Semi-synthesis and anti-proliferative activity evaluation of novel analogues of Honokiol

A series of honokiol analogues were synthesized by modifying the 5- and/or 3′-position(s) of honokiol to assess their anti-tumor effects. Some compounds exerted more potent anti-proliferative activities than those of honokiol on K562 leukemia cells, A549 alveolar basal epithelial cells, SPC-A1 adenocarcinoma cells and A2780 human ovarian carcinoma cells in vitro. Compounds 2b, 3a, and 3c displayed most potent anti-proliferative activities against these tested cell strains and their anti-drug resistance effects were evaluated in vitro on cisplatin-resistant A2780 human ovarian carcinoma cells. The structure–activity relationship was also proposed.     

Cytotoxicity and DNA binding property of the dimers of triphenylethylene–coumarin hybrid with one amino side chain

Novel dimers of triphenylethylene–coumarin hybrid containing one amino side chain were designed and synthesized by the condensation of four dicarboxylic acids with the amino monomeric hybrids catalyzed by HATU and DIPEA at room temperature. The adding order of the reactants had a significant effect on the condensation reaction when the malonic acid was used. The dimeric compounds 7a and 7b linked by the malonic acid, showed a broad-spectrum and good anti-proliferative activity against four tumor cells and low cytotoxicity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b, 8b, 9b, and 10b had significant interactions with Ct-DNA by the intercalative mode of binding. Both the DNA binding properties and the anti-proliferative activities would be enhanced by dimerization of the monomeric hybrid with one amino side chain, and were significantly affected by the length of the linker (dicarboxylic acids).     

Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4-oxadiazole moiety core with antitumor activities

Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.     

Synthesis,G-Quadruplex DNA binding and cytotoxic properties of naphthalimide substituted styryl dyes

G-Quadruplex DNAs, formed by G-rich DNA sequences in human genes, are promising targets for design of cancer drugs. In this study, two naphthalimide substituted styryl dyes with different sizes of aromatic groups were synthesized. The spectral analysis showed that the dye X-2 with a large aromatic group formed aggregates in buffer solution displaying very weak fluorescence intensity, and disaggregated in the presence of G-Quadruplex DNAs with large intensity enhancements (up to ~1800 fold). Moreover, X-2 displayed good selectivity to G-Quadruplex DNAs. In contrast, dye X-3 with the smaller aromatic group had much lower fluorescence enhancements and poor selectivity to G-Quadruplex DNAs, suggesting that the suitably sized aromatic ring was essential for the interaction with G-Quadruplex. Further binding studies suggested that X-2 mainly bound on G-quartet surface through end-stacking mode. Cytotoxicity assay showed that both of the two dyes showed good anti-proliferative activities against the cancer cell lines and less cytotoxicity in non-malignant cell lines, which were better than a standard drug 5-fluorouracil. In addition, living cell imaging was also studied and demonstrated the potential applications of the new dye X-2 in bioassays and cell imaging.     

Analogues of the Inhoffen–Lythgoe diol with anti-proliferative activity

The anti-proliferative activity of a series of ester- and amide-linked Inhoffen–Lythgoe side chain analogues is reported. Whereas the Inhoffen–Lythgoe diol was inactive in these studies, a number of aromatic and aliphatic ester-linked side chains demonstrated modest in vitro growth inhibition in two human cancepar cell lines, U87MG (glioblastoma) and HT-29 (colorectal adenocarcinoma). Structure–activity relationship (SAR) studies demonstrated the most active aromatic (13) and aliphatic (25 and 29) substituted analogues were approximately equipotent in U87MG and HT-29 cells. Further evaluation of 13, 25, and 29 indicated these analogues do not activate canonical vitamin D signaling nor antagonize Hedgehog (Hh) signaling. Thus, the cellular mechanism(s) that govern the anti-proliferative activity for this class of truncated vitamin D-based structures appears to be different from classical mechanisms previously identified for these scaffolds.     

Anti-cancer potential of (1,2-dihydronaphtho[2,1-b]furan-2-yl)methanone derivatives

A series of 1,2-dihydronaphtho[2,1-b]furan derivatives were synthesized by cyclizing 1-(aryl/alkyl(arylthio)methyl)-naphthalen-2-ol and pyridinium bromides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in very good yield. The synthesized compounds were evaluated for their anti-proliferative potential against human triple negative MDA-MB-468 and MCF-7 breast cancer cells and non-cancerous WI-38 cells (lung fibroblast cell) using MTT experiments. Among 21 synthesized compounds, three compounds (3a, 3b and 3 s) showed promising anti-cancer potential and compound 3b was found to have best anti-proliferative activities based on the results of several biochemical and microscopic experiments.     

Design,synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents

Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MTT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC₅₀ = 16.57, 5.45, 4.42 and 5.16 μM) and 33e (IC₅₀ = 20.14, 6.71, 4.62 and 5.62 μM) showed excellent anti-proliferative activities on MCF-7, HepG2, HCT116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties.     

Synthesis and anticancer activities of novel 3,5-disubstituted-1,2,4-oxadiazoles

A series of 3,5-disubstituted-1,2,4-oxadiazoles were synthesized and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4-oxadiazoles have been demonstrated across a wide array of tumor cell types and a few compounds exhibited specificity towards pancreatic (3f, 3h, 3j, and 3k) and prostate (3n) cancer cells. Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 3n is the most selective (>450-fold) and compound 3p is the most cytotoxic (10 nM) against prostate cancer cell lines.     

Orobanone analogues from acid-promoted aromatization rearrangement of curcumol inhibit hypoxia-inducible factor-1 (HIF-1) in cell-based reporter assays

In this paper, the mechanism of orobanone analogues formation via aromatization rearrangement of curcumol was minutely explored. Aromatization of curcumol with acetone under acidic condition was selected as the model reaction. The formation of a stable aromatic system was the driving force for this reaction. Based on the model reaction, other four new orobanone analogues were prepared through curcumol reacting with different carbonyl compounds. The results showed that the stability of carbocation, which was generated from the carbonyl compounds, and the steric hindrance were main factors affecting the aromatization. We also synthesized the analogue of aromaticane B using compound 2. In vitro anti-proliferative activity of some derivatives were tested by MTT assay. Two derivatives showed weak anti-tumor effect on two cancer cell lines (HepG2 and MCF7) under normoxia. Four orobanone analogue 2, 5, 6 and 9 significantly inhibited hypoxia-induced HIF-1 luciferase reporter activity in HeLa cells with the IC₅₀ values of 13.6, 6.6, 2.4 and 18.2 μM, respectively.     

Rational design,synthesis and anti-proliferative evaluation of novel benzosuberone tethered with hydrazide–hydrazones

Two different series of novel analogues of benzosuberones (5a–m and 9a–w) tethered with hydrazone–hydrazides (functional group alterations: Head group to Tail group and vice versa) have been synthesized by the reaction of appropriate aldehydes with substituted hydrazides in excellent yields (87–94%) and their structures were confirmed by ¹H NMR, ¹³C NMR, ESI-MS and HRMS. The newly synthesized compounds were evaluated for anti-proliferative activity against different human cancer cell lines (HeLa, MDA MB 231, MIAPACA and IMR32). Among the synthesized compounds, six compounds 5a, 5b, 5d, 5e, 5f and 9v exhibited potent anti-proliferative activity with GI₅₀ values less than 0.01 μM against MIAPACA, MDA-MB-231 and IMR32 human cancer cell lines.     

Cytotoxic abietane-type diterpenoids from twigs and leaves of Croton laevigatus

Seven new abietane-type diterpenoids, crotolaevigatones A–G (1–7), one new aromatic compound, hexyl Z-ferulate (8), along with three known diterpenoids (9–11) and one known aromatic ester, hexyl E-ferulate (12), were obtained from the twigs and leaves of Croton laevigatus. The structures of all isolated compounds were established on the basis of extensive NMR and MS spectroscopic analyses. Compounds 2 and 7 exhibited weak anti-proliferative activity against the A549 and MDA-MB-231 cancer cells, while compound 10 selectively showed significant inhibitory activity against the A549 cancer cells.     

Synthesis and biological evaluation of novel steroidal 5α,8α-epidioxyandrost-6-ene-3β-ol-17-(O-phenylacetamide)oxime derivatives as potential anticancer agents

Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel 5α,8α-epidioxyandrost-3β-ol-17-(O-phenylacetamide)oxime derivatives (9a–o). The anti-proliferative activity of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, Sk-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compounds 9d, 9f, 9h, 9j and 9m displayed good anti-proliferative activity (most IC₅₀ < 20 μM) in vitro. Furthermore, fluorescence imaging showed that the designed coumarin-9d conjugate (12) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure.     

Preparation and characterization of novel 4-bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide and the analogous phosphorus heterocycles or phospha sugars

4-Bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (3c) was first synthesized from 3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (2c) by a bromo-radical substitution reaction occurred at C-4 position by N-bromosuccinimide and 2,2′-azobisisobutyronitrile. The novel phospha sugar analogue 3c exerted high anti-proliferative effect on U937 cells evaluated by MTT in vitro methods and was much more efficient than that of Gleevec®, which is known as a molecule targeting chemotherapeutical agent. The substitution of 2-phospholenes at C-3 and C-4 position with methyl groups as well as 4-bromo substituent suggests a good anti-proliferative effect.     

Synthesis and anticancer evaluation of 3-aryl-6-phenylimidazo[2,1-b]thiazoles

A series of new 3,6-diphenylimidazo[2,1-b]thiazole derivatives (4a–l) are synthesized and evaluated for their anticancer activity. Some of the synthesized compounds have shown potent anti-proliferative activity against HeLa, MDA-MB-231, A549 and THP1 human cancer cell lines. Among the active compounds, 3-(3-trifluoromethylphenyl)-6-phenylimidazo[2,1-b]thiazole (4j) has caused significant cytotoxicity in HeLa cells, with IC₅₀ as low as 6.5 μM. Compound 4j has induced caspase-3 and caspase-8 activation, leading to an apoptotic cell death. FACS analysis has revealed that compound 4j arrests cells in G0/G1 phase. The presence of 3-(3-trifluoromethylphenyl)- or 3-(3-chlorophenyl)-substituent, in that order, on the 6-phenylimidazo[2,1-b]thiazole impacts more positively than other aryl-substituents, on the anti-proliferative properties of these compounds.     

Click chemistry based multicomponent approach in the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents

A series of spirochromenocarbazole tethered 1,2,3-triazoles were synthesized via click chemistry based one-pot, five component reaction between N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides and sodium azide using cellulose supported CuI nanoparticles (Cell-CuI NPs) as the heterogeneous catalyst. Antiproliferative activity of all the synthesized compounds was investigated against panel of cancer cell lines such as MCF-7, MDA-MB-231, HeLa, PANC-1, A-549, and THP-1. Many of the synthesized compounds exhibited good anti-proliferative activity against breast (MCF-7 and MDA-MB-231) and cervical (HeLa) cancer cells with IC₅₀ values less than 10 μM. In case of MCF-7 cells, among the nine compounds that showed good anti-proliferative activity, compounds 6f and 6j were found to be highly potent (IC₅₀ = 2.13 μM and 4.80 μM, respectively). In case of MDA-MB-231, three compounds (6k, 6j and 6s) showed antiproliferative activity amongst which 6k was the most potent one (IC₅₀ = 3.78 μM). On the other hand, in cervical cancer HeLa cells, compounds 6b, 6g, 6s and 6u showed excellent antiproliferative activity (IC₅₀ = 4.05, 3.54, 3.83, 3.35 μM, respectively). All the compounds were found to be nontoxic to the human umbilical vein endothelial cells (HUVECs). AO and EtBr staining and fluorescence microscopy studies of the active compounds (IC₅₀ < 5 μM) suggested that these compounds induce cell death by apoptosis.     

Synthesis and biological evaluation of scopoletin derivatives

A series of new scopoletin derivatives were designed and synthesized. Their anti-proliferative effect was initially evaluated against various human cancer cell lines. Among the tested compounds, A1, A2, and D6 showed significant anti-proliferative activities. Angiogenesis was detected by endothelial cell migration assay and tube formation study. The results showed that A1, A2, and D6 inhibited the vascular endothelial growth factor (VEGF)-stimulated proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. Moreover, they inhibited the vessel growth in the chorioallantoic membrane in vivo. This inhibition was correlated with a significant decrease in the VEGF-triggered phosphorylated forms of ERK1/2 and Akt. In summary, these findings strongly suggested that these scopoletin derivatives might be structurally novel angiogenesis inhibitors.     

Design,synthesis and insulin-sensitizing activity of indomethacin and diclofenac derivatives

A series of aromatic acetic acid compounds were designed and synthesized on the basis of Non-steroidal anti-inflammatory drugs indomethacin and diclofenac. Compounds 5a, 7a, 5h, 7h and 17 could strongly promote insulin-regulated differentiation of 3T3-L1 cells in vitro. They acted as full or partial PPARγ agonist, or improved insulin resistance through non-PPARγ pathway.     

CLEFMA—An anti-proliferative curcuminoid from structure–activity relationship studies on 3,5-bis(benzylidene)-4-piperidones

3,5-Bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anti-cancer and anti-inflammatory properties. We performed structure–activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC₅₀ <30 μM), and 16 compounds possessed reduced cell-killing efficacy (IC₅₀ >50 μM). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers.     

In vitro anti-proliferative,and in silico ribonucleotide reductase and pharmacokinetics studies of heteroleptic silver(I), nickel(II) and copper(II) complexes of 4-methyl-3-thiosemicarbazones and ibuprofen

ObjectivesThe present research focuses on the in vitro anti-proliferative, and in silico ribonucleotide reductase and pharmacokinetics studies of twelve heteroleptic metal complexes of the general formulae [Ag(L¹⁻⁴)(ibu)] (1–4) and [M(L¹⁻⁴)(ibu)₂] (5–12), where L¹⁻⁴ = 2-(1-(4-substitutedphenyl)ethylidene)-N-methylhydrazinecarbothioamide, ibu = non-steroidal anti-inflammatory drug (ibuprofen), and M = Cu(II) and Ni(II).MethodsVarious spectroscopic techniques were used to authenticate the structure of the synthesized complexes. UV-Vis and cyclic voltammetry techniques were used to analyse the stability and the reducing ability of the complexes. In vitro anti-proliferative studies by MTT assay, apoptotic behaviour and cellular uptake studies were investigated followed by the in silico interaction with ribonucleotide reductase (RNR) enzyme.ResultsThe spectral studies predicted distorted tetrahedral geometry around silver(I) ion and distorted octahedral geometry around nickel(II) and copper(II) ions. The reducing ability of the copper(II) complexes was analysed using ascorbic acid by UV-Vis and cyclic voltammetry techniques, which authenticate the reducing ability of the complexes and the possible interactions within the cells. The in vitro anti-proliferative activity of the synthesized complexes against three cancerous (estrogen positive (MCF-7), estrogen negative (MDA-MB-231) and pancreatic (PANC-1)) and one normal (MCF-10a) cell lines by MTT assay showed enhanced activity for copper(II) complexes 11 and 12 containing the hydrophobic substituents. The apoptotic and cellular uptake studies showed that the complex 12 is readily taken up by PANC-1 cell lines and induces ROS-mediated mitochondrial and caspase-dependent apoptosis. The in silico studies indicated hydrogen bonding, hydrophobic and π-pair (π–π, π–σ and π–cation) interactions between the complexes and the ribonucleotide reductase (RNR) enzyme. The in silico pharmacokinetics studies of the complexes predicted the drug-likeness characteristics of the complexes.ConclusionThe synthesized complexes are found to be less toxic to normal cells and inhibit the growth of cancerous cells by inducing mitochondrial-mediated and caspase dependent apoptotic pathway in PANC-1 cells.     

Synthesis and anti-proliferative activity of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs against human tumor cell lines

Based on previous SAR studies on N-benzylindole and barbituric acid hybrid molecules, we have synthesized a series of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs (3a–i) and evaluated them for their in vitro growth inhibition and cytotoxicity against a panel of 60 human tumor cell lines. Compounds 3c, 3d, 3f and 3g were identified as highly potent anti-proliferative compounds against ovarian, renal and breast cancer cell lines with GI₅₀ values in low the nanomolar range. The 4-methoxy-N-benzyl analog (3d) was the most active compound with GI₅₀ values of 20 nM and 40 nM against OVCAR-5 ovarian cancer cells and MDA-MB-468 breast cancer cells, respectively. Two other analogs, 3c (the 4-methyl-N-benzyl analog) and 3g (the 4-fluoro-N-benzyl analog) exhibited equimolar potency against MDA-MB-468 cells GI₅₀ = 30 nM). Analog 3f (the 4-chloro-N-benzyl analog) exhibited a GI₅₀ value of 40 nM against renal cancer cell line A498. These results suggest that aromatic substituted N-benzylindole dimethylbarbituric acid hybrids may have potential for development as clinical candidates to treat a variety of solid tumors.