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

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

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

Fingerprint

Paclitaxel
Tubulin
Microtubules
discodermolide
Excipients
Bioactivity
Drug Resistance
Refractory materials
Conformations
Neoplasms
Cells
Ligands
Cell Line
Molecules
Pharmaceutical Preparations

ASJC Scopus subject areas

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

Cite this

Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners. / Nadaradjane, Celine; Yang, Chia-Ping H.; Rodriguez-Gabin, Alicia; Ye, Qian K.; Sugasawa, Keizo; Atasoylu, Onur; Smith, Amos B.; Band Horwitz, Susan; McDaid, Hayley M.

In: Journal of Natural Products, Vol. 81, No. 3, 23.03.2018, p. 607-615.

Research output: Contribution to journalArticle

Nadaradjane, Celine ; Yang, Chia-Ping H. ; Rodriguez-Gabin, Alicia ; Ye, Qian K. ; Sugasawa, Keizo ; Atasoylu, Onur ; Smith, Amos B. ; Band Horwitz, Susan ; McDaid, Hayley M. / Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners. In: Journal of Natural Products. 2018 ; Vol. 81, No. 3. pp. 607-615.
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