Design, synthesis, and metabolite identification of Tamoxifen esterase-activatable prodrugs

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Rahma M. Elbagoury - , German University in Cairo (Author)
  • Miriam A. Shenouda - , German University in Cairo (Author)
  • Heba E. Elnakib - , German University in Cairo (Author)
  • Jannette Wober - , Chair of Didactics of Biology (Author)
  • Ashraf H. Abadi - , German University in Cairo (Author)
  • Nermin S. Ahmed - , German University in Cairo (Author)

Abstract

Tamoxifen (TAM) is used in treatment of hormonal dependent breast cancer, both in premenopausal and postmenopausal women. TAM is intrinsically metabolized by CYP450 enzymes to more active metabolites. Recent reports identified CYP2D6, an enzyme involved in the conversion of TAM to the more potent 4-OH-TAM, is encoded by the CYP2D6 gene, which is highly polymorphic. Women with inactive alleles are poor metabolizers; in many cases they suffer acquired TAM resistance. Herein we report synthesis and biological evaluation of novel TAM analogues. The novel analogues are designed to elude CYP2D6 metabolism. Hydrolysis of the carbamate moiety on ring C is mediated via carboxylesterases. Compound 3d [E/Z Benzyl-carbamic acid4-{2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-but-1-enyl}-phenyl ester] showed GI50 = 0.09 µM on MCF-7 and GI50 = 1.84 µM on MDA-MB231 cell lines. To further validate our hypothesis, metabolites of selected novel analogues were determined in vitro under different incubation conditions. The hydroxylated analogues were obtained under non CYP2D6 dependent conditions. Compound 8d, a benzyl carbamate derivative, was the least-stable analog and showed the highest rate of metabolism among all tested analogues. Our in silico model showed the novel flexible analogues can still adopt an antiestrogenic binding profile occupying the same pocket as 4-OH-TAM.

Details

Original languageEnglish
Article number106303
Number of pages11
JournalBioorganic Chemistry
Volume131
Publication statusPublished - Feb 2023
Peer-reviewedYes

External IDs

PubMed 36455483
unpaywall 10.1016/j.bioorg.2022.106303
WOS 000961226600003
ORCID /0000-0001-5397-7972/work/142245272

Keywords

Subject groups, research areas, subject areas according to Destatis

Sustainable Development Goals

Keywords

  • CYP2D6, Flexible, MCF-7, Poor metabolizers, Supersomes, Tamoxifen, Humans, Esterases, Prodrugs/pharmacology, Cytochrome P-450 CYP2D6/metabolism, Estrogen Antagonists, Female, Tamoxifen/pharmacology, Breast Neoplasms/drug therapy, Mcf-7