TY - JOUR
T1 - Guanidine platinum(II) complexes
T2 - synthesis, in vitro antitumor activity, and DNA interactions*
AU - Legin, Anton A.
AU - Jakupec, Michael A.
AU - Bokach, Nadezhda A.
AU - Tyan, Marina R.
AU - Kukushkin, Vadim Yu.
AU - Keppler, Bernhard K.
N1 - Funding Information:
The authors are indebted to the Austrian Science Fund (FWF ; project no. L567 ) and the Russian Fund for Basic Research (grant 12-03-33071 ) for the financial support. The authors also acknowledge Saint Petersburg State University for a research grant (2012–2013, 12.39.1050.2012).
PY - 2014/4
Y1 - 2014/4
N2 - The novel guanidine compounds trans-[Pt(NH
2Me)
2{NH=C(NHMe)NR}
2](Cl)
2 (R = NEt
2 [7], NC
5H
10 [8]) (trans-7,8) were synthesized by the nucleophilic addition of methylamine to dialkylcyanamide ligands of the push-pull nitrile complexes trans-[PtCl
2(RCN)
2] (R = NEt
2, NC
5H
10). In vitro cytotoxicity tests conducted for the entire series of the guanidine complexes, i.e. trans-7,8, the neutral cis- or trans-[PtCl
2{NH=C(NH
2)R}
2] (cis-1-3 and trans-1-3) and the cationic cis- or trans-[Pt(NH
3)
2{NH=C(NH
2)R}
2](Cl)
2 (cis-4-6 and trans-4-6) (R = NMe
2 [1,4], NEt
2 [2,5], NC
5H
10 [3,6]) in two human cancer cell lines, CH1 (ovarian carcinoma) and SW480 (colon cancer), confirmed that the cytotoxicity of several trans-configured (trans-3,6) complexes is higher than that of cis-congeners (cis-3,6). Cellular platinum levels were analyzed by inductively coupled plasma mass spectrometry upon treatment of SW480 cells, revealing a dependence of cellular accumulation on the geometrical isomerism and the steric hindrance of the variable substituent R on the guanidine ligand. DNA interactions of selected guanidine complexes were studied in order to find hints for the possible reasons for their different activities. Changes induced to the electrophoretic mobility of a dsDNA plasmid confirmed the potency of the guanidine complexes (e.g. trans-1,3,5,6 and cis-1,3,4) to significantly alter DNA secondary structure, indicating DNA as a possible critical target of these compounds.
AB - The novel guanidine compounds trans-[Pt(NH
2Me)
2{NH=C(NHMe)NR}
2](Cl)
2 (R = NEt
2 [7], NC
5H
10 [8]) (trans-7,8) were synthesized by the nucleophilic addition of methylamine to dialkylcyanamide ligands of the push-pull nitrile complexes trans-[PtCl
2(RCN)
2] (R = NEt
2, NC
5H
10). In vitro cytotoxicity tests conducted for the entire series of the guanidine complexes, i.e. trans-7,8, the neutral cis- or trans-[PtCl
2{NH=C(NH
2)R}
2] (cis-1-3 and trans-1-3) and the cationic cis- or trans-[Pt(NH
3)
2{NH=C(NH
2)R}
2](Cl)
2 (cis-4-6 and trans-4-6) (R = NMe
2 [1,4], NEt
2 [2,5], NC
5H
10 [3,6]) in two human cancer cell lines, CH1 (ovarian carcinoma) and SW480 (colon cancer), confirmed that the cytotoxicity of several trans-configured (trans-3,6) complexes is higher than that of cis-congeners (cis-3,6). Cellular platinum levels were analyzed by inductively coupled plasma mass spectrometry upon treatment of SW480 cells, revealing a dependence of cellular accumulation on the geometrical isomerism and the steric hindrance of the variable substituent R on the guanidine ligand. DNA interactions of selected guanidine complexes were studied in order to find hints for the possible reasons for their different activities. Changes induced to the electrophoretic mobility of a dsDNA plasmid confirmed the potency of the guanidine complexes (e.g. trans-1,3,5,6 and cis-1,3,4) to significantly alter DNA secondary structure, indicating DNA as a possible critical target of these compounds.
KW - Anticancer drug
KW - Guanidine complexes
KW - Cellular accumulation
KW - DNA interactions
KW - Structure-activity relationship
KW - BIOLOGICAL-ACTIVITY
KW - CYTOTOXIC ACTIVITY
KW - LIGANDS
KW - TRANS-PLATINUM(II)
KW - CONFIGURATION
KW - CHEMOTHERAPY
UR - http://www.scopus.com/inward/record.url?scp=84892749622&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2013.12.007
DO - 10.1016/j.jinorgbio.2013.12.007
M3 - Article
VL - 133
SP - 33
EP - 39
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
SN - 0162-0134
ER -
