title: Synthesis, characterization, and evaluation of cis-diphenyl pyridineamine platinum(II) complexes as potential anti-breast cancer agents.
abstract: Although cisplatin is considered as an effective anti-cancer agent, it has shown limitations and may produce toxicity in patients. Therefore, we synthesized two cis-dichlorideplatinum(II) compounds (13 and 14) composed of meta- and para-N,N-diphenyl pyridineamine ligands through a reaction of the amine precursors and PtCl2 with respective yields of 16 and 47 %. We hypothesized that compounds 13 and 14, with lipophilic ligands, should transport efficiently in cancer cells and demonstrate more effectiveness than cisplatin. When tested for biological activity, compounds 13 and 14 were found to inhibit the growth of MCF 7 and MDA-MB-231 cells (IC50s 1 ± 0.4 µM and 1 ± 0.2 µM for 13 and 14, respectively, and IC50 7.5 ± 1.3 µM for compound 13 and 1 ± 0.3 µM for compound 14). Incidentally, these doses were found to be lower than cisplatin doses (IC50 5 ± 0.7 µM for MCF 7 and 10 ± 1.1 µM for MDA-MB-231). Similar to cisplatin, 13 and 14 interacted with DNA and induced apoptosis. However, unlike cisplatin, they blocked the migration of MDA-MB-231 cells suggesting that in addition to apoptotic and DNA-binding capabilities, these compounds are useful in blocking the metastatic migration of breast cancer cells. To delineate the mechanism of action, computer-aided analyses (DFT calculations) were conducted for compound 13. Results indicate that in vivo, the pyridineamine ligands are likely to dissociate from the complex, forming a platinum DNA adduct with anti-proliferative activity. These results suggest that complexes 13 and 14 hold promise as potential anti-cancer agents.
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Jacqueline Gamboa
authors.initials: JG
authors.lastname: Varela
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Atasi
authors.initials: A
authors.lastname: De Chatterjee
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Guevara
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Verenice
authors.initials: V
authors.lastname: Ramirez
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Metta-Magaña
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Dino
authors.initials: D
authors.lastname: Villagrán
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramirez
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Nuñez
mesh_terms: D000631:Aminopyridines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds
references.citation: Anticancer Res. 2008 Sep-Oct;28(5A):2753-63
references.pmid: 19035306
references.citation: J Neurosci Methods. 1998 Dec 31;86(1):63-9
references.pmid: 9894786
references.citation: Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
references.pmid: 9944570
references.citation: PLoS One. 2013 Sep 09;8(9):e73508
references.pmid: 24039967
references.citation: Curr Opin Chem Biol. 2003 Aug;7(4):481-9
references.pmid: 12941423
references.citation: J Med Chem. 1989 Jan;32(1):128-36
references.pmid: 2909724
references.citation: Inorg Chem. 2002 Apr 22;41(8):2275-81
references.pmid: 11952385
references.citation: Oncology. 1999;57(2):115-20
references.pmid: 10461057
references.citation: Neoplasia. 2006 Jan;8(1):9-17
references.pmid: 16533421
references.citation: Inorg Chem. 2008 May 5;47(9):3474-6
references.pmid: 18380455
references.citation: J Am Chem Soc. 2002 Oct 23;124(42):12412-3
references.pmid: 12381173
references.citation: Acc Chem Res. 2010 Sep 21;43(9):1246-56
references.pmid: 20608673
references.citation: Mol Cell. 1998 Mar;1(4):543-51
references.pmid: 9660938
references.citation: Breast Cancer Res. 2009;11(1):R12
references.pmid: 19239702
references.citation: Folia Histochem Cytobiol. 2009;47(4):647-51
references.pmid: 20430734
references.citation: Inorg Chem. 2004 Jan 26;43(2):725-33
references.pmid: 14731036
references.citation: Angew Chem Int Ed Engl. 2007;46(15):2659-62
references.pmid: 17171742
references.citation: Curr Top Med Chem. 2004;4(15):1537-49
references.pmid: 15579095
references.citation: Chem Rev. 1999 Sep 8;99(9):2451-66
references.pmid: 11749486
references.citation: PLoS One. 2011;6(9):e25196
references.pmid: 21966453
references.citation: Acc Chem Res. 2011 May 17;44(5):349-59
references.pmid: 21446672
references.citation: J Org Chem. 2002 Jan 25;67(2):491-8
references.pmid: 11798322
references.citation: J Am Chem Soc. 2004 Apr 21;126(15):4958-71
references.pmid: 15080702
references.citation: J Am Chem Soc. 2003 Mar 19;125(11):3202-3
references.pmid: 12630861
references.citation: Biochemistry. 2003 May 27;42(20):6321-32
references.pmid: 12755637
references.citation: J Am Chem Soc. 2006 Apr 19;128(15):4962-3
references.pmid: 16608324
references.citation: Macromol Rapid Commun. 2010 May 12;31(9-10):861-7
references.pmid: 21590980
references.citation: Nature. 1978 Nov 30;276(5687):471-4
references.pmid: 723928
references.citation: Nature. 1965 Feb 13;205:698-9
references.pmid: 14287410
references.citation: Mol Cancer Ther. 2011 Sep;10(9):1709-19
references.pmid: 21750216
references.citation: Mol Pharmacol. 2009 Jul;76(1):208-14
references.pmid: 19403702
references.citation: Phys Rev A Gen Phys. 1988 Sep 15;38(6):3098-3100
references.pmid: 9900728
references.citation: Arch Pharm (Weinheim). 2004 Jun;337(6):349-59
references.pmid: 15188224
references.citation: Cell. 1996 Feb 9;84(3):359-69
references.pmid: 8608589
references.citation: Int J Cancer. 2005 Feb 20;113(5):803-10
references.pmid: 15499625
references.citation: Chem Pharm Bull (Tokyo). 1986 Sep;34(9):3563-72
references.pmid: 3815589
references.citation: J Immunol Methods. 1995 Jul 17;184(1):39-51
references.pmid: 7622868
references.citation: Cancers (Basel). 2011 Mar 15;3(1):1351-71
references.pmid: 24212665
references.citation: PLoS One. 2013;8(2):e56735
references.pmid: 23468877
references.citation: Cancer Metastasis Rev. 1992 Sep;11(2):121-39
references.pmid: 1327566
references.citation: Nature. 1969 Apr 26;222(5191):385-6
references.pmid: 5782119
references.citation: Cell. 1992 Apr 3;69(1):11-25
references.pmid: 1555235
references.citation: J Phys Chem A. 2009 Apr 9;113(14):3311-20
references.pmid: 19292436
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):11987-92
references.pmid: 22773807
references.citation: Chem Rev. 2005 Aug;105(8):2999-3093
references.pmid: 16092826
references.citation: Metallomics. 2013 Aug;5(8):1061-7
references.pmid: 23784536
references.citation: Immunol Lett. 1998 Jun;62(2):81-6
references.pmid: 9698102
references.citation: Arch Pharm (Weinheim). 2004 Jun;337(6):335-48
references.pmid: 15188223
references.citation: Cytometry. 1998 Jan 1;31(1):1-9
references.pmid: 9450519
references.citation: J Med Chem. 2008 Dec 11;51(23):7574-80
references.pmid: 19012390
references.citation: J Med Chem. 2012 Jun 14;55(11):5326-36
references.pmid: 22606945