Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

Kartik Temburnikar, Christina R. Ross, Gerald M. Wilson, Jan Balzarini, Brian M. Cawrse, Katherine L. Seley-Radtke

Research output: Contribution to journalArticle

Abstract

In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concentrations. Introduction of iodine at C7 resulted in significant enhancement of potency by reducing the IC50 into sub-micromolar levels, thereby suggesting the importance of a halogen at C7. This finding was further supported by an increased antiproliferative effect for 4 as compared to 3. Cell-cycle and apoptosis studies conducted on the two potent compounds 1 and 2 showed differences in their cytotoxic mechanisms in triple negative breast cancer MDA-MB-231 cells, wherein compound 1 induced cells to accumulate at the G2/M stage with little evidence of apoptotic death. In contrast, compound 2 robustly induced apoptosis with concomitant G2/M cell cycle arrest in this cell model.

Original languageEnglish (US)
Pages (from-to)4354-4363
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number15
DOIs
StatePublished - Jul 23 2015
Externally publishedYes

Fingerprint

Pyrimidines
Cells
G2 Phase Cell Cycle Checkpoints
Triple Negative Breast Neoplasms
Apoptosis
Halogens
Iodine
Inhibitory Concentration 50
Cell Cycle
Screening
Cell Line
Neoplasms

Keywords

  • Apoptosis
  • Cell cycle arrest
  • Cytostatic
  • Heterocyclic chemistry
  • Thieno[3,2-d]pyrimidine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Temburnikar, K., Ross, C. R., Wilson, G. M., Balzarini, J., Cawrse, B. M., & Seley-Radtke, K. L. (2015). Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines. Bioorganic and Medicinal Chemistry, 23(15), 4354-4363. https://doi.org/10.1016/j.bmc.2015.06.025

Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines. / Temburnikar, Kartik; Ross, Christina R.; Wilson, Gerald M.; Balzarini, Jan; Cawrse, Brian M.; Seley-Radtke, Katherine L.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 15, 23.07.2015, p. 4354-4363.

Research output: Contribution to journalArticle

Temburnikar, K, Ross, CR, Wilson, GM, Balzarini, J, Cawrse, BM & Seley-Radtke, KL 2015, 'Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines', Bioorganic and Medicinal Chemistry, vol. 23, no. 15, pp. 4354-4363. https://doi.org/10.1016/j.bmc.2015.06.025
Temburnikar, Kartik ; Ross, Christina R. ; Wilson, Gerald M. ; Balzarini, Jan ; Cawrse, Brian M. ; Seley-Radtke, Katherine L. / Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 15. pp. 4354-4363.
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