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Structure–activity relationships in platinum–acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity

  • Margaret C. Ackley
  • Colin G. Barry
  • Amanda M. Mounce
  • Michael C. Farmer
  • Beth-Erin Springer
  • Cynthia S. Day
  • Marcus W. Wright
  • Susan J. Berners-Price
  • Suzanne M. Hess
  • Ulrich BierbachEmail author
Original Article

Abstract

The synthesis, cytotoxicity, and nucleoside binding of some platinum–acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)2 {”PT-ACRAMTU”; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form} are reported. To establish structure–activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU·MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (1H NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.

Keywords

Acridine Cytotoxicity DNA targeted Platinum Steric hindrance 

Abbreviations

ACRAMTU

1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea

Boc

t-butyl carbamate

dGuo

2′-deoxyguanosine

dien

N 1-(2-aminoethyl)ethane-1,2-diamine

en

ethane-1,2-diamine

HEPES

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

PT-ACRAMTU

[PtCl(en)(ACRAMTU)](NO3)2

TSP

3-(trimethylsilyl)propionate, sodium salt

Notes

Acknowledgements

This work was supported by a Research Project Grant from the National Institutes of Health, R01 CA101880 (to U.B.). We thank Dr Junyong Zhang and Dr Lindsay Byrne (UWA) for their assistance with the NMR experiments. M.C.F. gratefully acknowledges support from the Richter International Fellowship program. We also thank Johnson Matthey PLC (Reading, UK) for a generous gift of potassium tetrachloroplatinate.

Supplementary material

Figure S1–S6

supp1.pdf (89 kb)
(PDF 90 KB)

Table S1–S6

supp2.pdf (72 kb)
(PDF 73 KB)

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Copyright information

© SBIC 2004

Authors and Affiliations

  • Margaret C. Ackley
    • 1
  • Colin G. Barry
    • 1
  • Amanda M. Mounce
    • 2
  • Michael C. Farmer
    • 1
    • 3
  • Beth-Erin Springer
    • 1
  • Cynthia S. Day
    • 1
  • Marcus W. Wright
    • 1
  • Susan J. Berners-Price
    • 3
  • Suzanne M. Hess
    • 2
  • Ulrich Bierbach
    • 1
    Email author
  1. 1.Department of ChemistryWake Forest UniversityWinston-SalemUSA
  2. 2.Department of Radiation OncologyWake Forest University School of MedicineWinston-SalemUSA
  3. 3.School of Biomedical and Chemical SciencesThe University of Western AustraliaPerthAustralia

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