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

Celine Nadaradjane, Chia Ping Huang Yang, Alicia Rodriguez-Gabin, Kenny Ye, Keizo Sugasawa, Onur Atasoylu, Amos B. Smith, Susan Band Horwitz, Hayley M. McDaid

Research output: Contribution to journalArticle

2 Scopus citations

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, E Max increased without concomitant improvements in EC 50 such that overall dose-response profiles resembled that of (+)-discodermolide.

Original languageEnglish (US)
Pages (from-to)607-615
Number of pages9
JournalJournal of Natural Products
Volume81
Issue number3
DOIs
StatePublished - Mar 23 2018

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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