Dinuclear Alkyldiamine Platinum Antitumor Compounds:  A Structure−Activity Relationship Study

Abstract

Six related dinuclear trans-platinum complexes, with the formula [[trans-PtCl(2)(NH(3))(L)](2)(mu-H(2)N(CH(2))(n)NH(2))](2+) (L = pyridine, 2-picoline, 4-picoline; n = 4, 6) and chloride or nitrate anions, are compared with known cytotoxic dinuclear compounds (L = NH(3); n = 4, 6) that overcome cisplatin resistance. The cytotoxicity of the compounds was determined in L1210 murine leukemia and L1210/2, a cisplatin-resistant derivative. Unlike the L = NH(3) compounds, the substituted n = 4 compounds are more susceptible toward the resistance mechanisms in L1201/2. The n = 6 compounds, however, have comparable IC(50) values in both cell lines. In general, the substituted compounds are less cytotoxic than their NH(3) counterparts. After incubation with equimolar concentrations, the amount of platinum bound to cellular DNA was determined. The compounds show comparable binding, except for the sterically hindered 2-picoline compounds that bind significantly less. The amounts of platinum bound to DNA do not correlate with the cytotoxicity data. As DNA is considered to be the cellular target of platinum antitumor drugs, structural details of the DNA adducts probably account for the differences in cytotoxic activity.

A kinetic study of aqua ligand substitution in dinuclear Pt(II) complexes containing four non-coplanar pyridine ligands

“…This was filtered off and washed with water and acetone. The crude product was recrystallized from CHCl 3 The title compound was prepared following the literature method [20][21][22]. To a solution of a known amount of trans-[PtCl 2 (Py) 2 ] in DMF (10 mL) was added one equivalent of AgClO 4 .…”

“…The synthesis of the new tetrapyridyl coordinated dinuclear complexes was adopted from a previously published method [22] starting with [trans-{PtCl(Py) 2 (DMF)}]ClO 4 and pyrazine derivatives as the bridging ligand, with some minor modifications. To a filtrate of [trans-{PtCl(Py) 2 (DMF)}]ClO 4 was added dropwise a solution of the pyrazine derivative (half equivalent that of the metal complex) in DMF (2 mL).…”

4-[Bis(2-chloroethyl)amino]benzaldehyde

“…Molecules containing heterocyclic substructures continue to be attractive targets for synthesis since they often exhibit diverse and important biological properties. For example, pyridine is used in the pharmaceutical industry as a raw material for various drugs, vitamins and fungicides, and as a solvent (Shinkai et al, 2000;Jansen et al, 2001;Amr et al, 2006) while 2-amino-3-cyanopyridines have been identified as IKK-inhibitors (Murata et al, 2003).…”

Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with α,ω-diamines

“…In order to enhance the therapeutic index, dinuclear complexes in which the bridging ligands are spermidine, or analogues containing carbamato groups, have been studied, obtaining species of remarkable activity [11]. Substitution of ammonia with pyridine or picolines in dinuclear alkyldiamine platinum complexes causes lower cytotoxicity, notwithstanding a DNA binding kinetics superior to cisplatin [12]. Attempts toward more effective polynuclear drugs consist in the insertion of functionalized groups in bridging polyamines, as amido-residues in bimetallic palladium and platinum complexes [13].…”