New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation.
Molecules
; 25(2)2020 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-31952332
ABSTRACT
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 ß-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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Prostatic Neoplasms
/
Drug Design
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Macrolides
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Drug Resistance, Neoplasm
/
Biomimetics
/
Cell Proliferation
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Antineoplastic Agents
Limits:
Humans
/
Male
Language:
En
Year:
2020
Type:
Article