Jian Zhao

Anticancer potency of platinum(II) complexes containing both chloride anion and chelated carboxylate as leaving groups.

Three platinum complexes with both a chloride anion and a chelated carboxylate as leaving groups were synthesized and spectrally characterized. In vitro cytotoxicity of complexes 1-3 was evaluated against human A549, HCT-116, MCF-7, and HepG-2 tumor cell lines. The results showed that all the compounds exhibited effective cytotoxicity against the tested cell lines, nearly comparable to those of cisplatin and oxaliplatin. Notably, the activity of complex 2 was about 2-fold better than that of oxaliplatin against the HCT-116 cell line. Flow cytometry analysis indicated that these complexes produced death of tumor cells through an apoptotic pathway. The DNA-binding properties of the platinum-based compounds were also studied by agarose gel electrophoresis. The kinetics study showed that the chloride anion departs from the Pt atom quickly, whereas the five and/or six-membered ring formed by coordination of N,O-donors and the metal ion is opened a little more slowly by the rupture of a Pt-O bond, which helps us to further understand the mechanism of action of the newly synthesized complexes with biomolecules. Furthermore, the reaction rate constants of complexes 1-3 were roughly the same.

Study on Antitumor Platinum(II) Complexes of Chiral Diamines with Dicyclic Species as Steric Hindrance.

A series of platinum(II) complexes, characteristic of chiral trans-bicyclo[2.2.2]octane-7,8-diamine as ligand possessing dicyclic steric hindrance, were designed and synthesized. Biological evaluation showed that almost all complexes had cytotoxic activity against the tested cancer cell lines, among which most of chiral (R,R)-enantiomeres had stronger cytotoxicity than their (S,S)-counterparts, and 2a, [trans-bicyclo[2.2.2]octane-7R,8R-diamine](oxalato-O,O)platinum(II), is the most effective agent. Significantly, its counterpart, 2b, was much more sensitive to cisplatin resistant SGC7901/CDDP cancer cell line at a higher degree than 2a. Docking study and agarose gel electrophoresis revealed that the interaction of 2a with DNA was similar to that of oxaliplatin. Western blot analysis demonstrated that 2a could induce a better effect than cisplatin on a mitochondrial-dependent apoptosis pathway. Kinetic study indicated that the dicyclic ligand can accelerate the reaction rate of the complex.

Potent Anticancer Activity and Possible Low Toxicity of Platinum(II) Complexes with Functionalized 1,1‐Cyclobutanedicarboxylate as a Leaving Ligand

Two platinum(II) complexes, DN603 and DN604, were designed and prepared by using 3-oxocyclobutane-1,1-dicarboxylate as a ligand. The compounds were prepared according to the concept that incorporation of a functionalized moiety in the leaving ligand that did not affect its coordination bonding to the metal atom would play a key role in the anticancer activity of the resulting platinum complex. The newly prepared compounds were found to show potent in vitro anticancer activity comparable to cisplatin and oxaliplatin; especially DN604, which exhibited low acute toxicity similar to carboplatin, and presented acceptable solubility and stability in water. Chemical and biological results indicated that the functionalized moiety, uncoordinated, led to potent anticancer activity and low apparent toxicity of the platinum complexes by affecting the kinetic properties of the compounds.

Design, synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes

Five dinuclear platinum(II) complexes with a novel chiral ligand, 2-(((1R,2R)-2-aminocyclohexylamino)methyl)phenol (HL), were designed, prepared and spectrally characterized. In vitro cytotoxicity of all the resulting platinum(II) compounds was evaluated against human HEPG-2, A549 and HCT-116 cell lines, respectively. Results indicated that all compounds showed positive biological activity. Particularly, compound D4 has lower IC(50) values than carboplatin toward HEPG-2 and A549, while compound D5 shows better activity than carboplatin against A549.

Cytotoxicity profile of novel sterically hindered platinum(II) complexes with (1R,2R)-N1,N2-dibutyl-1,2-diaminocyclohexane

Four Pt(II) complexes of (1R,2R)-N(1),N(2)-dibutyl-1,2-diaminocyclohexane with two alkyl branches as steric hindrance have been designed and synthesized. In vitro cytotoxicity of these compounds indicated complex 4 is a cytotoxic agent more potent than its parent molecule, oxaliplatin, against almost all the tested cell lines. Agarose gel electrophoresis study showed that the kinetic reactivity of complex 4 with DNA is slow down due to the sterically hindered effect, demonstrating that it may possess a different mechanism of action from cisplatin. Flow cytometry results revealed that complex 4 induced apoptosis of tumor cells by blocking the cell-cycle progression in the G2/M phase. Western blot analysis showed it had a similar apoptotic mechanism to cisplatin which could induce apoptosis via a mitochondrial-dependent pathway.

Platinum(II) complexes with N-monoalkyl 1R,2R-diaminocyclohexane derivatives as carrier ligands and 3-hydroxycyclobutane-1,1-dicarboxylate as a leaving group: Potent cytotoxicity and DNA binding ability

A series of novel platinum(II) complexes with N-monoalkyl 1R,2R-diaminocyclohexane derivatives and 3-hydroxycyclobutane-1,1-dicarboxylate as ligands were designed and synthesized. The cytotoxicity study revealed that most of synthesized complexes showed moderate to potent activity against all four tested tumor cell lines. Particularly, 1d showed much higher cytotoxic activity than carboplatin and oxaliplatin against MCF-7 and A549 cell lines. Due to the employment of N-monoalkyl 1R,2R-diaminocyclohexane derivatives and 3-hydroxycyclobutane-1,1-dicarboxylate as ligands, the calculated log P values of the complexes are around 1, suggesting a good balance of the lipophilicity and hydrophilicity. The aqueous solubility of 1d is also improved, reaches 24.6 mg/mL. Furthermore, both docking study and agarose gel electrophoresis have confirmed the DNA-binding ability of 1d.

Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety

By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase.

Synthesis and antiproliferative activity of (1R,2R)-N1-(2-butyl)-1,2-cyclohexanediamine platinum(II) complexes with malonate derivatives

Three new platinum(II) complexes of (1R,2R)-N1-(2-butyl)-1,2-cyclohexanediamine with malonate derivatives as leaving groups have been synthesized and spectrally characterized. They were tested in vitro against four human cancer cell lines. [(1R,2R)-N1-(2-butyl)-1,2-cyclohexanediamine-N,N′](2-ethylmalonato-O,O′)platinum(II) turned out to be more active (IC50 = 4.65 μM) than oxaliplatin (IC50 = 6.55 μM) against the MCF-7 cell line and is superior to its parent complex, [(1R,2R)-N1-(2-butyl)-1,2-cyclohexanediamine-N,N′](malonato-O,O′)platinum(II). In addition, agarose gel electrophoresis study revealed that the interaction of the complex with pET22b plasmid DNA had a different behavior from that of cisplatin or oxaliplatin. Graphical Abstract Three new platinum(II) complexes with 2-substituted malonate derivatives as leaving groups have been designed, synthesized, and spectrally characterized. They were tested in vitro against four human cancer cell lines. In addition, the DNA unwinding capability was also investigated.

Antitumor platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with dicarboxylates as leaving groups.

Four platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with different bidentate dicarboxylates (1 oxalate, 2 malonate, 3 1,1-cyclobutanedicarboxylate and 4 3-hydroxy-1,1-cyclobutanedicarboxylate) as leaving groups were synthesized and characterized by elemental analyses, IR and (1)HNMR spectra together with ESI-MS spectroscopy. All complexes showed considerable cytotoxicity against the tested four human tumor cell lines including A549, HCT-116, HepG-2 and MCF-7. Especially, complex 4 showed good cytotoxicity against A549 (IC50=3.5μM) and HCT-116 (IC50=0.9μM) cancer cell lines. Moreover, complex 3 is the most effective agent among the tested compounds against MCF-7 cell line (IC50=1.1μM). The DNA binding behavior of both complexes 3 and 4, studied by agarose gel electrophoresis, revealed that they bound to DNA in almost the same way as cisplatin.

Antitumor platinum(II) complexes of N-monoalkyl 1R,2R-diamino-cyclohexanes with 3-(nitrooxy)cyclobutane-1,1-dicarboxylate as a leaving group

A series of platinum(II) complexes of N-monoalkyl-1R,2R-diaminocylclohexanes with 3-(nitrooxy)cyclobutane-1,1-dicarboxylate as a leaving group were synthesized and characterized by elemental analysis, IR, (1)H, (13)C and (195)Pt NMR spectroscopy together with ESI-MS spectrometer. Inxa0vitro cytotoxicity study on these complexes indicated they have considerable cytotoxicity against the tested cancer cell lines. Notably, complexes 2, 4, 6 and 8 showed high cytotoxicity against human A549 and HCT-116 cancer cell lines. The DNA binding of the platinum-based complexes 1 and 3-5 studied by agarose gel electrophoresis was in accordance with cytotoxicity to some extent. Reactions between the corresponding aqua analogues of the resulting complexes and glutathione (GSH) were studied by kinetics method under pseudo-first-order conditions using UV-Vis spectrophotometric technique. The results indicated that the introduction of alkyl moieties in 1R,2R-diaminocyclohexane (1R,2R-DACH) decreased the reaction rates of the aqua analogues of complexes 3-5 and GSH under the tested condition. Moreover, the stability of complex 8 was investigated by HPLC-MS technique at different time in 36xa0h.