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Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners

Author:
Nadaradjane, Celine, Yang, Chia-Ping Huang, Rodriguez-Gabin, Alicia, Ye, Kenny, Sugasawa, Keizo, Atasoylu, Onur, Smith, Amos B., Horwitz, Susan Band, McDaid, Hayley M.
Source:
Journal of natural products 2018 v.81 no.3 pp. 607-615
ISSN:
1520-6025
Subject:
bioactive properties, cell lines, dose response, drug resistance, flow cytometry, median effective concentration, microtubules, models, moieties, neoplasm cells, neoplasms, paclitaxel, prediction, transcription (genetics), tubulin
Abstract:
(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMₐₓ increased without concomitant improvements in EC₅₀ such that overall dose-response profiles resembled that of (+)-discodermolide.
Agid:
6043160