Norcantharimide analogues possessing terminal phosphate esters and their anti-cancer activity

A family of norcantharidin analogues possessing a terminal alcohol (ethanol, propanol, butanol, pentanol, hexanol and cyclohexanol) moiety were treated with either chlorodiethyl, chlorodiphenyl or chloro-bis-trichloroethyl-phosphate to afford highly focused libraries of the corresponding phosphate esters. Subsequent biological screening against a panel of nine human cancer cell lines identified a trend between the ease of phosphate unmasking (phosphate ester hydrolysis) and cell death. The most potent analogues possessed either a diphenyl or a bis-trichloroethyl moiety. The effect of alkyl spacer was also examined with the hexyl analogues typically more potent. 4-Aza-4-(3-{bis(2,2,2-trichloroethyl)phosphate}propyl)-10-oxatricyclo[5.2.1.0]decane-3,5-dione (10b) was the most potent analogue synthesised with an average GI(50) of 11 μM across a panel of nine human carcinoma cell lines: colon carcinoma (HT29 and SW480); breast carcinoma (MCF-7); ovarian carcinoma (A2780); lung carcinoma (H460); skin carcinoma (A431); prostate carcinoma (DU145); neuronal carcinoma (BE2-C) and brain carcinoma (SJ-G2). This represents a fivefold improvement in anti-proliferative activity relative to the lead, norcantharidin.     

Modified norcantharidins; synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity

Fourteen modified norcantharidin analogues have been synthesised and screened for their ability to inhibit the serine/threonine protein phosphatases 1 and 2A. The most potent compounds found were 10 (PP1 IC(50)=13+/-5 microM; PP2A IC(50)=7+/-3 microM) and 16 (PP1 IC(50)=18+/-8 microM; PP2A IC(50)=3.2+/-0.4 microM). Overall, only analogues possessing at least one acidic residue at the former anhydride warhead displayed any PP1 or PP2A inhibitory action. The ability of these analogues to inhibit PP1 and PP2A correlates well with their observed anti-cancer activity against a panel of five cancer cell lines: A2780 (human ovarian carcinoma), G401 (human kidney carcinoma), HT29 (human colorectal carcinoma), H460 (human lung carcinoma) and L1210 (murine leukemia).     

Norcantharidin-induced post-G(2)/M apoptosis is dependent on wild-type p53 gene

Norcantharidin (NCTD), a synthetic analogue of phosphatase type 2A inhibitors, cantharidin, was shown to have limited effects in treating human and animal tumors. The tumor cell killing mechanisms by norcantharidin, however, remain unclear. In this report, we wished to investigate the mechanisms of norcantharidin-mediated cytotoxicity. Effort was made to investigate whether norcantharidin exerted its cytotoxicity through a p53-dependent or -independent mechanism. RT-2 (wtp53) and U251 (mutant p53) glioblastoma cell lines were exposed to norcantharidin at different dosages. Time-course fluorescent-activated cell sorting (FACS) analysis showed that high doses of norcantharidin arrested the cells at the G(2)/M phase and subsequent post-G(2)/M apoptosis in RT-2 cell line. In comparison, the U251 cell line was found resistant to norcantharidin-induced cytotoxicity. Restoring wild-type p53 gene function in the U251 cell line after adenoviral infections induced tumor cell cytotoxicity after exposure to norcantharidin. These results showed that norcantharidin kills tumor cells efficiently corresponding to their endogenous p53 gene status. The results also showed the feasibility of using adenoviral p53 gene therapy to enhance chemosensitivity of tumor cells to norcantharidin.     

The antiplasmodial activity of norcantharidin analogs

The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 μM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 μM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 μM, representing a fivefold enhancement over norcantharidin.     

Heterocyclic substituted cantharidin and norcantharidin analogues--synthesis, protein phosphatase (1 and 2A) inhibition, and anti-cancer activity

Norcantharidin (3) is a potent PP1 (IC(50)=9.0+/-1.4 microM) and PP2A (IC(50)=3.0+/-0.4 microM) inhibitor with 3-fold PP2A selectivity and induces growth inhibition (GI(50) approximately 45 microM) across a range of human cancer cell lines including those of colorectal (HT29, SW480), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (DU145), neuroblastoma (BE2-C), and glioblastoma (SJ-G2) origin. Until now limited modifications to the parent compound have been tolerated. Surprisingly, simple heterocyclic half-acid norcantharidin analogues are more active than the original lead compound, with the morphilino-substituted (9) being a more potent (IC(50)=2.8+/-0.10 microM) and selective (4.6-fold) PP2A inhibitor with greater in vitro cytotoxicity (GI(50) approximately 9.6 microM) relative to norcantharidin. The analogous thiomorpholine-substituted (10) displays increased PP1 inhibition (IC(50)=3.2+/-0 microM) and reduced PP2A inhibition (IC(50)=5.1+/-0.41 microM), to norcantharidin. Synthesis of the analogous cantharidin analogue (19) with incorporation of the amine nitrogen into the heterocycle further increases PP1 (IC(50)=5.9+/-2.2 microM) and PP2A (IC(50)=0.79+/-0.1 microM) inhibition and cell cytotoxicity (GI(50) approximately 3.3 microM). These analogues represent the most potent cantharidin analogues thus reported.     

Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity

Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low muM IC(50)s) comparable to that of norcantharidin (PP1 IC(50)=10.3+/-1.37 microM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC(50)=2.69+/-1.37 microM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC(50)=6.5+/-2.3 microM; and PP2A IC(50)=7.9+/-0.82 microM (PP1/PP2A=0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC(50)=48+/-9; and PP2A IC(5) 85+/-3 microM (PP1/PP2A=0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC(50)s of 89+/-6 and 42+/-3 microM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.     

Comparison of Transfection Efficiency of Nonviral Gene Transfer Reagents

This study compared six commercially available reagents (Arrest-In, ExpressFect, FuGENE HD, jetPEI, Lipofectamine 2000, and SuperFect) for gene transfection. We examined the efficiency and cytotoxicity using nine different cell lines (MC3T3-E1 mouse preosteoblasts, PT-30 human epithelial precancer cells, C3H10T1/2 mouse stem cells, MCF-7 human breast cancer cells, HeLa human cervical cancer, C2C12 mouse myoblasts, Hep G2 human hepatocellular carcinoma, 4T1 mouse mammary carcinoma, and HCT116 human colorectal carcinoma), and primary cells (HEKn human epidermal keratinocytes) with two different plasmid DNAs encoding luciferase or β-galactosidase in the presence or absence of serum. Maximal transfection efficiency in MC3T3-E1, C3H10T1/2, HeLa, C2C12, Hep G2, and HCT116 was seen using FuGENE HD, in PT-30, 4T1, and HEKn was seen using Arrest-In, and in MCF-7 was seen using jetPEI. Determination of cytotoxicity showed that the largest amount of viable cells was found after transfection with jetPEI and ExpressFect. These results suggest that FuGENE HD is the most preferred transfection reagent for many cell lines, followed by Arrest-In and jetPEI. These results may be useful for improving nonviral gene and cell therapy applications.     

In vitro and in vivo anticancer activity of a synthetic glycolipid as Toll-like receptor 4 (TLR4) activator

Activation of Toll-like receptor 4 (TLR4) triggers the innate immune response and leads to the induction of adaptive immunity. TLR4 agonists are known to function as immunostimulants and exhibit promising therapeutic potential for cancer immunotherapy. We have previously developed a synthetic serine-based glycolipid (designated as CCL-34) that can activate TLR4-dependent signaling pathways. In this study, the anticancer immunity of CCL-34 was further demonstrated. CCL-34-activated macrophages induced cancer cell death via the apoptotic pathway, and this cytotoxicity was significantly inhibited by NG-monomethyl-L-arginine (an inducible NOS inhibitor). Notably, conditioned medium collected from CCL-34-treated splenocytes also induced cytotoxicity toward cancer cells. Furthermore, CCL-34 treatment suppressed tumor growth and increased the survival rate in TLR4-functional C3H/HeN mice but not in TLR4-defective C3H/HeJ mice. Increased apoptosis, the induction of cytokines (IFN-γ and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice. Structure-and-activity relationship analysis of CCL-34 and its structural analogs revealed that a sugar moiety is essential for its activity. However, the substitution of the galactose in CCL-34 with glucose or fucose did not reduce its activity. Altogether, this study reveals the anticancer activity of a new synthetic TLR4 agonist and broadens the molecular basis of TLR4-activating glycolipids.     

Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents

A series of coumarin-chalcone hybrids have been synthesized and evaluated for their in vitro cytotoxicity against a panel of four human cancer cell lines and normal fibroblasts (NIH3T3). Among 21 compounds screened, three compounds (23, 25 and 26) showed IC(50) range from 3.59 to 8.12 μM. The most promising compound 26 showed around 30-fold more selectivity towards C33A (cervical carcinoma) cells over normal fibroblast NIH3T3 cells with an IC(50) value of 3.59 μM.     

Synthesis and Antioxidant Activity of New Norcantharidin Analogs

New norcantharidin analogs were designed and obtained as compounds with biological activity. As a starting material, exo‐7‐oxabicyclo[2.2.1]heptane‐2,3‐dicarboxylic acid anhydride was used. Three groups of compounds: dicarboximides, triazoles and thiazolidines were obtained in multistep reactions. The ¹H‐ and ¹³C‐NMR spectra were used to confirm the structures of all obtained products and they were in agreement with the proposed structure of substances. All derivatives were screened for their antioxidant activity. The most promising group was dicarboximides ( 1 – 4 , 6 ). Derivatives 2–4 displayed antioxidant activity with EC₅₀=7.75–10.89 μg/ml, which may be comparable to strong antioxidant Trolox (EC₅₀=6.13 μg/ml). Excellent activity with EC₅₀=10.75 μg/ml also presented norcantharidin analog with 1,2,4‐triazole system ( 12 ).     

Synthesis,characterization, and anticancer evaluation of novel 4-hydrazinothiazole analogs

Single-step synthesis of novel 4-hydrazinothiazole derivatives 6a–e was achieved under mild conditions using the sequential four-components method involving isothiocyanate, aminoguanidine, carbonyl adduct, and α-haloketone derivatives. Deprotection of these hydrazinothiazoles was influenced by acylation, providing a novel group of diacylated molecular structures with a broader scope for the design of thiazolyl-containing drugs 7a and 7b . FTIR, ¹H/¹³C NMR, LC–MS spectroscopy, and CHN elemental analyses were used to study the compound chemical structures. Using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human periodontal ligament fibroblast (HPDLF) cells, the 4-hydrazinothiazole derivatives were screened for cytotoxicity in an in vitro cytotoxicity investigation. The 4-hydrazinothiazole compound 6b bearing an isopropylidene-hydrazino group demonstrated strongly potent cytotoxicity against CAKI1 (IC₅₀ = 1.65 ± 0.24 μM) and A498 (IC₅₀ of 0.85 ± 0.24 μM). Furthermore, the chloroacetyl-containing thiazole compound 7a displayed efficient inhibition of growth against the test cell lines CAKI1 and A498 at low micromolar concentrations, IC₅₀ 0.78 and 0.74 μM, respectively.     

Synthesis, antimicrobial and anticancer activities of a novel series of diphenyl 1-(pyridin-3-yl)ethylphosphonates

A novel series of diphenyl 1-(arylamino)-1-(pyridin-3-yl)ethylphosphonates 1-5 was obtained in high yields from reactions of 3-acetyl pyridine with aromatic amines and triphenylphosphite in the presence of lithium perchlorate as a catalyst. The structures of the synthesized compounds were confirmed by IR, (1)H NMR spectral data and microanalyses. Compounds 1-5 showed high antimicrobial activities against Escherichia coli (NCIM2065) as a Gram-negative bacterium, Bacillus subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram-positive bacteria and Candidaalbicans and Saccharomyces cerevisiae as fungi, at low concentrations (10-100 μg/mL). Also, the synthesized compounds showed significant cytotoxicity anticancer activities against liver carcinoma cell line (HepG2) and human breast adenocarcinoma cell line (MCF7). The lethal dose of the synthesized compounds was also determined and indicated that most compounds are safe to use.     

Microwave-assisted solvent-free synthesis of some novel thiazole-substituted thiosemicarbazone analogues: antimicrobial and anticancer studies

The increased resistance to antibiotics has compelled researchers to devise novel active compounds targeting multidrug-resistant pathogenic microorganisms. A series of thiosemicarbazone derivatives was synthesized by reacting thiosemicarbazide with 2-aryl-4-formylthiazole, 2-aryl-5-formyl-4-methylthiazole, and/or 5-acetyl-2-aryl-4-methylthiazole compounds. These thiosemicarbazone-based thiazole adducts were evaluated for their inhibitory activities against tuberculosis H37Ra and Bovis BCG mycobacteria. Their cytotoxicity was assessed against two cancer cell lines: colonic carcinoma (HCT-116) and cervical cancer (HeLa). Notably, these thiosemicarbazones exhibited minimal cytotoxic effects on these cell lines even at their highest concentrations. Furthermore, the prepared thiosemicarbazone derivatives demonstrated significant antimicrobial efficacy against Bacillus subtilis and Staphylococcus aureus (Gram-positive bacterial pathogens) as well as Escherichia coli and Pseudomonas fluorescens (Gram-negative bacterial pathogens). While most of the prepared thiosemicarbazone derivatives exhibited moderate activity against Candida albicans (a fungal strain), their performance was notable. The thiosemicarbazone-based thiazole adducts were also successfully synthesized using a solvent-free approach under microwave irradiation. Compared with conventional reflux methods, the microwave-assisted technique yielded high thiazole yields within just 5 min, obviating the need for catalysis. This study signifies significant strides toward the rational design of more potent antimycobacterial agents.     

Heat shock inactivates cellular antioxidant defenses against hydrogen peroxide: protection by glucose

Hyperthermia is used in cancer treatment and potentiates the cytotoxicity of radiation and certain chemotherapy drugs. The mechanism(s) of heat killing and those involved in heat potentiation of cytotoxic modalities are not understood. This study examines whether heat shock causes a redox imbalance, leading to oxidative changes in Chinese hamster ovary cells. Decreases in the GSH/GSSG ratio reflected an oxidative imbalance in heated (42 degrees C) and in H(2)O(2)-challenged cells. Glucose provided protection against these changes. Glucose also protected cells against cytotoxicity of H(2)O(2) and/or hyperthermia (42 to 43 degrees C). Glucose appears to protect cells against H(2)O(2) and heat shock by providing NADPH through its metabolism via the pentose phosphate cycle (PC). When cells were deprived of glucose, there was a marked decrease in the GSH/GSSG ratio and in NADPH levels, indicating a severe redox imbalance. Glucose deprivation caused cell death, which was consistent with increased accumulation of H(2)O(2), since three distinct H(2)O(2)-detoxifying systems (N-acetyl-L-cysteine, sodium pyruvate, and catalase) rescued cells against cytotoxicity. Nontoxic levels of H(2)O(2) stimulated a corresponding increase in both PC activity and NADPH levels. NADPH levels and basal activity of the PC increased at 42 degrees C. However, the oxidant-stimulated increases in PC activity and NADPH levels were lost in heated cells. Therefore, heat shock inactivates an important cellular defense mechanism against oxidants. These findings suggest that heat shock may enhance the cytotoxicity of oxidants by inhibiting increases in PC activity following oxidative stress. These data are potentially relevant to understanding the potentiation of cytotoxicity of radiation and oxidant-generating drugs by heat shock, used in combined modality cancer treatment.     

Newin vitro fluorimetric microtitration assays for toxicological screening of drugs

Flow cytometry has been widely used to quantify fluorescent probes in cell culture. However, FCM is not adapted to toxicological screenings due to the cost, the length and the poor reproducibility of this technique. Moreover, several multicenter studies have preferred microtitration methodologies for drug screening. A new fluorimetric technology has been designed that is sensitive and adapted to direct screening in 96-well microplates. This fluorimeter uses cold light technology (CLF) with chemical and physical modifications of the lighting system (Rat et al., 1995). CLF allows reading of UV, visible and near infrared fluorescence by increasing light energy (from 1000 to 2300 lumens) and reducing the calorific part of light (IR>900 nm, Joule effect). It induces a decrease in background and a 500- to 1000-fold improvement of detection limit of probes in comparison with classical fluorimeters and permits detection of pg/ml to fg/ml. CLF allows easy evaluation of cell injury induced by physical agents (UVA) or chemical toxins (CCl₄). Four biological endpoints for cytotoxicity evaluation have been tested with several probes: proliferation (H33258); viability (fluorescent Neutral Red); cell-cell adhesion (calcein-AM); and mitochondrial metabolic effects (Rhodamine 123). Rh 123 assay appeared more sensitive than fluorimetric or photometric detection of Neutral Red assay. Cold light fluorimetry (CLF) permits direct detection of low concentrations of probes (pg/ml to fg/ml). CLF is shown to improve classical cytotoxicity assays and, owing to its adaptability to microtitration (in 6-, 12- or 96-well plates and in Petri dishes), it is thus a promising alternative to flow cytometry for drug cytotoxicity screening.Abbreviations CLF cold light fluorimetry - FCM flow cytometry - H33258 Hoechst 33258 - IR infrared - NIR near infrared - UV ultraviolet - MTT tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide) - Rh123 Rhodamine 123     

Effect of metal ion complexation and chalcogen donor identity on the antiproliferative activity of 2-acetylpyridine N,N-dimethyl(chalcogen)semicarbazones

Three chalcogensemicarbazones, viz., 2-acetylpyridine N,N-dimethylsemicarbazone (HL(1)), 2-acetylpyridine N,N-dimethylthiosemicarbazone (HL(2)) and 2-acetylpyridine N,N-dimethylselenosemicarbazone (HL(3)), their corresponding gallium(III) complexes [Ga(L(1-3))(2)]PF(6) and the ruthenium(III) compound [Ru(L(2))(2)]PF(6) have been prepared and characterised by X-ray crystallography and spectroscopic techniques (IR, UV/vis, (1)H, (13)C, (15)N, (77)Se NMR) in order to elucidate the effect of metal ion complexation and chalcogen donor identity on the cytotoxicity of chalcogensemicarbazones in two human tumour cell lines 41M (ovarian carcinoma) and SK-BR-3 (mammary carcinoma).     

Syntheses of 1-[(2-hydroxyethoxy)methyl]- and 1-[(1,3-dihydroxy-2-propoxy)methyl]- derivatives of 5-substituted-2,4-difluorobenzene: unnatural acyclo thymidine mimics for evaluation as anticancer and antiviral agents

A group of 1-[(2-hydroxyethoxy)methyl]- (12) and 1-[(1,3-dihydroxy-2-propoxy)methyl]- (13) derivatives of 2,4-difluorobenzene possessing a variety of C-5 substituents (R = Me, H, I, NO2) were designed with the expectation that they may serve as acyclic 5-substituted-2'-deoxyuridine (thymidine) mimics. Compounds 12 and 13 (R = Me, H, I) were inactive as anticancer agents (CC50 = 10(-3) to 10(-4) M range), whereas the 5-nitro compounds (12d, 13d) exhibited weak-to-moderate cytotoxicity (CC50 = 10(-5) to 10(-6) M range) against a variety of cancer cell lines. All compounds prepared (12a-d, 13a-d) were inactive as antiviral agents in a broad-spectrum antiviral screen that also included the human immunodeficiency virus (HIV-1 and HIV-2) and herpes simplex virus (HSV-1 and HSV-2).     

Suppression of phorbol myristate acetate-triggering of macrophage H2O2 release by sarcoma 180 originating factor

A high molecular weight proteinaceous factor in the cell extract of sarcoma 180 (S-180) was found to inhibit phorbol myristate acetate (PMA)-triggering of macrophage H2O2 release. This factor (S-180 factor) was stable at 56 C for 1 hr and resistant to ultraviolet-irradiation. The S-180 factor inhibited the specific binding of PMA to macrophages and this was accompanied by a parallel reduction of PMA-triggered H2O2 release. S-180 factor preferentially depressed macrophage H2O2 release in response to phorbol diesters including PMA, 4 beta-phorbol 12 13 beta,13 alpha-diacetate, 4 beta-phorbol 12 beta,13 alpha-didecanoate, 4 beta-phorbol 12 beta,13 alpha-dibenzoate, and 4-omicron-methyl-PMA rather than the H2O2 release triggered by wheat germ agglutinin or by phagocytosis of latex particles. The S-180 factor failed to affect the PMA-elicited macrophage cell spreading and macrophage phagocytic activity against latex beads with or without PMA-mediated stimulation. A similar inhibitory factor was found in the extracts of some other murine tumor cells (Ehrlich carcinoma and thymic leukemia) and normal cells (liver, spleen, and peritoneal exudate cells).     

The phosphatidylcholine transfer protein from bovine liver discriminates between phosphatidylcholine isomers. A monolayer study

The activity of the phosphatidylcholine transfer protein from bovine liver toward phosphatidylcholine isomers carrying a long and a short fatty acyl chain on either the sn-1- or sn-2-position was determined by way of the monolayer-vesicle assay. In this assay equimolar mixtures of the isomers were spread at the air/water interface and their transfer measured to the vesicles in the subphase initiated by addition of the transfer protein. The following isomers were tested: 1-decanoyl-2-[3H]oleoyl-sn-glycero-3-phosphocholine (C10:0/[3H]C18:1-PC) and 1-oleoyl-2-decanoyl-sn-glycero-3-phospho[14C]choline (C18:1/C10:0-[14C]PC); 1-lauroyl-2-[3H]oleoyl-sn-glycero-3-phosphocholine (C12:0/[3H]C18:1-PC) and 1-oleoyl-2-[14C]lauroyl-sn-glycero-3-phosphocholine (C18:1/[14C]C12:0-PC); 1-myristoyl-2-[3H]oleoyl-sn-glycero-3-phosphocholine (C14:0/[3H]C18:1-PC) and 1-oleoyl,2-myristoyl-sn-glycero-3-phospho[14C]choline (C18:1/C14:0-[14C]PC). It was found that the protein transferred C10:0/[3H]C18:1-PC twice as fast as C18:1/C10:0-[14C]PC. Similar differences in rate were observed for C12:0/[3H]C18:1-Pc and C18:1/[14C]C12:0-PC but not for the isomers carrying myristic acid. We propose that the transfer protein can discriminate between PC isomers due to the presence of distinct binding sites for the sn-1- and sn-2-acyl chain (Berkhout et al. (1984) Biochemistry, 23, 1505-1513).     

Synthesis of substituted benzimidazolyl curcumin mimics and their anticancer activity

A novel curcumin mimic library (14a-14h and 15a-15h) possessing variously substituted benzimidazole groups was synthesized through the aldol reaction of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (7) or (E)-4-(3-hydroxy-4-methoxyphenyl)but-3-en-2-one (13) with diversely substituted benzimidazolyl-2-carbaldehyde (12a-12h). The MTT assay of the cancer cells MCF-7, SH-SY5Y, HEP-G2, and H460 showed that compound 14c with IC(50) of 1.0 and 1.9μM has a strong inhibitory effect on the growth of SH-SY5Y and Hep-G2 cells, respectively, and that compound 15h with IC(50) of 1.9μM has a strong inhibitory effect on the growth of MCF-7 cancer cells.