Design and synthesis of various quinizarin derivatives as potential anticancer agents in acute T lymphoblastic leukemia

A series of quinizarin derivatives containing quaternary ammonium salts and/or thiourea groups were synthesized and their anticancer activities against leukemia cell lines have been tested. Results showed that most of quinizarin derivatives could inhibit the proliferation of leukemia cells. Among these derivatives, compound 3 showed good inhibition activity against various leukemia cells with IC₅₀ values ranging from 0.90?±?2.55?μM to 10.90?±?3.66?μM. At the same time, compound 3 also inhibited the growth of human embryonic kidney-293 cell (HEK-293). Molt-4 and Jurkat cells, acute T lymphoblastic leukemia (T-ALL) cell lines, were selected to reveal potential anticancer mechanism of compound 3. Compound 3 inhibited the proliferation of Molt-4 and Jurkat cells in a dose- and time-dependent manner and led to a marked G0/G1 phase arrest. Analysis of Annexin V-APC and intracellular reactive oxygen species (ROS) level by flow cytometry showed that compound 3 induced significant apoptosis in Molt-4 and Jurkat cells. Western blotting assay showed that compound 3 activated the caspase-dependent apoptosis pathway and induced the degradation of Bcl-2 and c-myc protein.     

Sesquiterpenoids from the roots of Inula helenium inhibit acute myelogenous leukemia progenitor cells

One new eudesmane sesquiterpenoid, 11β-hydroxy-13-chloro-eudesm-5-en-12, 8-olide (1), was isolated from the roots of Inula helenium together with nine eudesmanolides (2–10) and one germacranolide (11). Their structures were elucidated on the basis of detailed spectroscopic analyses. All isolates were evaluated for their antiproliferative activities against human leukemia stem-like cell line KG1a. Compound 10 exhibited the most potent effect with the IC₅₀ value of 3.36 ± 0.18 μM. A further investigation revealed that compound 10 could significantly induce apoptosis of KG1a cells. Additionally, compound 10 had an obvious effect on the levels of apoptosis-related proteins (Bcl-2, Bax, cytochrome c, caspase 9 and caspase 3), indicating that the antiproliferative effect of compound 10 on KG1a cells might be mediated through a mitochondria-dependent apoptotic pathway.     

Synthesis and cytotoxic activity of metallic complexes of lawsone

In the present study, a series of metallic complexes of the 1,4-naphthoquinone lawsone (2–6) were synthesized and evaluated for potential cytotoxicity in a mouse leukemic macrophagic RAW 264.7 cell line. Cell viability was determined by the MTT assay. Significant growth inhibition was observed for the copper complex (4) with an IC₅₀ value of 2.5 μM. This compound was selected for further evaluation of cytotoxic activity on several human cancer cells including HT-29 (human colorectal adenocarcinoma), HepG2 (human hepatocellular carcinoma) and HeLa, (human cervical adenocarcinoma cells). Significant cell viability decrease was also observed in HepG2 cells. The apoptotic potential of this complex was evaluated in these cells. Compound 4 induced apoptosis by a mechanism that involves the activation of caspases 3, 8 and 9 and modulation of apoptotic-related proteins such as Bax, Bad, and p53. These results indicate that metal complexes of lawsone derivatives, in particular compound 4, might be used for the design of new antitumoral agents.     

Synthesis and evaluation of piperazine and homopiperazine analogues of JS-K,an anti-cancer lead compound

Here we report a number of novel JS-K structural analogues with sub-micromolar anti-proliferative activities against human leukemia cell lines HL-60 and U937; JS-K is the anti-cancer lead compound O²-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. The ability of these compounds to generate intracellular nitric oxide correlated well with their observed anti-proliferative effects: analogues that had potent inhibitory activity against leukemia cells formed elevated levels of intracellular nitric oxide.     

Discovery and development of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as Bcl-2/Mcl-1 inhibitors

Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (K_i = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-X_L protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.     

Design,synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC₅₀?=?2.1?μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.     

Neuroprotective effects of mercaptoethylleonurine and mercaptoethylguanidine analogs on hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells

A series of mercaptoethylleonurine and mercaptoethylguanidine derivatives were designed and synthesized. Their neuroprotective effects toward H₂O₂-induced apoptosis were investigated in human SH-SY5Y cells. The results from these studies identified several potent compounds, with compound 8k emerging as the most effective. Further investigation demonstrated that 8k reduced H₂O₂-induced activation of mitochondrial apoptosis by inhibiting the expression of Bax and elevating the expression of Bcl-2. Moreover, the molecular mechanism underlying the observed neuroprotective effects of 8k was exerted via the Akt and JNK pathways. Compound 8k can be a lead compound for further discovery of neuroprotective medicine.     

Synthesis,anticancer effect and molecular modeling of new thiazolylpyrazolyl coumarin derivatives targeting VEGFR-2 kinase and inducing cell cycle arrest and apoptosis

New thiazolylpyrazolyl coumarin derivatives were synthesized and tested for their anticancer potential in vitro against five different human cell lines, including breast MCF-7, lung A549, prostate PC3, liver HepG2 and normal melanocyte HFB4. Breast carcinoma revealed higher sensitivity towards compounds 7a, 8c, 9b, 9c and 9d with IC₅₀ values ranging from 5.41 to 10.75 μM in comparison to the reference drug doxorubicin (IC₅₀ = 6.73 μM). In addition, no noticeable toxicity was exhibited towards normal cells HFB4. Moreover, in vitro studies of the VEGFR-2 inhibition in human breast cancer MCF-7 cell line for the promising cytotoxic compounds showed that compounds 7a, 8c, 9b, 9c and 9d were potent inhibitors at low micromolar concentrations (IC₅₀ = 0.034–0.582 μM) compared to the reference drug, sorafenib (IC₅₀ = 0.019 μM). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis. The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compound 9d due to its remarkable cytotoxic activity against MCF-7 and significant VEGFR-2 inhibition. Flow cytometeric analysis showed that compound 9d induced cell growth cessation at G2/M phase and increased the percentage of cells at pre-G1 phase that stimulates the apoptotic death of MCF-7 cells. Furthermore, real time PCR assay illustrated that compound 9d up regulated p53 gene expression and elevated Bax/Bcl-2 ratio which confirmed the mechanistic pathway of compound 9d. Moreover, the apoptotic induction of breast cancer cells MCF-7 was enhanced effectively through activation of caspases-7 and 9 by compound 9d. On the other hand, a set of in silico methods such as molecular docking, molecular dynamics simulation, QSAR analysis as well as ADMET analysis was performed in order to study the protein-ligand interactions and the relationship between the physicochemical properties and the inhibitory activity of the promising compounds 7a, 8c and 9d. Based on the aforementioned findings, compound 9d could be considered as effective apoptosis modulator and promising lead for future development of new anti-breast cancer agents.     

Discovery and development of substituted tyrosine derivatives as Bcl-2/Mcl-1 inhibitors

Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound 1 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a K_i value of 5.2?µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-X_L protein. Promisingly, compound 6i inhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with a K_i value of 450 and 190?nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.     

Novel benzotriazole N-acylarylhydrazone hybrids: Design,synthesis, anticancer activity,effects on cell cycle profile,caspase-3 mediated apoptosis and FAK inhibition

A series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC₅₀ values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC₅₀ values in nano-molar range between 25 and 130 nM. They showed 18–2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC₅₀ values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC₅₀ values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC₅₀ = 32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism.     

1-(2-((Z)-6-(2-(Trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one as a new potent apoptosis agent

Compounds 4a–f, 5a–f and 6–9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.     

Enzymatic biosynthesis and biological evaluation of novel 17-AAG glucoside as potential anti-cancer agents

A novel 17-allylamino-17-demethoxygeldanamycin (17-AAG) glucoside (1) was obtained from in vitro enzymatic glycosylation using a UDP-glycosyltransferase (YjiC). The water-solubility of compound 1 was approximately 10.5 times higher than that of the substrate, 17-AAG. Compound 1 showed potential anti-proliferative activities against five human cancer cell lines, with IC₅₀ values ranging from 5.26 to 28.52 μM. Further studies also indicated that compound 1 could inhibit the growth of CNE-2Z cells by inducing the degradation of Hsp90 client proteins (Akt, c-Raf, Bcl-2, and HIF-1α). In addition, compound 1 showed greater potential anti-tumor efficacy than 17-AAG in nude mice xenografted with CNE-2Z cells. Therefore, we suggest that in vitro enzymatic glycosylation is a powerful approach for the structural optimization of 17-AAG.     

Design,synthesis and biological evaluation of novel β-pinene-based thiazole derivatives as potential anticancer agents via mitochondrial-mediated apoptosis pathway

A series of novel β-pinene-based thiazole derivatives were synthesized and characterized by HRMS, ¹H NMR, and ¹³C NMR analyses as potential antineoplastic agents. Derivatives were evaluated for their anticancer activities in vitro, and the data manifested that most target compounds showed potent anti-proliferative activities against three human cancer cell lines. Especially, compound 5g displayed excellent cytotoxic activity against Hela, CT-26, and SMMC-7721 cell lines with IC₅₀ values of 3.48 ± 0.14, 8.84 ± 0.16, and 6.69 ± 0.15 µM, respectively. To determine the underlying mechanism of compound 5g on cell viability, DAPI staining, Annexin-V/PI staining, JC-1 staining, DCFDA staining, and Western blot analysis were performed. Our data showed that compound 5g inhibited cell proliferation by inducing apoptosis and cell cycle arrest of Hela cells at the G0/G1 phase in a dose dependent manner. Further studies revealed that compound 5g enhanced levels of reactive oxygen species (ROS), caused a decrease in mitochondrial membrane potential, increased the release of mitochondrial cytochrome C, and affected the expression of Bax, Bcl-2, caspase-3 and caspase-9. Thus, our findings indicated that compound 5g induced apoptosis in Hela through ROS-mediated mitochondrial dysfunction signaling pathways.     

Design and synthesis of functionalized coumarins as potential anti-austerity agents that eliminates cancer cells' tolerance to nutrition starvation

Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer cells’ tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl)amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC₅₀ value of 0.44 μM, without exhibiting toxicity in normal, nutrient-rich medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.     

Two novel neo-clerodane diterpenoids from Scutellaria barbata

Two novel neo-clerodane diterpenoids, barbatellarines A (1) and B (2), were isolated from the whole plants of Scutellaria barbata, along with the known compound scutebarbatine F (3). The chemical structures and relative stereochemistry of the isolated compounds were established by NMR (1D and 2D) and mass spectroscopic analyses. Compounds 2 and 3 were evaluated for in vitro cytotoxic activity against the HL-60 (human leukemia), MCF7 (human breast cancer), and LLC (Lewis lung carcinoma) cancer cell lines. Compound 2 exhibited weak cytotoxic activity against HL-60 cells, with an IC₅₀ value of 41.4 μΜ.     

Chemical characterization of cytotoxic indole acetic acid derivative from mulberry fruit (Morus alba L.) against human cervical cancer

The fruit of the white mulberry tree (Morus alba L.) is a multiple fruit with a sweet flavor commonly consumed around the world. Chemical investigation of the fruits led to the isolation of two indole acetic acid derivatives (1 −2) including a new compound, which turned out to be an isolation artifact, 3S-(β-D-glucopyranosyloxy)-2,3-dihydro-2-oxo-1H-indole-3-acetic acid butyl ester (1), along with five known compounds (3 −7). Compounds 2 and 7 were newly identified from mulberry fruit. The new isolation artifact (1) exhibited cytotoxic effect on human cervical cancer Hela cells in a dose-dependent manner. Compound 1 activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Simultaneous alterations in protein expression of mitochondrial factors Bax, BID and Bcl-2 were also observed. A comparison between compounds 1 and 2 led to a structure-activity relationship analysis of the cytotoxic effect. These results suggest that compound 1 could be beneficial in human cervical cancer treatment, and provide a theoretical basis for further application of compound 1.     

A natural phenylpropionate derivative from Mirabilis himalaica inhibits cell proliferation and induces apoptosis in HepG2 cells

Bioactivity-guided study led to the isolation of a natural phenylpropionate derivative, (E)-3-(4-hydroxy-2-methoxyphenyl)-propenoic acid 4-hydroxy-3-methoxyphenyl ester from the roots of Mirabilis himalaica. Cellular analysis showed that compound 1 specifically inhibited the cancer cell growth through the S phase arrest. Mechanistically, compound 1 was able to induce the apoptosis in HepG2 cells through mitochondrial apoptosis pathway in which Bcl-2 and p53 were required. Interestingly, the cellular phenotype of compound 1 were shown specifically in cancer cells originated from hepatocellular carcinoma (HepG2) while compromised influence by compound 1 were detected within the normal human liver cells (L-02). Consistently, the in vivo inhibitory effects of compound 1 on tumor growth were validated by the in xenograft administrated with HepG2 cells. Our results provided a novel compound which might serve as a promising candidate and shed light on the therapy of the hepatocellular carcinoma.     

Inhibitory effect of novel somatostatin peptide analogues on human cancer cell growth based on the selective inhibition of DNA polymerase β

The present study was designed to investigate the anticancer activity of novel nine small peptides (compounds 1–9) derived from TT-232, a somatostatin structural analogue, by analyzing the inhibition of mammalian DNA polymerase (pol) and human cancer cell growth. Among the compounds tested, compounds 3 [tert-butyloxycarbonyl (Boc)-Tyr-Phe-1-naphthylamide], 4 (Boc-Tyr-Ile-1-naphthylamide), 5 (Boc-Tyr-Leu-1-naphthylamide) and 6 (Boc-Tyr-Val-1-naphthylamide) containing tyrosine (Tyr) but no carboxyl groups, selectively inhibited the activity of rat pol β, which is a DNA repair-related pol. Compounds 3–6 strongly inhibited the growth of human colon carcinoma HCT116 p53^+/+ cells. The influence of compounds 1–9 on HCT116 p53^?/? cell growth was similar to that observed for HCT116 p53^+/+ cells. These results suggest that the cancer cell growth suppression induced by these compounds might be related to their inhibition of pol. Compound 4 was the strongest inhibitor of pol β and cancer cell growth among the nine compounds tested. This compound specifically inhibited rat pol β activity, but had no effect on the other 10 mammalian pols investigated. Compound 4 combined with methyl methane sulfonate (MMS) treatment synergistically suppressed HCT116 p53^?/? cell growth compared with MMS alone. This compound also induced apoptosis in HCT116 cells with or without p53. From these results, the influence of compound 4, a specific pol β inhibitor, on the relationship between DNA repair and cancer cell growth is discussed.     

Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors

A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC₅₀ = 2.2 µM) and EGFR binding (IC₅₀ = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G₂/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = −34.581 Kcal/mol.     

Design,synthesis and cytotoxicity of cell death mechanism of rotundic acid derivatives

In the present investigation, 16 new rotundic acid (RA) derivatives modified at the C-3, C-23 and C-28 positions were synthesized. The cytotoxicities of the derivatives were evaluated against HeLa, A375, HepG2, SPC-A1 and NCI-H446 human tumor cell lines by MTT assay. Among these derivatives, compounds 4–7 exhibited stronger cell growth inhibitory than RA and compound 4 was found to be the best inhibition activity on five human tumor cell lines with IC₅₀ <10 μM. The apoptosis mechanism of compound 4 in HeLa cells was investigated by western blot analysis. The results indicated that compound 4 could induce apoptosis through increasing protein expression of cleaved caspase-3 and Bax, and decreasing protein expression of Bcl-2. In summary, the present work suggests that compound 4 might serve as an effective chemotherapeutic candidate.