title: Cytotoxic malonate platinum(II) complexes with 1,2,4-triazolo[1,5-a]pyrimidine derivatives: structural characterization and mechanism of the suppression of tumor cell growth.
abstract: A series of malonate (mal) platinum(II) complexes of the general formula [Pt(mal)(L)2], where L=5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) (1), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) (2) or 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) (3), has been prepared and characterized using multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR, IR and electrospray ionization mass spectrometry (ESIMS). Furthermore, the crystal structures of [Pt(mal)(dmtp)2]∙4H2O (1a) and [Pt(mal)(dbtp)2]∙CHCl3 (3a) have been determined using single-crystal X-ray diffraction. The spectroscopic characterization unambiguously confirmed the square-planar geometry of Pt(II) with two monodentate N3-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines and one O-chelating malonate. The antiproliferative activities of the compounds against the human cell lines T47D (cisplatin-resistant human ductal breast epithelial tumor cell line) and A549 (lung adenocarcinoma epithelial cell line) and the mouse cell line 4T1 (mouse breast tumor model) were assessed using an in vitro screening assay. Compounds (2) and (3) exhibited substantial antigrowth properties against T47D cells, whereas only (3) exhibited an IC50 value that was lower than cisplatin and carboplatin against the 4T1 cell line. Additionally, compounds (2, 3) are capable of arresting the cell cycle of A549 cells at the G0/G1 phase, whereas cisplatin and carboplatin arrested the cells at the G2/M phase, indicating differences in the mechanism of the suppression of tumor cell growth. Finally, in the quest for low toxicity platinum drugs, the in vitro antiproliferative activity against normal mouse fibroblast cells (BALB/3T3) was evaluated. The inhibition of BALB/3T3 cell proliferation by the evaluated Pt(II) complexes increased in the order (1)<(2)<<carboplatin<<(3)<cisplatin.
authors.affiliation: Bioinorganic Chemistry Research Group, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland. Electronic address: iwolak@chem.umk.pl.
authors.forename: Iwona
authors.initials: I
authors.lastname: Łakomska
authors.affiliation: Bioinorganic Chemistry Research Group, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Department of Crystallochemistry and Biocrystallography, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wojtczak
authors.affiliation: National Institute of Medicines, Chełmska 30/34, 00-725 Warszawa, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Sitkowski
authors.affiliation: Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Maj
authors.affiliation: Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wietrzyk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008314:Malonates / Q000737:chemistry*; D051379:Mice; D041681:NIH 3T3 Cells; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003603:Cytotoxins; D008314:Malonates; D009944:Organoplatinum Compounds; D011743:Pyrimidines; D014230:Triazoles; C030290:malonic acid; D002945:Cisplatin
keywords: (15)N NMR; Cell cycle; Platinum(II) complexes; X-ray diffraction; n vitro cytotoxicity