Feihong Chen

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.

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.

Toward overcoming cisplatin resistance via sterically hindered platinum(II) complexes.

A number of platinum(II) complexes with steric hindrance derived from (1R,2R)-N(1)-benzylcyclohexane-1,2-diamine derivatives were designed and prepared. Biological assay indicated that most complexes showed antitumor activity against the tested cancer cell lines, especially those with chloride anions as leaving groups had compatible or superior activity to cisplatin and oxaliplatin. Complex 2a, as the most potent agent, is also sensitive to cisplatin resistant SGC7901/CDDP cancer cell line, which has been subsequently studied by cellular uptake, flow cytometry, gel electrophoresis and western blot assays. The steric hindrance resulting from a pending 2-fluorobenzyl moiety of the ligand might be the key factor for its ability to overcome cisplatin resistant cancer cells.

Study on the cytotoxic activity of platinum(II) complexes of (1 R ,2 R )- N 1 -cyclopentyl-1,2-cyclohexanediamine with substituted malonate derivatives

Three platinum(II) complexes of (1R,2R)-N(1)-cyclopentyl-1,2-cyclohexanediamine with malonate derivatives were designed, synthesized and spectrally characterized. MTT assay showed that the complexes possessed positive cytotoxic effect on the four human solid tumor cell lines. Among the complexes, complex 2 demonstrated the strongest cytotoxic activity compared to cisplatin and oxaliplatin against HepG2 cell line (IC50=3.04μM). Furthermore, the results of gel electrophoresis revealed that complex 2 interacted with DNA in a different mode from that of cisplatin. Mechanism studies of cell proliferation inhibition and cellular uptake indicated that complex 2 entered HepG2 cell more efficiently than cisplatin, exhibited massive G2 accumulation and then induced apoptosis.

Reversal of cisplatin resistance in human gastric cancer cells by a wogonin-conjugated Pt(IV) prodrug via attenuating Casein Kinase 2-mediated Nuclear Factor-κB pathways

Graphical abstract A model for a wogonin‐conjugated Pt(IV) prodrug to circumvent cisplatin resistance via attenuating CK2‐mediated NF‐&kgr;B pathways and inducing DNA double and single strands breaks in human gastric cancer cells. Figure. No caption available. Abstract Pt(IV) prodrugs, with two additional coordination sites in contrast to Pt(II) drugs, have been actively studied nowadays, for they can perform well in enhancing the accumulation and retention of the corresponding Pt(II) drugs in cancer cells. Our designed Pt(II) drug, DN604, was recently found to exhibit significant anticancer activity and low toxicity, while, wogonin, a naturally O‐methylated flavones, has been widely investigated for its tumor therapeutic potential. Thus, two Pt(IV)‐based prodrugs were derived by addition of a wogonin unit to the axial position of DN604 and its analogue DN603 via a linker group. In vitro cytotoxicity assay indicated that the resulting compound 8 not only inherited the genotoxicity of DN604 on gastric cancer cells, but also obtained the COX inhibitory property arising from wogonin. Further studies revealed that compound 8 caused the accumulation of ROS production and decreased the mitochondrial membrane potential (&Dgr;&PSgr;m). The CK2&agr; kinase activity assay, ChIP and luciferase assays showed that CK2 plays an important role in the blockade of compound 8 on activated NF‐&kgr;B survival pathways, which were established for sensitivity of cancer cells to platinum drugs. Similarly in vivo, in nude mice with SGC‐7901/cDDP xenografts, compound 8 improved the effectiveness of DN604 via reversing tumor resistance and maintaining low toxicity. Overall, compound 8 is a promising Pt(IV) prodrug, which could be used to promote the anticancer activity of its counterpart Pt(II) species and reverse drug resistance via attenuating CK2‐mediated NF‐&kgr;B pathways during platinum‐based chemotherapies.

Design, Synthesis, and Biological Features of Platinum(II) Complexes with Rigid Steric Hindrance

A series of platinum(II) complexes, with N-monosubstituted 1R,2R-diaminocyclohexane bearing methoxy-substituted benzyl groups as carrier ligands, were designed and synthesized. The newly prepared compounds, with chloride anions as leaving groups, were found to be very active against the tested cancer cell lines, including a cisplatin-resistant cell line. Despite their efficacy against tumor cells, they also showed low toxicity to a human normal liver cell line. Among them, complex 1 had superior cytotoxic activity against A549, HCT-116, MCF-7, SGC7901, and SGC7901/CDDP cancer cell lines. The DNA binding assay is of further special interest, as an unusual monofunctional binding mode was found, due to the introduction of a rigid substituted aromatic ring in the 1R,2R-diaminocyclohexane framework as steric hindrance. The linkage of complex 1 with DNA was stable and insensitive to nucleophilic attack. Moreover, studies including cellular uptake, gel electrophoresis, apoptosis and cell cycle, and Western blot analysis have provided insight into the high potency of this compound.

DN604: A platinum(II) drug candidate with classic SAR can induce apoptosis via suppressing CK2-mediated p-cdc25C subcellular localization in cancer cells

ABSTRACT DN604, a carboplatin analogue with a functional dicarboxylato ligand, was deeply investigated to explore its ability to induce apoptosis as well as its antitumor mechanism of action. Both in vitro and in vivo assays indicated that DN604 could effectively inhibit cell viability of SGC‐7901 gastric cancer cells and exhibited stronger antitumor activity than carboplatin and comparable activity to cisplatin. Significantly in contrast to cisplatin, DN604 resulted in negligible toxic effects in vivo with the same tumor growth inhibition effect as cisplatin. The mechanism study indicated that DN604 inhibited CK2‐phosphorylated cdc25C activation to decrease p‐cdc25C subcellular localization, leading to the inactivation of cdc2/Cyclin B and G2/M cell cycle arrest and apoptosis in SGC‐7901 cancer cells. Our research revealed for the first time that the dicarboxylato ligand containing a suitable functional moiety as the leaving group in the platinum(II) complex can effectively induce cell cycle arrest and apoptosis via inhibiting key checkpoint proteins. Graphical abstract DN604: a platinum(II) drug candidate with classic SAR can induce apoptosis via suppressing CK2‐mediated p‐cdc25C subcellular localization in cancer cells. Figure. No Caption available. HighlightsDN604 exhibited stronger comparable cytotoxicity to cisplatin.DN604 showed more potent in vivo antitumor activity than carboplatin.DN604 resulted in negligible toxic effects as the same effect as cisplatin in vivo.DN604 could suppress CK2‐induced p‐cdc25C activation and subcellular localization.

Oxidative DNA double strand breaks and autophagy in the antitumor effect of sterically hindered platinum(II) complexes in NSCLCs

A series of novel platinum(II) complexes with (1R,2R)-N1,N2-diisobutyl-1,2-diaminocyclohexane as a carrier ligand, while N1,N2-diisobutyl moiety serving as steric hindrance were designed, synthesized and characterized. The in vitro biological assays demonstrated that complex 3 had increased cytotoxicity against lung cancer cells, especially non-small-cell lung cancer (NSCLC) compared to its mono-substituted complex 3a, indicating that the sterically hindered alkyl moieties have significant influences on its antitumor property. However, the mechanism still remains unclear. The further studies revealed that complex 3 could induce ROS overproduction, severe DNA double strands breaks and inhibit the activation of DNA damage repair proteins within nucleus, leading to cell-cycle arrest and cell death. Moreover, complex 3 could induce autophagy via the accumulation of autophagic vacuoles and alterations of autophagic protein expression. Interestingly, the ROS scavengers, N-acetyl-cysteine (NAC) could reverse complex 3-induced DNA double strands breaks and autophagic responses more significantly compared to complex 3a. The results demonstrated that the ROS generation plays an important role in the DNA double strands breaks and autophagic responses in the antitumor effect of complex 3 with N1,N2-diisobutyl moiety. Our study offered a novel therapeutic strategy and put new insights into the anticancer research of the complexes with N1,N2-diisobutyl moiety served as steric hindrance.

Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance

Two hybrids of Pt(IV) species were designed and prepared by addition of a chlorambucil unit to the axial positions of the Pt(IV) complexes derived from DN603 and DN604. In vitro studies of two hybrids against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound 5 had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drug resistance. Mechanistic investigation suggested that the potent antitumor activity of compound 5 arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand break (DSB) repair. In nude mice with A549/CDDP xenografts, compound 5 exhibited higher anticancer efficacy than cisplatin and chlorambucil by reversing drug resistance, displayed improved effectiveness, and had no toxicity effects. Overall, compound 5 is a promising drug candidate, which could promote the anticancer activity and reverse drug resistance by attenuating CK2-induced MRN-dependent DSB repair.