title: Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Kartik W
authors.initials: KW
authors.lastname: Temburnikar
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Ross
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Wilson
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cawrse
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: kseley@umbc.edu.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Seley-Radtke
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D054879:Halogenation; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine
keywords: Apoptosis; Cell cycle arrest; Cytostatic; Heterocyclic chemistry; Thieno[3,2-d]pyrimidine