A number of novel chiral diamines 3, (1R,2R)-N-monoalkylcyclohexane-1,2-diamines, were designed and synthesized from trans-cyclohexane-1,2-diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β-nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)-N¹-(4-methylpentan-2-yl)cyclohexane-1,2-diamine (3g), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g–Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti-selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β-nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition-state model. Copyright © 2014 John Wiley & Sons, Ltd.

A series of oxaliplatin derivatives with (1R,2R)-N¹-alkyl-1,2-cyclohexane-1,2-diamine (alkyl=Bu or ⁱPr) as carrier ligands and 1-(methoxy- or methyl-substituted benzyl)azetidine-3,3-dicarboxylate anions as leaving groups were synthesized and spectrally characterized. Generally, Complexes 10–15 with an ⁱPr substituent at N(1) showed higher activities in vitro than carboplatin against MCF-7 human breast carcinoma and A549 human non-small-cell lung cell lines, although they were less potent than oxaliplatin. The typical complex 14 exhibited cytotoxicity superior to that of carboplatin and comparable to that of oxaliplatin against two selected tumor cell lines. Additionally, agarose gel electrophoresis was applied to investigate the DNA-cleavage ability of complex 14, which demonstrated that it has a different mode of DNA distortion from that of oxaliplatin.

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.

Five novel dinuclear platinum(II) complexes with a new chiral ligand, 3-(2-amino-cyclohexylamino)-propionic acid (HP), were designed, prepared and spectrally characterized. The in vitro cytotoxicities of these compounds were evaluated against the HepG-2, MCF-7, A549, and HCT-116 cell lines. The results indicated that all compounds showed cytotoxicity towards the HepG-2 cell line. Particularly, complex X5, which has SO as a bridge, exhibited better cytotoxicity than carboplatin or oxaliplatin against all selected cell lines. Moreover, double dyeing flow cytometric resection indicated that the target compounds inhibited tumor cell growth by inducing apoptosis.

Six dicarboxylato-bridged dinuclear platinum(II) complexes S1–S6, with a newly designed chiral ligand, 2-{[(1R,2R)-2-aminocyclohexyl]amino}propanoic acid (HL), were prepared and spectrally characterized. The in vitro cytotoxicity of all resulting platinum(II) complexes was evaluated against human HCT-116, MCF-7, and HepG-2 tumor cell lines. The results show that all compounds exhibit positive biological activity toward HCT-116 and MCF-7 cell lines, of which complexes S3, S4, and S5, with succinate and its derivatives as bridges, showing better activity than the positive controls. Moreover, double-dyeing flow cytometric resection experiments indicate that the target compounds inhibit tumor cell growth by inducing apoptosis; gel electrophoresis experiments demonstrate the compounds′ ability to prompt pET22b plasmid DNA degradation in almost the same way as oxaliplatin.

A series of platinum(II) complexes with N-monocyclopentyl/cyclohexyl derivatives of 1R,2R-diaminocyclohexane as carrier ligands and dicarboxylate anions as leaving groups were synthesized and characterized. All complexes were characterized by elemental analysis, IR, ¹H NMR, and ¹³C NMR spectroscopy, as well as ESIMS. The in vitro antiproliferative activities were tested by MTT assay against four human cancer cell lines; breast carcinoma (MCF-7) and colon cancer (HCT-116) cells were particularly sensitive, especially to complexes 1 f (IC₅₀=9.81 and 1.49 μM) and 2 f (IC₅₀=4.59 and 0.36 μM). Flow cytometry indicated that representative compounds exert cytotoxicity toward MCF-7 and HCT-116 cells through induction of apoptosis and blockage of cell-cycle progression in the S phase, similar to cisplatin. The interaction between the platinum(II) complexes and pET22b plasmid DNA was observed by agarose gel electrophoresis, revealing that complex 2 f has the capacity to distort plasmid DNA in a manner distinct from that of oxaliplatin.

Promoted by NiCl₂ coordination in the mixed solvent MeOH/CH₂Cl₂, diverse in situ S–S bond reactions, such as S-oxidation and S–S and C–S bond scission, occurred in the disulfide ligand of 2-ppds {bis[4-(pyridin-2-yl)pyrimidin-2-yl]disulfane} to yield three new components identified as 2-mpp [2-methoxy-4-(pyridin-2-yl)pyrimidine], 2-ppst {S-[4-(pyridin-2-yl)pyrimidin-2-yl] 4-(pyridin-2-yl)pyrimidine-2-sulfonothioate} and 2-pps {bis[4-(pyridin-2-yl)pyrimidin-2-yl]sulfane}. More importantly, such in situ reactions could be efficaciously controlled so that they proceed in a highly selective manner. Thus, NiCl₂-mediated in situ reaction of 2-ppds with the aid of continuous air bubbling through the reaction mixture exclusively led to 2-pps, whereas replacement of NiCl₂ by Cu(OAc)₂ afforded 2-mpp alone. A confirmatory experiment proved that 2-ppst served as a decisive intermediate in these in situ reactions.