Guanidine platinum(II) complexes: synthesis, in vitro antitumor activity, and DNA interactions.
The novel guanidine compounds trans-[Pt(NH2Me)2{NH=C(NHMe)NR}2](Cl)2 (R=NEt2 [7], NC5H10 [8]) (trans-7,8) were synthesized by the nucleophilic addition of methylamine to dialkylcyanamide ligands of the push-pull nitrile complexes trans-[PtCl2(RCN)2] (R=NEt2, NC5H10). In vitro cytotoxicity tests conducted for the entire series of the guanidine complexes, i.e. trans-7,8, the neutral cis- or trans-[PtCl2{NH=C(NH2)R}2] (cis-1-3 and trans-1-3) and the cationic cis- or trans-[Pt(NH3)2{NH=C(NH2)R}2](Cl)2 (cis-4-6 and trans-4-6) (R=NMe2 [1,4], NEt2 [2,5], NC5H10 [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.
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
Anton A
AA
Legin
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria. Electronic address: michael.jakupec@univie.ac.at.
Michael A
MA
Jakupec
Department of Chemistry, Saint Petersburg State University, Universitetsky Pr. 26, 198504 Stary Petergof, Russian Federation.
Nadezhda A
NA
Bokach
Department of Chemistry, Saint Petersburg State University, Universitetsky Pr. 26, 198504 Stary Petergof, Russian Federation.
Marina R
MR
Tyan
Department of Chemistry, Saint Petersburg State University, Universitetsky Pr. 26, 198504 Stary Petergof, Russian Federation.
Vadim Yu
VY
Kukushkin
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria. Electronic address: bernhard.keppler@univie.ac.at.
Bernhard K
BK
Keppler
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects*; D019791:Guanidine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA; D019791:Guanidine
Anticancer drug; Cellular accumulation; DNA interactions; Guanidine complexes; Structure–activity relationship