New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation
1
Department of Chemistry, California State University, Fresno, CA 93740, USA
2
Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(2), 362; https://doi.org/10.3390/molecules25020362
Received: 26 December 2019 / Revised: 9 January 2020 / Accepted: 14 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)
Zampanolide is a promising microtubule-stabilizing agent (MSA) with a unique chemical structure. It is superior to the current clinically used MSAs due to the covalent nature of its binding to β-tubulin and high cytotoxic potency toward multidrug-resistant cancer cells. However, its further development as a viable drug candidate is hindered by its limited availability. More importantly, conversion of its chemically fragile side chain into a stabilized bioisostere is envisioned to enable zampanolide to possess more drug-like properties. As part of our ongoing project aiming to develop its mimics with a stable side chain using straightforward synthetic approaches, 2-fluorobenzyl alcohol was designed as a bioisosteric surrogate for the side chain based on its binding conformation as confirmed by the X-ray structure of tubulin complexed with zampanolide. Two new zampanolide mimics with the newly designed side chain have been successfully synthesized through a 25-step chemical transformation for each. Yamaguchi esterification and intramolecular Horner–Wadsworth–Emmons condensation were used as key reactions to construct the lactone core. The chiral centers at C17 and C18 were introduced by the Sharpless asymmetric dihydroxylation. Our WST-1 cell proliferation assay data in both docetaxel-resistant and docetaxel-naive prostate cancer cell lines revealed that compound 6 is the optimal mimic and the newly designed side chain can serve as a bioisostere for the chemically fragile N-acetyl hemiaminal side chain in zampanolide.
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Keywords:
natural product; anticancer agent; synthesis; zampanolide
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MDPI and ACS Style
Chen, G.; Jiang, Z.; Zhang, Q.; Wang, G.; Chen, Q.-H. New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation. Molecules 2020, 25, 362. https://doi.org/10.3390/molecules25020362
AMA Style
Chen G, Jiang Z, Zhang Q, Wang G, Chen Q-H. New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation. Molecules. 2020; 25(2):362. https://doi.org/10.3390/molecules25020362
Chicago/Turabian StyleChen, Guanglin; Jiang, Ziran; Zhang, Qiang; Wang, Guangdi; Chen, Qiao-Hong. 2020. "New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation" Molecules 25, no. 2: 362. https://doi.org/10.3390/molecules25020362
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