TY - JOUR
T1 - Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance
AU - Firdous, Farhat
AU - Riaz, Sharon
AU - Furqan, Muhammad
AU - Fozail, Salman
AU - Fatima, Khushboo
AU - Pohl, Sebastian Öther Gee
AU - Doleschall, Nora Julia
AU - Myant, Kevin B.
AU - Kahfi, Jordan
AU - Emwas, Abdul Hamid
AU - Jaremko, Mariusz
AU - Chotana, Ghayoor Abbas
AU - Saleem, Rahman Shah Zaib
AU - Faisal, Amir
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/10/12
Y1 - 2023/10/12
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cell cycle arrest
KW - Microtubule assembly
KW - Multidrug resistance
KW - Podophyllotoxin
KW - Tubulin polymerization
UR - http://www.scopus.com/inward/record.url?scp=85172863170&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.3c00258
DO - 10.1021/acsmedchemlett.3c00258
M3 - Article
C2 - 37849542
AN - SCOPUS:85172863170
SN - 1948-5875
VL - 14
SP - 1369
EP - 1377
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 10
ER -
