
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.

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