N-苄基吲哚类熊果酸衍生物的合成及抗肝癌活性

为开发高效低毒的抗肝癌天然产物衍生物,依据药物拼合原理设计并合成了一系列未见文献报道的熊果酸衍生物。将熊果酸与不同取代的N-苄基吲哚片段通过Claisen-Schmidt缩合反应得到目标化合物,其化学结构均经过核磁氢谱、核磁碳谱以及质谱的联合确证。采用噻唑蓝(MTT)法考察其体外抗肝癌活性,结果表明,2-{[1-(2-氟苄基)-1 H-吲哚基]-3-次甲基}-3-羰基熊果酸(4b)与2-{[1-(3-氟苄基)-1 H-吲哚基]-3-次甲基}-3-羰基熊果酸(4c)对HepG2及BEL-7402两种肝癌细胞株的抑制活性优于熊果酸及阳性对照药氟尿嘧啶,同时对正常肝细胞L02的毒性显著降低。化合物4c的体外抗肝癌活性最为理想(针对HepG2的IC₅₀值为3.22μmol/L,选择性指数为6.89),分子对接实验模拟其作用靶标或为RNA聚合酶Ⅱ,可对其深入研究用以开发高效低毒的抗肝癌药物。     

Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance

ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.     

Production of the criegee ozonide during the ozonation of 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes

It is likely that Criegee ozonides are formed in small amounts in the lungs of animals breathing ozone-containing air. This makes these compounds potential candidates to act as secondary toxins which relay the toxic effects of ozone deeper into lung tissue than ozone itself could penetrate. Therefore, we have determined the yields of Criegee ozonides from unsaturated lipids in liposomal systems as a model of the types of yields of Criegee ozonides that might be expected both in the lung lining fluid layer and in biological membranes. Ozonation of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes produced bothcis- andtrans-Criegee ozonides. These ozonides have been isolated by solid phase extraction and high-performance liquid chromatography of the ozonized lipid, and the products have been identified by two-dimensional¹H nuclear magnetic resonance. The combined yield of thecis- andtrans-Criegee ozonides is 10.7±2.8% (avg. ±SD, n=7) with small unilamellar liposomes and 10.6±2.7% (n=3) with large multilamellar liposomes. We had previously reported (Chem. Res. Toxicol. 5 505–511, 1992) that ozonation of methyl oleate in sodium dodecylsulfate micelles also produces an 11% yield of the Criegee ozonides. Thus, ozonation in a variety of models gives about 11% of the Criegee ozonide, suggesting that these products also would be formed in small but significant amounts in the lungs of animals breathing polluted air. Further research on the pharmacokinetics and possible toxicity of the Criegee ozonides of fatty acids is suggested.     

Synthesis of Fluorinated Imidazole[4,5f][1,10]phenanthroline Derivatives as Potential Inhibitors of Liver Cancer Cell Proliferation by Inducing Apoptosis via DNA Damage

Phenanthroline derivatives containing fluorinated imidazole ring are effective anti-neoplastic agents. Herein, a series of four fluorinated imidazole[4,5f][1,10]phenanthroline derivatives were synthesized and investigated as potential inhibitors to fight against the growth of liver cancer cells. The in vitro antitumor activity of targeted compounds have been evaluated by using MTT assay, and results showed that compound 4 (2-(2,3-difluorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) exhibited excellent inhibitory effect against the growth of various tumor cells, particularly for HepG2 cells, with IC₅₀ value of approximately 0.29 μM. This result has been further confirmed by colony formation assay, showing that compound 4 suppressed the proliferation of HepG2 cells. Moreover, cell apoptosis (AO/PI dual staining and flow cytometry) analyses as well as comet assay showed that compound 4 may induce apoptosis of HepG2 cells through triggering DNA damage. Furthermore, the in vivo anti-tumor activity were evaluated on zebrafish bearing HepG2 cells showed that compound 4 can observably block the growth of liver cancer cells. All in together, these compounds, particularly compound 4 , may be developed as a potential agent to treat liver cancer in the future.     

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine analogue (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC₅₀ equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.     

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose–response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs. Among the oleanane type triterpenoids, C2-[4-pyridinylidene]-oleanonic C28-morpholinyl amide exhibited sub-micromolar potencies against 15 different tumor cell lines and revealed particular selectivity for non-small cell lung cancer (HOP-92) with a GI₅₀ value of 0.0347 μM. On the other hand, superior results were observed for C2-[3-pyridinylidene]-ursonic N-methyl-piperazinyl amide 29, which exhibited a broad-spectrum inhibition activity with GI₅₀ < 1 μM against 33 tumor cell lines and <2 μM against all 60 cell lines. This compound has been further evaluated for cell cycle analysis to decipher the mechanism of action. The data indicate that compound 29 could exhibit both cytostatic and cytotoxic activity, depending on the cell line evaluated. The cytostatic activity appears to be determined by induction of the cell cycle arrest at the S (MCF-7, SH-SY5Y cells) or G₀/G₁ phases (A549 cells), whereas cytotoxicity of the compound against normal cells is nonspecific and arises from apoptosis without significant alterations in cell cycle distribution (HEK293 cells). Our results suggest that the antiproliferative effect of compound 29 is mediated through ROS-triggered apoptosis that involves mitochondrial membrane potential depolarization and caspase activation.     

Design,Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents

A novel series of synthetic functionalized arylvinyl-1,2,4-trioxanes ( 8 a – p ) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine-resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green-I fluorescence assay. Compounds 8 g (IC₅₀=0.051 μM; SI=589.41) and 8 m (IC₅₀=0.059 μM; SI=55.93) showed 11-fold and >9-fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC₅₀=0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl-1,2,4-trioxanes ( 8 g and 8 m ) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a – p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a , 8 h , 8 l , 8 m and 8 o (IC₅₀=1.65–31.7 μM; SI=1.08–10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC₅₀=100 μM), chloroquine (IC₅₀=100 μM) and artesunic acid (IC₅₀=9.85 μM; SI=0.76). In fact, the most active 4-naphthyl-substituted analogue 8 l (IC₅₀=1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m , against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl-vinyl-1,2,4-trioxanes ( 8 a – p ) has been shown to display dual potency as promising antiplasmodial and anticancer agents.     

Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis,Tyrosinase Inhibition,Mechanism of Action,DFT Calculation,and Molecular Docking Studies

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a–3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC₅₀ values of 1.51–3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8–70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC₅₀ distinct correlation with experiment.     

Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents

Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC₅₀ values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC₅₀ for HEK-293/IC₅₀ for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents.     

Anticancer Activity of Electron-Deficient Metal Complexes against Colorectal Cancer in vitro Models

An evaluation of the in vitro cytotoxicity of nine electron-deficient half-sandwich metal complexes towards two colorectal cancer cell lines (HCT116 p53+/+, HCT116 p53−/−) and one normal prostate cell line (PNT2) is presented herein. Three complexes were found to be equally cytotoxic towards both colorectal cancer cell lines, suggesting a p53-independent mechanism of action. These complexes are 12 to 34× more potent than cisplatin against HCT116 p53+/+ and HCT116 p53−/− cells. Furthermore, they were found to exhibit little or no cytotoxicity towards PNT2 normal cells, with selectivity ratios greater than 50. To gain an insight into the potential mechanisms of action of the most active compounds, their effects on the expression levels of a panel of genes were measured using qRT-PCR against treated HCT116 p53+/+ and HCT116 p53−/− cells, and cell-cycle analysis was carried out.     

铁棒锤总生物碱、3-乙酰乌头碱和宋果灵抗肿瘤活性研究

本文从铁棒锤总生物碱中提取分离得到3-乙酰乌头碱和宋果灵,应用MTT比色法研究药物的细胞毒型、细胞形态学实验方法观察细胞形态、流式细胞术分析细胞凋亡和细胞周期,激光共聚焦从形态上分析细胞的凋亡等多方面对其抑制人肝癌细胞的生理活性进行研究。3-乙酰乌头碱和宋果灵的抗肿瘤细胞研究表明,随着浓度的逐步增加,其抗肿瘤效果逐步增强;药物作用于人肝癌细胞后,细胞数量明显减少,具有明显的抑制HepG2生长的能力,并且使细胞发生早期凋亡和晚期凋亡的比率增大,随处理时间的延长细胞G1期细胞逐渐增多,G2期和S期细胞逐渐减少。3-乙酰乌头碱和宋果灵的体外抗肿瘤实验研究初步证实了其具有抑制肿瘤细胞增殖、诱导肝癌细胞凋亡的作用,显示3-乙酰乌头碱和宋果灵可能成为新的肝癌细胞凋亡诱导剂,为寻找新型抗肿瘤药物的先导化合物奠定了基础。     

Ozonation of sunflower oil: Spectroscopic monitoring of the degree of unsaturation

Consumption of ozone by unsaturated FA moieties of sunflower oil (SFO) was monitored by ¹H NMR and FTIR spectroscopy. Degradation of linoleate was found to be 1.5 and 1.8 times higher than oleate when SFO was ozonized in the absence and presence of water, respectively. Products of ozonation in both cases include aldehydes and ozonides with 1,2,4-trioxolane ring. Hydroxyl-containing compounds, which could be carboxylic acids and/or hydroperoxides, were also detected in samples ozonized in the presence of water. The extent of ozonation had very little effect on the aldehyde/ozonide ratio obtained from NMR spectra, especially in the ozonation of neast SFO. The aldehyde/ozonide ratios obtained regardless of the extent of ozonation were 10.5:89.5 and 46.6:53.4 for SFO ozonized in the absence and presence of water, respectively.     

Synthesis and Anticancer Evaluation of 1,4-Naphthoquinone Derivatives Containing a Phenylaminosulfanyl Moiety

1,4-Naphthoquinones are exceptional building blocks in organic synthesis and have been used to synthesize several well-known pharmaceutically active agents. Herein we report the synthesis, structural characterization, and biological evaluation of new phenylaminosulfanyl-1,4-naphthoquinone derivatives. We evaluated the cytotoxic activity of the synthesized compounds against three human cancer cell lines: A549, HeLa, and MCF-7. Most of the synthesized compounds displayed potent cytotoxic activity. Specifically, compounds 5 e [3,5-dichloro-N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)benzamide], 5 f [N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)-3,5-dinitrobenzamide], and 5 p [N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)thiophene-2-carboxamide] showed remarkable cytotoxic activity. The synthesized compounds showed low toxicity in normal human kidney HEK293 cells. The cytotoxic mechanism of compounds 5 e , 5 f , and 5 p was explored in MCF-7 cells. The results confirmed that these three compounds induce apoptosis and arrest the cell cycle at the G₁ phase. In addition, compounds 5 e , 5 f , and 5 p were found to induce apoptosis via upregulation of caspase-3 and caspase-7 proteins as well as by upregulation of the gene expression levels of caspases-3 and -7. Our findings demonstrate that compounds 5 e , 5 f , and 5 p could be potent agents against a number of cancer types.     

Cytotoxic salan-titanium(IV) complexes: high activity toward a range of sensitive and drug-resistant cell lines, and mechanistic insights

The cytotoxicities of highly efficient salan-Ti(IV) complexes toward a range of cell lines, including drug-resistant cells, are reported along with preliminary mechanistic insights. Five salan-Ti(IV) complexes were investigated toward eight different human and murine cancer-derived cell lines, including colon, ovarian, lung, cervical, pancreatic, leukemic, skin, and breast. The salan complexes are more active toward the cells analyzed than cisplatin and the known titanium compound (bzac)(2) Ti(OiPr)(2) , and no cell line resistant to the salan complexes was identified. Moreover, the salan-Ti(IV) complexes are highly active toward both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780CisR) human ovarian cancer cell lines. Similarly, the salan complexes are cytotoxic toward multi-drug-resistant (ABCB1-expressing) mouse lymphoma cell lines HU-1 and HU-2. Importantly, minimal or no activity was observed toward primary murine cells (bone marrow, heart, liver, kidney, spleen, and lung), supporting selectivity for cancer cells. Additionally, the salan complexes maintain high cytotoxicity for up to 24 h following exposure to cell culture medium, whereas reference complexes (bzac)(2) Ti(OiPr)(2) and Cp(2) TiCl(2) rapidly lose much of their activity upon exposure to medium, within ~1 h. The upregulation of p53 followed by cell-cycle arrest in G(1) phase is likely one mechanism of action of the salan complexes. Taken together, the results indicate that these compounds are selectively toxic to cancer cells and are able to circumvent two independent mechanisms of drug resistance, thus expanding the scope of their potential medicinal utility.     

Preparation of Titanocene–Gold Compounds Based on Highly Active Gold(I)-N-Heterocyclic Carbene Anticancer Agents: Preliminary in vitro Studies in Renal and Prostate Cancer Cell Lines

Heterometallic titanocene-based compounds containing gold(I)-phosphane fragments have been extremely successful against renal cancer in vitro and in vivo. The exchange of phosphane by N-heterocyclic carbene ligands to improve or modulate their pharmacological profile afforded bimetallic complexes effective against prostate cancer, but less effective against renal cancer in vitro. Herein we report the synthesis of new bimetallic Ti–Au compounds by the incorporation of two previously reported highly active gold(I)-N-heterocyclic carbene fragments derived from 4,5-diarylimidazoles. The two new compounds [(η⁵-C₅H₅)₂TiMe(μ-mba)Au(NHC)] (where NHC=1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene, NHC-Bn 2 a ; or 1,3-diethyl-4,5-diphenylimidazol-2-ylidene, NHC-Et 2 b ) with the dual linker (-OC(O)-p-C₆H₄-S-) containing both a carboxylate and a thiolate group were evaluated in vitro against renal and prostate cancer cell lines. The compounds were found to be more cytotoxic than previously described Ti–Au compounds containing non-optimized gold(I)-N-heterocyclic fragments. We present studies to evaluate their effects on cell death pathways, migration, inhibition of thioredoxin reductase (TrxR) and vascular endothelial growth factor (VEGF) in the PC3 prostate cancer cell line. The results show that the incorporation of a second metallic fragment such as titanocene into biologically active gold(I) compounds improves their pharmacological profile.     

Toxicity of fatty ozonides and peroxides

Studies on the acute toxicity of the ozonides and hydroperoxides of methyl linoleate are reported. High purity preparations of these compounds were injected intravenously or administered orally to adult male rats. The lethal dose by iv injection of these compounds was virtually the same −0.07 mmol/100 g body wt. No deaths were caused in a 24 hr period by single oral dosages of these compounds of ca. 10-fold that causing death by the iv route. The major effect of these compounds was on the lungs. The lungs became enlarged from edema and accumulation of fluid, and the animals died of lung congestion and injury similar to the effects of ozone toxicity. There was no destruction of vitamin E in the tissues of animals given lethal dosages of ozonides or peroxides intravenously, but significant changes occurred in fatty acid composition of the lipids of the serum and lung. Arachidonic acid increased at the expense of linoleic and oleic acids in these tissues. Only small amounts of peroxidic and TBA positive substances were detected in lung and serum, indicating that the injected ozonides and hydroperoxides were destroyed in the tissues.     

Novel Pyridine-Based Hydroxamates and 2′-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide ( 5 b ) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6 – 8 , 9 b , as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide ( 9 b ) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates ( 9 a , 9 c – f , and 11 a – f ) and 2′-aminoanilides ( 10 a – f and 12 a – f ), related to 9 b , to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC₅₀: 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2′-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC₅₀^HDAC3=0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e , 11 c , and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b , 11 c , 10 b , 10 e , and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC₅₀ values at single-digit to sub-micromolar level.     

Antitumor Activity of Ionic Liquids Based on Ampicillin

Significant antiproliferative effects against various tumor cell lines were observed with novel ampicillin salts as ionic liquids. The combination of anionic ampicillin with appropriate ammonium, imidazolium, phosphonium, and pyridinium cations yielded active pharmaceutical ingredient ionic liquids (API‐ILs) that show potent antiproliferative activities against five different human cancer cell lines: T47D (breast), PC3 (prostate), HepG2 (liver), MG63 (osteosarcoma), and RKO (colon). Some API‐ILs showed IC₅₀ values between 5 and 42 nM , activities that stand in dramatic contrast to the negligible cytotoxic activity level shown by the ampicillin sodium salt. Moreover, very low cytotoxicity against two primary cell lines—skin (SF) and gingival fibroblasts (GF)—indicates that the majority of these API‐ILs are nontoxic to normal human cell lines. The most promising combination of antitumor activity and low toxicity toward healthy cells was observed for the 1‐hydroxyethyl‐3‐methylimidazolium–ampicillin pair ([C₂OHMIM][Amp]), making this the most suitable lead API‐IL for future studies.     

Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells

Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds—namely, compounds 11 and 12—were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC₅₀ values of 1.7 ± 0.5 μM for 11 and 2.0 ± 0.7 μM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed long-lasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.