TY - JOUR
T1 - Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners
AU - Nadaradjane, Celine
AU - Yang, Chia Ping Huang
AU - Rodriguez-Gabin, Alicia
AU - Ye, Kenny
AU - Sugasawa, Keizo
AU - Atasoylu, Onur
AU - Smith, Amos B.
AU - Horwitz, Susan Band
AU - McDaid, Hayley M.
N1 - Publisher Copyright:
© 2018 American Chemical Society and American Society of Pharmacognosy.
PY - 2018/3/23
Y1 - 2018/3/23
N2 - (+)-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, E Max increased without concomitant improvements in EC 50 such that overall dose-response profiles resembled that of (+)-discodermolide.
AB - (+)-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, E Max increased without concomitant improvements in EC 50 such that overall dose-response profiles resembled that of (+)-discodermolide.
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U2 - 10.1021/acs.jnatprod.8b00111
DO - 10.1021/acs.jnatprod.8b00111
M3 - Article
C2 - 29522336
AN - SCOPUS:85044411228
SN - 0163-3864
VL - 81
SP - 607
EP - 615
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 3
ER -