Mono- and polynuclear [alkylamine]platinum(II) complexes of [1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II): synthesis and investigations on cytotoxicity, cellular distribution, and DNA and protein binding.
A series of mononuclear and dinuclear alkylamine derivatives of [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (m-4F-PtL-R1 and (m-4F-PtL)2-R2; R(1) = alkylamine, R(2) = alkyldiamine, L = DMSO or Cl) as well as the DAB(PA)(4) polyimine dendrimer complex ((m-4F-PtDMSO)4DAB(PA)4; DAB(PA)4 = N,N,N',N'-tetrakis(3-aminopropyl)butane-1,4-diamine) were synthesized and tested for cytotoxicity, intracellular distribution, and DNA and protein binding. All compounds strongly bound to human serum albumin by hydrophobic and electrostatic interactions. These inactivation reactions hindered the uptake into tumor cells and prevented strong cytotoxic effects. If serum-free medium was used, a high accumulation grade in MCF-7 breast cancer cells and a high DNA binding was observed. As most efficient compound (m-4F-PtDMSO)4DAB(PA)4 was identified. It showed a 20-fold higher cellular uptake and an approximately 700-fold higher DNA binding than cisplatin.
Kapp
Timo
T
Institute of Pharmacy, Free University of Berlin, Königin Luise Strasse 2+4, 14195 Berlin, Germany.
Dullin
Anja
A
Gust
Ronald
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D012709:Serum Albumin; C509001:tetra(meso-1,2-bis(4-fluorophenyl)ethylenediamine)di(sulfinylbis(methane)-S)(N,N,N',N'-tetrakis(3-aminopropyl)butane-1,4-diamine)tetraplatinum(II); D004247:DNA