Structural Characterization and Assessment of Anti-Inflammatory Activities of Polyphenols and Depsidone Derivatives from Melastoma malabathricum subsp. normale.

The roots of Melastoma malabathricum subsp. normale (D. Don) Karst. Mey have been used in traditional ethnic medicine systems in China to treat inflammation-triggered ailments, such as trauma, toothache, and fever. Therefore, the aim of this study is to screen for compounds with anti-inflammatory activity in the title plant. The extract of M. malabathricum subsp. normale roots was separated using various chromatographic methods, such as silica gel, ODS C18, MCI gel, and Sephadex LH-20 column chromatography, as well as semi-preparative HPLC. One new complex tannin, named whiskey tannin D (1), and an undescribed tetracyclic depsidone derivative, named guanxidone B (2), along with nine known polyphenols (2-10) and three known depsidone derivatives (12-14) were obtained from this plant. The structures of all compounds were elucidated by extensive NMR and CD experiments in conjunction with HR-ESI-MS data. All these compounds were isolated from this plant for the first time. Moreover, compounds 1-4, 8, and 10-14 were obtained for the first time from the genus Melastoma, and compounds 1, 2, and 11-14 have not been reported from the family Melastomataceae. This is the first report of complex tannin and depsidone derivatives from M. malabathricum subsp. normale, indicating their chemotaxonomic significance to this plant. Compounds 1-12 were investigated for their anti-inflammatory activities on the production of the nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and compounds 1, 11, and 12 showed anti-inflammatory activities with IC50 values of 6.46 ± 0.23 µM, 8.02 ± 0.35 µM, and 9.82 ± 0.43 µM, respectively. The structure-activity relationship showed that the catechin at glucose C-1 in ellagitannin was the key to its anti-inflammatory activity, while CH3O- at C-16 of aromatic ring A in depsidone derivatives had little effect on its anti-inflammatory activity. The study of structure-activity relationships is helpful to quickly discover new anti-inflammatory drugs. The successful isolation and structure identification of these compounds, especially complex tannin 1, not only provide materials for the screening of anti-inflammatory compounds, but also provide a basis for the study of chemical taxonomy of the genus Melastoma.

Synthesis, Characterization, and Cytotoxicity of the Cobalt (III) Complex with N,N-Diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline.

A cobalt(III) complex, [Co(L)2 ](ClO4 )3 (1), in which the ligand L was N,N-diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline (L), was synthesized and fully characterized. This new cobalt(III) complex 1 exhibited selective cytotoxicity against HeLa, T-24, A549, MGC80-3, HepG2, and SK-OV-3 cells with IC50 values in the micromolar range (0.52 - 4.33 µm), and it exhibited low cytotoxicity against normal HL-7702 cells. The complex 1 was the most potent against the T-24 cells. It was found that 1 could cause the cell cycle arrest in G1 phase, and it exerted its antitumor activity mainly via disruption of mitochondrial function.

Complexes of oxoplatin with rhein and ferulic acid ligands as platinum(iv) prodrugs with high anti-tumor activity.

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.

Novel Quinoline-based Ir(III) Complexes Exhibit High Antitumor Activity in Vitro and in Vivo.

Eight novel Ir(III) complexes listed as [Ir(H-P)2(P)]PF6 (PyP-Ir), [Ir(H-P)2(dMP)]PF6 (PydMP-Ir), [Ir(H-P)2(MP)]PF6 (PyMP-Ir), [Ir(H-P)2(tMP)]PF6 (PytMP-Ir), [Ir(MPy)2(P)]PF6 (MPyP-Ir), [Ir(MPy)2(dMP)]PF6 (MPydMP-Ir), [Ir(MPy)2(MP)]PF6 (MPyMP-Ir), [Ir(MPy)2((tMP)]PF6 (MPytMP-Ir) with 2-phenylpyri-dine (H-P) and 3-methyl-2-phenylpyridine (MPy) as ancillary ligands and pyrido-[3,2-a]-pyrido[1',2':1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido[1',2':1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido [3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (tMP) as main ligands, respectively, were designed and synthesized to fully characterize and explore the effect of their toxicity on cancer cells. Cytotoxic mechanism studies demonstrated that the eight Ir(III) complexes exhibited highly potent antitumor activity selectively against cancer cell lines NCI-H460, T-24, and HeLa, and no activity against HL-7702, a noncancerous cell line. Among the eight Ir(III) complexes, MPytMP-Ir exhibited the highest cytotoxicity with an IC50 = 5.05 ± 0.22 nM against NCI-H460 cells. The antitumor activity of MPytMP-Ir in vitro could be contributed to the steric or electronic effect of the methyl groups, which induced telomerase inhibition and damaged mitochondria in NCI-H460 cells. More importantly, MPytMP-Ir displayed a superior inhibitory effect on NCI-H460 xenograft in vivo than cisplatin. Our work demonstrates that MPytMP-Ir could potentially be developed as a novel potent Ir-based antitumor drug.

Strong in vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives.

A series of novel organoplatinum(II) complexes, [PtII(QC1)(H-QC1)Cl] (Pt1), [PtII(QC2)(H-QC2)Cl] (Pt2), [PtII(QC3)(H-QC3)Cl] (Pt3), [PtII(QC4)(H-QC4)Cl]⋅CH3OH (Pt4), [PtII(QC5)(H-QC5)Cl] (Pt5), [PtII(H-QC6)(DMSO)Cl2] (Pt6), [PtII(H-QC7)(DMSO)Cl2]⋅H2O (Pt7), [PtII(H-QC8)(DMSO)Cl2] (Pt8), [PtII(H-QC9)(DMSO)Cl2]⋅CH3OH (Pt9), [PtII(H-QC10)(DMSO)Cl2] (Pt10) and [PtII(H-QC11)(DMSO)Cl2] (Pt11), bearing quinoline-coumarin derivatives (H-QC1-H-QC11) have been first designed. Complexes Pt1-Pt11 selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC50 values as low as 100 nM-10.33 µM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4 (100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2'-quinolyl)-6-hydroxy-coumarin (H-QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported coumarin derivatives metal complexes.

Synthesis of two platinum(II) complexes with 2-methyl-8-quinolinol derivatives as ligands and study of their antitumor activities.

Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other spectroscopic and analytical studies of ClQ-Pt and BrQ-Pt revealed that the coordination geometry of Pt(II) can be described as a four-coordinated square planar geometry. By MTT assay, ClQ-Pt displayed the most potent activity, with IC50 values of 5.02-34.38 µM against MGC80-3, T-24, Hep-G2 and BEL-7402 tumor cells. Among them, the T-24 cells the highest sensitivity to ClQ-Pt and BrQ-Pt with IC50 value of 5.02 ±â€¯0.62 µM and 18.02 ±â€¯1.05 µM, respectively. In addition, ClQ-Pt caused a higher percentage of apoptotic T-24 cells (ca. 33.75%) than that of BrQ-Pt (ca. 23.85%) and cisplatin (ca. 12.82%). Mechanistic studies revealed that ClQ-Pt and BrQ-Pt caused T-24 cell cycle arrest at the S phase, as shown by the down-regulation of cyclin A and CDK2 expression levels. In addition, ClQ-Pt and BrQ-Pt also caused mitochondrial dysfunction. Interestingly, the in vitro anticancer activity of ClQ-Pt was higher than those of BrQ-Pt and cisplatin, more selective for T-24 tumor cells than for normal HL-7702 cells. Taken together, we concluded that the 5- and 7-substitution groups of the ClQ ligands play an important role in determining the anti-proliferation activity of the corresponding Pt(II) complexes.

In vitro and in vivo antitumor activities of three novel binuclear platinum(II) complexes with 4'-substituted-2,2':6',2″-terpyridine ligands.

Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl3] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (qlbtpy-Pt) with 4'-(3-thiophenecarboxaldehyde)-2,2':6',2″-terpyridine (tpbtpy), 4'-(3,5-bis (1,1-dimethylethyl)-2-hydroxy-benzaldehyde)-2,2':6',2″-terpyridine (dthbtpy) and 4'-(2-quinolinecarboxaldehyde)-2,2':6',2″-terpyridine (qlbtpy) as ligands, respectively. All three novel binuclear platinum(II) complexes tpbtpy-Pt, dthbtpy-Pt, and qlbtpy-Pt were characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR, 1H NMR), and elemental analysis. Additionally, the cytotoxicity of tpbtpy-Pt, dthbtpy-Pt and qlbtpy-Pt was assessed with human non-small cell lung cancer cell line (NCIH460 cells), yielding IC50 values in the range of 0.35-12.09 µM with tpbtpy-Pt as the most potent and qlbtpy-Pt as the least potent complexes. Mechanistic studies indicated that tpbtpy-Pt and dthbtpy-Pt induced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCIH460 xenograft model, when administered at 10.0 mg kg-1 every 2 days, tpbtpy-Pt was shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%, p < 0.05). Therefore, tpbtpy-Pt is a promising Pt(II) complex for further translational studies and clinical evaluation as an antitumor agent.

Complexes of lanthanides(iii) with mixed 2,2'-bipyridyl and 5,7-dibromo-8-quinolinoline chelating ligands as a new class of promising anti-cancer agents.

Five novel lanthanides(iii) complexes, [Lu(Me)(MBrQ)2NO3] (MeMBrQ-Lu), [Ho(MeO)(MBrQ)2NO3] (MeOMBrQ-Ho), [Ho(Me)(MBrQ)2NO3] (MeMBrQ-Ho), [La(Me)2(BrQ)2NO3] (MeBrQ-La) and [Sm(Me)(BrQ)2(CH3OH)NO3] (MeBrQ-Sm), have been synthesized, in which 2,2'-bipyridyl (4,4'-dimethyl-2,2'-bipyridyl (Me) and 4,4'-dimethoxy-2,2'-bipyridine (MeO)) and 5,7-dibromo-8-quinolinoline derivatives (5,7-dibromo-2-methyl-8-quinolinol (MBrQ-H) and 5,7-dibromo-8-quinolinol (BrQ-H)) act as the chelating ligands. The in vitro cytotoxic activities of the five Ln(iii) complexes have been studied with the SK-OV-3/DDP, NCI-H460 and HeLa cancer cells. MeMBrQ-Lu, MeOMBrQ-Ho, MeMBrQ-Ho, MeBrQ-La and MeBrQ-Sm show higher cytotoxicity against the HeLa cells (IC50 values of 1.00 nM-3.45 µM) than cisplatin (13.11 ± 0.53 µM). In particular, the MeOMBrQ-Ho and MeMBrQ-Ho complexes exhibit superior cytotoxic activity, with IC50 values at 1.00 ± 0.34 nM and 125.00 ± 1.08 nM. We further demonstrate that MeOMBrQ-Ho and MeMBrQ-Ho inhibit the proliferation of HeLa cells by inhibiting telomerase and targeting mitochondria to induce DNA damage-mediated apoptosis. In addition, MeOMBrQ-Ho significantly inhibits tumor growth with a tumor growth inhibition rate (IR) of 50.8% in a HeLa mouse xenograft model. Taken together, MeOMBrQ-Ho is a novel lanthanide(iii) complex with promising antitumor activity.

High in vitro and in vivo antitumor activities of luminecent platinum(II) complexes with jatrorrhizine derivatives.

Two highly active anticancer Pt(II) complexes, [Pt(Jat1)Cl]Cl (Pt1) and [Pt(Jat2)Cl]Cl (Pt2), containing jatrorrhizine derivative ligands (Jat1 and Jat2) are described. Cell intake study showed high accumulation in cell nuclear fraction. Pt1 and Pt2 exhibited high selectivity for HeLa cancer cells (IC50 = 15.01 ±â€¯1.05 nM and 1.00 ±â€¯0.17 nM) comparing with HL-7702 normal cells (IC50 > 150 µM), by targeting p53 and telomerase. Pt2 containing Jat2 ligand was more potent and showed high selectivity for telomerase. It also caused mitochondria and DNA damage, sub-G1 phase arrest, and a high rate of cell apoptosis at the low dose of 1.00 nM. The HeLa tumor inhibition rate (TIR) of Pt2 was 48.8%, which was even higher than cisplatin (35.2%). In addition, Pt2 displayed green luminescent property and potent telomerase inhibition. Our findings demonstrated the promising development of platinum(II) complexes containing jatrorrhizine derivatives as novel Pt-based anti-cancer agents.

Two telomerase-targeting Pt(ii) complexes of jatrorrhizine and berberine derivatives induce apoptosis in human bladder tumor cells.

Two novel Pt(ii) complexes, [Pt(B-TFA)Cl]Cl (Pt1) and [Pt(J-TFA)Cl]Cl (Pt2) with jatrorrhizine and berberine derivatives (B-TFA and J-TFA) were first prepared as desirable luminescent agents for cellular applications and potent telomerase inhibitors, which can induce bladder T-24 tumor cell apoptosis by targeting telomerase, together with induction of mitochondrial dysfunction, telomere DNA damage and cell-cycle arrest. Importantly, T-24 tumor inhibition rate (TIR) was 50.4% for Pt2, which was higher than that of Pt1 (26.4%) and cisplatin (37.1%). Taken together, all the results indicated that jatrorrhizine and berberine derivatives Pt1 and Pt2 show low toxicity and could be novel Pt-based anti-cancer drug candidates.

Synthesis, characterization and biological evaluation of six highly cytotoxic ruthenium(ii) complexes with 4'-substituted-2,2':6',2''-terpyridine.

Herein, six ruthenium(ii) terpyridine complexes, i.e. [RuCl2(4-EtN-Phtpy)(DMSO)] (Ru1), [RuCl2(4-MeO-Phtpy)(DMSO)] (Ru2), [RuCl2(2-MeO-Phtpy)(DMSO)] (Ru3), [RuCl2(3-MeO-Phtpy)(DMSO)] (Ru4), [RuCl2(1-Bip-Phtpy)(DMSO)] (Ru5), and [RuCl2(1-Pyr-Phtpy)(DMSO)] (Ru6) with 4'-(4-diethylaminophenyl)-2,2':6',2''-terpyridine (4-EtN-Phtpy), 4'-(4-methoxyphenyl)-2,2':6',2''-terpyridine (4-MeO-Phtpy), 4'-(2-methoxyphenyl)-2,2':6',2''-terpyridine (2-MeO-Phtpy), 4'-(3-methoxyphenyl)-2,2':6',2''-terpyridine (3-MeO-Phtpy), 4'-(1-biphenylene)-2,2':6',2''-terpyridine (1-Bip-Phtpy), and 4'-(1-pyrene)-2,2':6',2''-terpyridine (1-Pyr-Phtpy), respectively, were synthesized and fully characterized. The MTT assay demonstrates that the in vitro anticancer activity of Ru1 is higher than that of Ru2-Ru6 and more selective for Hep-G2 cells than for normal HL-7702 cells. In addition, various biological assays show that Ru1 and Ru6, especially the Ru1 complex, are telomerase inhibitors targeting c-myc G4 DNA and also cause apoptosis of Hep-G2 cells. With the same Ru center, the in vitro antitumor activity and cellular uptake ability of the 4-EtN-Phtpy and 1-Bip-Phtpy ligands follow the order 4-EtN-Phtpy > 1-Bip-Phtpy.

Synthesis, crystal structure and biological evaluation of a new dasatinib copper(II) complex as telomerase inhibitor.

A new copper(II) complex of dasatinib (DAS) was synthesized and characterized via ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction analysis, 1H and 13C NMR spectroscopy, and elemental analysis. The composition of the new complex (1) was found to be [Cu(DAS + H)(NO3)2(H2O)]NO3·(H2O)·(CH3OH). Through MTT assay, it was found that 1 had high cytotoxicity towards A549, HeLa, BEL-7402, Hep-G2, NCI-H460, and MGC80-3 tumor cell lines, with IC50 values in 4.04-13.04 µM. The Hep-G2 cells were the most sensitive to 1. It is worth noting that compared with DAS and cisplatin, 1 not only had higher in vitro anticancer activity but also exhibited greater selective toxicity towards Hep-G2 cells than for normal HL-7702 cells. Experimental results from cell apoptosis analysis, cellular uptake, TRAP-silver staining assay, RT-PCR, western blot, and transfection assays showed that 1 was most likely a telomerase inhibitor that targeted c-myc G-quadruplex DNA. The high cytotoxicity and biological behaviors of 1 could be correlated with the central copper(II) atom in the coordinated mode with DAS.

Synthesis and in vitro biological evaluation of three 4'-(4-methoxyphenyl)-2,2':6',2″-terpyridine iridium(III) complexes as new telomerase inhibitors.

There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl3] (1), [Ir(2-MeO-Phtpy)Cl3] (2) and [Ir(4-MeO-Phtpy)Cl3] (3) with 4'-(3-methoxyphenyl)-2,2':6',2″-terpyridine (3-MeO-Phtpy), 4'-(2-methoxyphenyl)-2,2':6',2″-terpyridine (2-MeO-Phtpy) and 4'-(4-methoxyphenyl)-2,2':6',2″-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC50 values of 3.19-27.77 µM against four cancer cell lines (BEL-7404, Hep-G2, NCI-H460 and MGC80-3 cells). Cellular mechanism studies suggested that complexes 1-3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1-3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the in vitro antitumor activities of complexes 1-3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand.

Synthesis and antitumor mechanisms of two novel platinum(ii) complexes with 3-(2'-benzimidazolyl)-7-methoxycoumarin.

Two novel platinum(ii) complexes, [PtCl2(H-MeOBC)(DMSO)] (Pt1) and [Pt2Cl3(MeOBC)(DMSO)2] (Pt2), with 3-(2'-benzimidazolyl)-8-methoxycoumarin (H-MeOBC) as the ligand were synthesized and evaluated for their antiproliferative activity. Among all the tumor cells, dual-Pt(ii) complex Pt2 exhibited the most potent activity, with an IC50 value of 0.5 ± 0.2 µM against cisplatin-resistant SK-OV-3/DDP cancer cells. In the case of SK-OV-3/DDP cells, Pt2 displayed a 20.1-196.0-fold increased activity when compared with cisplatin, H-MeOBC and Pt1. Importantly, Pt1 and Pt2 displayed low inhibitory rates against normal HL-7702 cells. Further investigation revealed that Pt2 is a novel telomerase inhibitor binding to c-myc promoter elements. Mechanistic studies demonstrated that dual-Pt(ii) complex Pt2 arrests the cell cycle at the G2/M phase and induces apoptosis and causes mitochondrial dysfunction.

Design, synthesis and pharmacological evaluation of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents.

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a1-5d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a3 exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d3 displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a3 and 5d3 could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a3 and 5d3 exerted their antitumor activity by up-regulation of Bax, intracellular Ca2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.

Novel tacrine platinum(II) complexes display high anticancer activity via inhibition of telomerase activity, dysfunction of mitochondria, and activation of the p53 signaling pathway.

In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH3OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4'-dimethyl-2,2'-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1Pt7 exhibited cytotoxic activity against the tested NCIH460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC50 value of 0.13 ±â€¯0.16 µM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug.

Platinum(ii) complexes with rutaecarpine and tryptanthrin derivatives induce apoptosis by inhibiting telomerase activity and disrupting mitochondrial function.

Four new platinum(ii) complexes, [Pt(Rut)(DMSO)Cl2] (Rut-Pt), [Pt(Try)(DMSO)Cl2] (Try-Pt), [Pt(ITry)(DMSO)Cl2] (ITry-Pt) and [Pt(BrTry)(DMSO)Cl2] (BrTry-Pt), with rutaecarpine (Rut), tryptanthrin (Try), 8-iodine-tryptanthrin (ITry) and 8-bromo-tryptanthrin (BrTry) as ligands were synthesized and fully characterized. In these complexes, the platinum(ii) adopts a four-coordinated square planar geometry. The inhibitory activity evaluated by the MTT assay showed that BrTry-Pt (IC50 = of 0.21 ± 0.25 µM) could inhibit the growth of T-24 tumor cells (human bladder cancer cell line) more so than the other three complexes. In addition, all of these Pt complexes exhibited low toxicity against non-cancerous HL-7702 cells. BrTry-Pt induced cell cycle arrest in the S phase, leading to the down-regulation of cyclin A and CDK2 proteins. BrTry-Pt acts as a telomerase inhibitor targeting the c-myc promoter. In addition, BrTry-Pt also caused mitochondrial dysfunction. Importantly, the in vitro anticancer activity of BrTry-Pt was higher than those of Rut-Pt, Try-Pt and ITry-Pt, and it was more selective for T-24 cells than for non-cancerous HL-7702 cells.

Synthesis and antitumor mechanism of a new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands.

A new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol (HClMQ) as ligands, i.e., [Fe(ClMQ)2Cl] (1), was synthesized and evaluated for its anticancer activity. Compared to the HClMQ ligand, complex 1 showed a higher cytotoxicity towards a series of tumor cell lines, including Hep-G2, BEL-7404, NCI-H460, A549, and T-24, with IC50 values in the range of 5.04-14.35 µM. Notably, the Hep-G2 cell line was the most sensitive to complex 1. Mechanistic studies indicated that complex 1 is a telomerase inhibitor targeting c-myc G-quadruplex DNA and can trigger cell apoptosis via inducing cell cycle arrest and DNA damage.