A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs

Abstract

A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models.

Figure 1

Synthesis of novel diam(m)inebis(dicarboxylato)platinum(IV) complexes of the type Pt(diam(m)ine)(R(COO)₂)₂: A = NH₃, EtNH₂, or cha (cyclohexylamine) or A₂ = en (ethane-1,2-diamine) or DACH ((1R,2R)-diaminocyclohexane); R(COOH)₂ = oxalic, malonic, 3-methylmalonic, or 1,1-cyclobutanedicarboxylic acid.

Figure 2

Chemical structures of novel diam(m)inebis(dicarboxylato)platinum(IV) complexes along with their NMR numbering schemes.

Figure 3

NH₂ (left) and NH₃ (right; ¹J_N,H = 52.6 Hz, ²J_Pt,H = 51.4 Hz) signals of complex 5b in the ¹H NMR spectrum.

Figure 4

ORTEP view of complex 1c with its atom labeling scheme. The thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and bond angles (deg): Pt–N1 2.023(3), Pt–N2 2.024(2), Pt–O1 1.988(2), Pt–O3 2.016(2), Pt–O5 2.020(2), Pt–O7 1.988(2), N1–Pt–N2 84.65(10), O3–Pt–O5 96.83(8), N1–Pt–O5 88.45(9), N2–Pt–O3 90.10(9), O1–Pt–O3 92.54(10), O5–Pt–O7 93.22(9), O1–Pt–O7 172.54(9).

Figure 5

ORTEP view of complex 4a with its atom labeling scheme. The thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and bond angles (deg): Pt–N1 2.029(10), Pt–N2 2.032(8), Pt–O1 2.027(8), Pt–O2 1.999(8), Pt–O5 1.993(8), Pt–O6 2.028(8), N1–Pt–N2 84.3(4), O1–Pt–O5 87.0(3), N1–Pt–O5 93.1(4), N2–Pt–O1 95.6(3), O1–Pt–O2 84.6(3), O5–Pt–O6 84.7(3), O2–Pt–O6 176.3(3).

Figure 6

Time-dependent reduction of 1b* and 5b* (2 mM) in the presence of sodium ascorbate (30 mM) at ambient temperature.

Figure 7

ESP color-mapped electron density for complex 4b.

Figure 8

Frontier orbitals (with their energies) of complex 3b.

Figure 9

Anticancer activity of 4b in vivo: (A) Kaplan–Meier plots showing the survival (days after tumor implantation) of L1210 leukemia-bearing mice treated intraperitoneally with the indicated doses of 4b (n = 4) on days 1, 5, and 9 compared to that of solvent-treated controls (n = 8). (B) CT-26 cells were injected subcutaneously into the right flank of BALB/c mice. Mice were treated on days 4, 7, 11, and 14 with 30 mg/kg (i.p.) of 4b or 9 mg/kg (i.v.; maximal tolerated dose) of oxaliplatin. Animals were sacrificed on day 15, and tumors were collected. Statistical analysis was performed by Student’s t test (* p < 0.05 compared to control mice).

Figure 10

Platinum accumulation in mouse tissues, blood pellet, and serum collected on day 15 from the CT-26 experiment shown in Figure 9B; values are normalized relative to the platinum content found in the tumor (~5 μg/g for 4b and ~1 μg/g for oxaliplatin, respectively). Mice were treated on days 4, 7, 11, and 14 with 30 mg/kg of 4b (intraperitoneal, ip) or 9 mg/kg of oxaliplatin (intravenous, iv).

Scheme 1. Chemical Structures of Platinum(II) Complexes with Worldwide Clinical Approval (Cisplatin, Carboplatin, and Oxaliplatin) and Platinum(IV)-Based Drug Candidate in Clinical Trials (Satraplatin)