Water-soluble third generation antitumor platinum complexes, [2,2-bis(aminomethyl)-1,3-propanediol-N,N']-[1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylato(2-)-O,O'][tetrahydro-4H-pyran-4,4-dimethanamine-N,N']platinum(II)

Abstract

The synthesis, stability, and antitumor activity of a series of water-soluble third generation platinum(II) complexes have been described. Among these complexes, [2,2-bis(aminomethyl)-1,3- propanediol-N,N'] [1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylate(2-)-O,O'](tetrahydro-4H-pyran-4,4- dimethanamine-N,N'-)platinum(II) have shown the greatest promise for further investigation and are currently under clinical evaluation.

Pentaerythrityltetramine Scaffolds for Solid-Phase Combinatorial Chemistry1

“…The first large-scale synthesis of pentaerythrityltetramine [tetrakis(aminomethyl)methane, TAM] was based on displacement of the bromo substituents from pentaerythrityl tetrabromide with p -toluenesulfonamide ion and subsequent hydrolysis of the sulfonamide groups with sulfuric acid . The more recent syntheses include treatment of pentaerythrityl tetrachloride with excess of supercritical ammonia and reduction of the explosive tetra azide analogue. − The conversion of commercially available 2,2-bis(bromomethyl)propane-1,3-diol ( 14 ) to 2,2-bis(azidomethyl)propane-1,3-diol and further to 2,2-bis(hydroxymethyl)propane-1,3-diamine ( 15 ), described by Bitha et al, , appeared, however, a more appropriate method to obtain the desired branching units 1 and 2 . The amino groups of 15 were Boc-protected ( 16 ) and the hydroxy groups mesylated ( 17 ).…”

Unique Fluxional Behavior. Synthesis, Structure, and Properties of Novel (Diamine)platinum(II) Complexes of 9-Fluorenylidene- and Benzhydrylidenemalonate Ligands

“…One of the molecules and its labeling scheme for (DACH)Pt(FM) is depicted in Figure , and selected bond distances and angles are listed in Table . The local geometry around the platinum atom approximates to a square planar arrangement: distances of Pt(1)−N(1), Pt(1)−N(2), Pt(1)−O(1), and Pt(1)−O(3) are 2.05(1), 2.04(1), 2.01(1), and 2.03(1) Å, respectively, and the bond angles of N(1)−Pt(1)−N(2), N(1)−Pt(1)−O(1), N(2)−Pt(1)−O(3), and O(1)−Pt(1)−O(3) are 83.5(5), 175.7(4), 175.9(4), and 89.7(4)°, respectively, which are similar to the corresponding values of cis -[Pt(OXTDMA)(CH 2 (CO 2 ) 2 ] .…”

“…Potassium tetrachloroplatinate(II)(Kojima) and DACH (Aldrich) were used as received. THPDMA was prepared according to the literature . The FM and BHM ligands were prepared by literature procedures and converted to barium salts, which were reacted with (diamine)platinum sulfate…”

“…It does not exhibit significant nephrotoxicity and emesis compared with cisplatin. , The nephrotoxicity of cisplatin has been known to be associated with its active hydrolysis products, which form over a period of minutes, whereas the relatively lower toxicities of carboplatin were found to be related to its pharmacokinetic stability in solution . Accordingly, the platinum complexes of various dicarboxylate ligands have been screened for more effective anticancer drugs with less toxicities. − As a consequence, several platinum complexes of carboxylate ligands have entered clinical trials for new generation platinum anticancer agents. − Thus, the structure and behavior of the anionic carboxylate ligands play an important role in determining the pharmacokinetic stability of their platinum complexes.…”

“…In this paper, (diamine)platinum(II) complexes of structurally interesting dicarboxylate ligands, 9-fluorenylidenemalonate (FM)and benzhydrylidenemalonate (BHM), have been synthesized, and their dynamic structural behaviors in solution are reported based on their multinuclear NMR spectra along with the X-ray crystal structures of the FM and BHM complexes. As carrier ligand trans -(±)-1,2-diaminocyclohexane (DACH) and tetrahydro-4H-pyran-4,4-diylbis(methylamine) (THPDMA) were used since not only do they form stable platinum complexes, but also their platinum complexes exhibit high antitumor activity with no cross-resistance to cisplatin …”