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 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.
Highlights
Prostate cancer is still one of the big health concerns, as evidenced by its high incidence and mortality rate in American men
As part of our ongoing project to develop simplified and stabilized zampanolide mimics, this paper presents the design, total synthesis, and antiproliferative evaluation of zampanolide mimics in which the N-acyl hemiaminal side chain is substituted by more stable 2-fluorobenzyl alcohol appendages
The binding conformation confirmed by the high-resolution crystal structure of zampanolide tubulin complex [22] indicates the hydroxyl group at the C20 position in zampanolide is hydrogen-bonded to the carbonyl oxygen of Thr276 in β-tubulin
Summary
Prostate cancer is still one of the big health concerns, as evidenced by its high incidence and mortality rate in American men. Prostate cancer is driven by the androgen receptor (AR)-regulated gene expression that is initiated by the binding of androgen to the AR [2]. Androgen deprivation therapy (ADT) has been the main treatment for prostate cancer over 70 years. The median duration of ADT response is merely 18–24 months due to inevitable progression to castration-resistant prostate cancer (CRPC) [3]. Approximately 30,000 prostate cancer deaths in the United State each year are caused by CRPC as well as resistance to the current treatments. The current first-line and second-line chemotherapeutics for CRPC are two microtubule-stabilizing cytotoxic agents (MSA), docetaxel and cabazitaxel [6,7,8]. Promotion of mitotic arrest is the initially well-established mechanism underlying the action of MSAs as anticancer agents [9].
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