Effect of substituents at the C3´, C3´N, C10 and C2-meta-benzoate positions of taxane derivatives on their activity against resistant cancer cells

Toxicol Appl Pharmacol. 2024 Aug:489:116993. doi: 10.1016/j.taap.2024.116993. Epub 2024 Jun 12.

Abstract

We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.

Keywords: C10 taxane derivatives; C2 taxane derivatives; C3´ and C3´N taxane derivatives; Resistant breast cancer cells; Resistant ovarian cancer cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B* / genetics
  • ATP Binding Cassette Transporter, Subfamily B* / metabolism
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzoates / chemistry
  • Benzoates / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Female
  • Humans
  • MCF-7 Cells
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology
  • Structure-Activity Relationship
  • Taxoids / chemistry
  • Taxoids / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ABCB1 protein, human
  • Taxoids
  • Paclitaxel
  • Antineoplastic Agents
  • Benzoates