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Two novel γ -lactone derivatives, trigoheterophines A ( 1 ) and B ( 2 ), together with four known furan derivatives ( 3 – 6 ), were isolated from the stems and leaves of Trigonostemon heterophyllus . The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A ( 1 ) and B ( 2 ) represent an unusual type of γ -lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds ( 3 – 6 ) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . Compounds 1 – 6 showed significant antiproliferative effects against various human cancer cell lines with IC 50 values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ -lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents. [ABSTRACT FROM AUTHOR]

Liriodenine, an oxoaporphine alkaloid with anticancer activity isolated from Zanthoxylum nitidum (rutaceous anticancer traditional Chinese medicine), was selected as a bioactive ligand to react with HAuCl and NaAuCl to afford [LH][AuCl] ( 1) and [AuClL] ( 2), respectively (where L is liriodenine). The structures of 1 and 2 were characterized by IR spectroscopy, electrospray ionization mass spectrometry, H-NMR spectroscopy, and elemental analysis. The single-crystal X-ray diffraction analysis of 1 revealed that it is an ionic compound consisting of protonated liriodenine cation [LH] and [AuCl] anion. The spectroscopic analysis showed that 2 is a coordination compound, in which one liriodenine coordinates to gold via its 7-N donor. In aqueous solution, 1 is relatively stable, but 2 undergoes rapid hydrolysis. The in vitro cytotoxicity towards five human tumor cell lines shows that 1 and 2 manifest roughly similar biological behavior and appreciable antiproliferative properties, with IC values falling in the 2-16 μM range. The flow-cytometric analysis of 1 and 2 suggests that both compounds induced an S-phase arrest. Compounds 1 and 2 significantly poison topoisomerase I in vitro at low concentration (25 μM or less). DNA binding studies indicate that both 1 and 2 interact with DNA mainly via intercalation between the neighboring base pairs of the DNA double helix. Electrostatic interactions of 1 and 2 with the polyanionic DNA phosphate backbone may reinforce the intercalation because both 1 and 2 are composed of planar cationic species. Graphical abstract: Two liriodenine (L) gold(III) compounds [LH][AuCl] ( 1) and [AuClL] ( 2) were synthesized. The in vitro cytotoxicity towards five human tumor cell lines was tested and shows that 1 and 2 manifest appreciable antiproliferative properties, with IC values falling in the 2-16 μM range. Both 1 and 2 interact with DNA mainly via an intercalation mode, but electrostatic binding may exist. They both inhibit topoisomerase I activity at low concentration (25 μM or less). [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15–20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy. [Copyright &y& Elsevier]

• A new derivative of podophyllotoxin (GHGT-17) was synthesized by incorporation of cyclopropyl, formyl, piperazinyl groups. • GHGT-17 exhibits significant cytotoxicity against a variety of cancer cells. • The IC 50 of GHGT-17 was less than 100 nM against A549 and H460 cells and greater than 100 µM against 16HBE cells. • In silico ADMET analysis suggests GHGT-17 is unlikely to toxic to normal organs. • Molecular docking study indicates that GHGT-17 could directly bind to the colchicine binding pocket of tubulin. Podophyllotoxin (PPT) is a naturally occurring lignan extracted from the rhizomes of the Podophyllum plant. It exhibits toxicity towards a broad spectrum of cancer cells and can induce cell death by inhibiting the polymerization of microtubule proteins. In our pursuit of more potent anticancer drug candidates, 4α-(cyclopropyl formylpiperazinyl)-4-deoxypodophyllotoxin (GHGT-17) was successfully synthesized by introducing a piperazine group, formyl group, and cyclopropyl group at the C-4 position of PPT. The activity of GHGT-17 against various types of cancer cells was evaluated using the MTT assay. It exhibited significant potency against lung cancer cells, with IC 50 values of 0.080 ± 0.020 μM (A549) and 0.086 ± 0.004 μM (H460), without obvious toxicity towards lung epithelial cells 16HBE (IC 50 > 100 μM). Further investigations demonstrated that GHGT-17 induced morphological changes in A549 and H460 cells, inhibited proliferation in a time- and dose-dependent manner. Furthermore, GHGT-17 inhibited the formation of cell colonies in a dose-dependent manner. It was found to inhibit cell migration, arrest the cell cycle in the G2/M phase, induce nuclear wrinkling, decrease mitochondrial membrane potential, and inhibit microtubule protein polymerization. These effects ultimately contribute to the induction of endogenous apoptosis. In silico studies, ADMET analysis revealed that GHGT-17 exhibited a satisfactory bioavailability with good water solubility, easy absorption, and well-proportioned distribution in the body. Molecular docking was performed to predict the binding mode and interactions of GHGT-17 with tubulin protein (1SA0). Additionally, GHGT-17 was submitted to molecular dynamics simulation and RMSD, RMSF, Rg, hydrogen bonding was analyzed. The complex showed a rather low binding free energy (−36.37 kJ mol−1) and thus exhibited a superior binding affinity towards to tubulin protein. In summary, the combined results indicated that GHGT-17 exhibits promise as a prospective potential novel drug candidate worthy of further investigation for its potential application in lung cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Mcl-1 is an anti-apoptotic member of Bcl-2 family proteins. The development of inhibitors of Mcl-1 has been challenging. To develop metal-based Mcl-1inhibitors, twenty two copper(II) complexes 25 – 46 with 9-substituted β-carboline derivatives were reported. Complexes 38 and 39 showed higher cytotoxicity than the corresponding ligands or cisplatin. The most potent complex 39 presented higher selectivity to Mcl-1 than other Bcl-2 family proteins, and killed cancer cells via Bax/Bak mediated apoptosis. Complex 39 showed an excellent safety profile in mouse model, and significantly inhibited the tumor growth in NCI-H460 tumor bearing model, which is more potent than AZD5991 at the same dosage. Complex 39 prolonged the survival time of the tumor bearing mice. Complex 39 is the first metal-based Mcl-1 inhibitor acting as a potential anticancer agent. Image 1 • Complex 39 is a novel metal-based Mcl-1 inhibitor with strong antitumor activity. • Complex 39 induced Bax/Bak mediated apoptosis. • Complex 39 significantly inhibited tumor growth in mouse xenograft model. • Complex 39 increased the survival time in mouse xenograft model. • Complex 39 showed a good safety margin in mice. [ABSTRACT FROM AUTHOR]

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives. [ABSTRACT FROM AUTHOR]

Seven new iridals ( 1 – 7 ), designated as iritectols C–F, 22-epiiritectol D, 22-epiiritectol E, 22-epiiritectol F together with three known analogues were isolated from the rhizomes of Iris tectorum . Among them, compounds 2 and 3 , 4 and 5 , and 6 and 7 were found to be three pairs of C-22 epimers, some of which were separated by chiral column chromatography. This is the first report on the occurrence of epimers of monocyclic iridals. Their structures were elucidated on the basis of extensive spectroscopic analysis. The isolates were evaluated for their cytotoxic activities against five human tumor cell lines. Compound 1 but not others exhibited moderate cytotoxic activities, with IC 50 values ranging from 4.1 to 9.8 μM. The structure–activity relationship of the tested compounds was briefly discussed. [ABSTRACT FROM AUTHOR]

Abstract: Three new copper(II) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline (PYP), i.e. [Cu2(PYP)2Cl4] (1), [Cu4(PYP)4(ClO4)2(H2O)2](ClO4)2·2H2O (2), and [Cu2(PYP)2Cl4] n (3), were synthesized and fully characterized. In comparison to free PYP, complexes 1–3 exhibited enhanced cytotoxicity against tested human tumor cell lines BEL-7404, SK-OV-3, A549, A375, MGC-803 and NCI-H460, with IC50 values ranging from 0.31 to 30.76 μM. Complexes 1–3 exhibited lower cytotoxicity to HL-7702 than them to cancer cells. Complex 1 induced apoptotic death of BEL-7404, which involved mitochondria in the process. Caspase-3 activation assay indicated that 1 could be an efficient activator of caspase-3. DNA binding studies by UV–vis, DNA-melting, competitive binding, CD, viscosity measurement and agarose gel electrophoresis, revealed that intercalation might be the most likely binding mode of 1 with DNA. [Copyright &y& Elsevier]

Abstract In the present study, one novel Pt(II) complex, [Pt(CTD)(DMSO)Cl 2 ] (1) with 9‑chloro‑5,6,7,8‑tetrahydroacridine (CTD) as ligand, was synthesized and fully characterized. The CTD Pt(II) complex 1 was an anti-cancer drug candidate, and it possessed potent therapeutic efficacy for hepatocellular carcinoma (HCC). To explore its mechanism against HCC, Hep‑G2 cells were treated with the CTD Pt(II) complex 1 in vitro. MTT assay showed that the CTD Pt(II) complex 1 had inhibitory activity against five human cancer cells, such as SK‑OV‑3, Hep‑G2, NCI‑H460, MGC80‑3 and HL‑7702, and it displayed the strongest inhibitory activity against Hep‑G2 cells with an IC 50 value of 10.48 ± 0.83 μM. Moreover, the CTD Pt(II) complex 1 also exhibited selective cytotoxicity toward the cancer cells. In addition, the CTD Pt(II) complex 1 had low toxicity against non-cancerous HL‑7702 cells. The CTD Pt(II) complex 1 caused mitochondrial dysfunction, leading to the down-regulation of bcl‑2 protein and up-regulation of some mitochondria-initiated apoptotic proteins (including apaf‑1, cytochrome c and bax) in Hep‑G2 cells. Taken together, the CTD Pt(II) complex 1 -triggered Hep‑G2 cell apoptosis was mainly mediated via interaction with c‑myc promoter and disruption of mitochondrial pathway. Collectively, our findings supported that the CTD Pt(II) complex 1 could be used as a potential drug candidate for chemoprevention or chemotherapy of HCC. Graphical abstract The CTD Pt(II) complex 1 triggered Hep‑G2 cell apoptosis mainly through inhibiting telomerase activity by interacting with c‑myc promoter elements and disruption of mitochondrial pathway. Unlabelled Image Highlights • The CTD Pt(II) complex 1 with 9‑chloro‑5,6,7,8‑tetrahydroacridine was designed and synthesized. • The CTD Pt(II) complex 1 was more selective for Hep‑G2 tumor cells versus normal cells (HL‑7702). • The CTD Pt(II) complex 1 was a potent inhibitor of telomerase. • The CTD Pt(II) complex 1 also caused mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Graphical abstract Pt(II) complex 1- induced mitochondrial dysfunction could be an valuable target for the development of new anticancer drugs. Abstract Two new Pt(II) and Ru(II) complexes, [Pt(BFCY)Cl 2 ] (1) and [RuCl 2 (BMCY)(DMSO)] (2) with 3-(1H-benzoimidazol-2-yl)-8-fluoro-chromen-2-ylideneamine (BFCY) and 3-(1H-benzoimidazol-2-yl)-8-methyl-chromen-2-ylideneamine (BMCY), were synthesized. The BFCY Pt(II) complex 1 adopted an approximately four-coordinated square planar geometry, while BMCY complex 2 formed a distorted octahedral geometry. Among the seven selected human cancer cell lines, the two new Pt(II) and Ru(II) complexes 1 and 2 exhibited more potent activities against cisplatin-resistant SK-OV-3/DDP tumor cells (IC 50 = 2.08 ± 1.04 μM and 18.06 ± 0.36 μM, respectively), compared with the free BFCY and BMCY ligands as well as cisplatin. In addition, the BFCY Pt(II) complex 1 could induce cell cycle arrest in S phase and regulate the S-phase cell cycle-related proteins. Remarkably, the BFCY Pt(II) complex 1 also induced mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

A series of hybrids of scopoletin and substituted cinnamic acid were designed, synthesized and evaluated in vitro and in vivo against five human tumor cell lines [MCF-7, MDA-MB-231, A549, HCT-116, and HeLa] with doxorubicin as the positive control. Compounds 17a , 17b , 17c and 17g exhibited potent cytotoxic activity. Especially, compound 17b displayed broad spectrum activity with IC 50 values ranging from 0.249 μM to 0.684 μM. Moreover, in a preliminary pharmacological study, 17b not only remarkably induced cellular apoptosis, but also clearly induced A549 cells cycle arrest at S phase. In vivo study showed that 17b significantly suppressed tumor growth in a dose-dependent manner without causing the loss of the mean body weight of mice, which was superior to doxorubicin. These preliminary results indicate that 17b is an optimal anti-cancer leading compound and merit further structural modification. [ABSTRACT FROM AUTHOR]

Abstract: Three new compounds of Ga(III), Au(III), Sn(IV) with matrine (MT), [H-MT][GaCl4] ( 1 ), [H-MT][AuCl4] ( 2 ) and [Sn(H-MT)Cl5] ( 3 ), have been synthesized and characterized by elemental analysis, IR, ESI-MS and single crystal X-ray diffraction methods. The crystal structural analyses indicate that 1 and 2 are ionic compounds, whereas 3 is a tin(IV) complex formed by the monodentate MT via its carbonyl oxygen atom of MT coordinating to Sn(IV). Their in vitro cytotoxicity towards eight selected tumour cell lines has been evaluated by MTT (3-[4,5-Dimentylthiazole-2-yl]-2,5-diphenpyltetra-zolium bromide) method, and compounds 1 and 2 exhibit enhanced activity, such as 1 to SW480, 2 to HeLa, HepG2 and MCF-7, which exceeds matrine and cisplatin, and display synergistic contribution of their components. The cell cycle analyses show that compounds 1 , 3 and MT exhibit cell cycle arrest at the G2/M phase. Interactions of these compounds with calf thymus DNA (ct-DNA) have been investigated by spectroscopic analyses. The planar extension of the intercalative metal–matrine compounds increases the interaction of the metal–matrine with DNA, indicating that the cationic metal ions and configuration of the intercalated metal–matrine will affect the extent of interaction. Compound 2 , [H-MT][AuCl4], exhibits more intensive binding ability to DNA, which may correlate with intercalation and other action mode. The circular dichroism spectra of the ct-DNA bound with metal–MT compounds also suggest that ct-DNA interacted with 1 , 2 , 3 does not influence its secondary structure. Furthermore, both compounds 1 and 2 exhibit effective inhibition ability to topoisomerase (TOPO I) at concentration of 50μM, while matrine and compound 3 do not. [ABSTRACT FROM AUTHOR]