Cytotoxic effects of two organotin compounds and their mode of inflicting cell death on four mammalian cancer cells

In this report, we have tested the cytotoxicity of two organotin (OT) compounds by flow cytometry on a panel of immortalized cancer cell lines of human and murine origin. Although the OT compounds exhibited varying levels of cytotoxicity, diphenylmethyltin chloride was more toxic than 1,4-bis (diphenylchlorostannyl)p-xylene on all cell lines tested. The OT compounds were found to be highly cytotoxic to lymphoma cell lines with lower toxicity toward the HeLa cervical cancer cell line. In order to discern the mechanism by which cell death was induced, additional experiments were conducted to monitor characteristic changes consistent with apoptosis and/or necrosis. Cell lines treated with the experimental compounds indicated that there was no consistent mode of cell death induction. However, both compounds induced apoptosis in the pro-B lymphocyte cell line, NFS-70. The work presented here also demonstrates that the two OT compounds possess selective cytotoxicity against distinct transformed cell lines.     

One pot synthesis and anticancer activity of dimeric phloroglucinols

A series of dimeric phloroglucinol compounds were synthesized in a single step using commercially available phloroglucinol and methanesulfonic acid. Based on the reported anticancer activity of plant derived dimeric phloroglucinols, these synthesized compounds were evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Several compounds demonstrated in vitro cytotoxic effects across a wide array of tumor cell types. The compound 29 with pyridin-3-yl group on linker methylene and two diisovaleryl phloroglucinol moieties was found to be the most active in all the five cancer cell lines having a low IC(50) of 5.5 μM in colon cancer cell lines (HCT116).     

A comprehensive study of Sansalvamide A derivatives: The structure–activity relationships of 78 derivatives in two pancreatic cancer cell lines

We report an extensive structure–activity relationship (SAR) of 78 compounds active against two pancreatic cancer cell lines. Our comprehensive evaluation of these compounds utilizes SAR that allow us to evaluate which features of potent compounds play a key role in their cytotoxicity. This is the first report of 19 new second-generation structures, where these new compounds were designed from the first generation of 59 compounds. These 78 structures were tested for their cytotoxicity and this is the first report of their activity against two pancreatic cancer cell lines. Our results show that out of 78 compounds, three compounds are worth pursuing as leads, as they show potency of ?55% in both cancer cell lines. These three compounds all have a common structural motif, two consecutive d-amino acids and an N-methyl moiety. Further, of these three compounds, two are second-generation structures, indicating that we can incorporate and utilize data from the first generation to design potency into the second generation. Finally, one analog is in the mid nanomolar range, and has the lowest IC₅₀ of any reported San A derivative. These analogs share no structural homology to current pancreatic cancer drugs, and are cytotoxic at levels on par with existing drugs treating other cancers. Thus, we have established Sansalvamide A as an excellent lead for killing multiple pancreatic cancer cell lines.     

Identification of Sansalvamide a analog potent against pancreatic cancer cell lines

Thirty-one Sansalvamide A peptide derivatives were synthesized. (3)H thymidine inhibition assays were performed using two pancreatic cancer cell lines (PL45 and BxPC-3). Six compounds possess 140-fold increased differential selectivity for cancer cell lines over normal cell lines (WS1, skin fiberblasts) and are 140 times more active against pancreatic cancer cell lines than compounds used clinically to treat these cancers (e.g., 5-FU). Structure-activity relationship studies show the inclusion of a single N-methyl and/or d-amino acid appears to be critical for presenting the active conformation of the six San A peptide derivatives to their biological target(s).     

Somatic mutation patterns and compound response in cancers

The use of various cancer cell lines can recapitulate known tumor-associated mutations and genetically define cancer subsets. This approach also enables comparative surveys of associations between cancer mutations and drug responses. Here, we analyzed the effects of ∼40,000 compounds on cancer cell lines that showed diverse mutation-dependent sensitivity profiles. Over 1,000 compounds exhibited unique sensitivity on cell lines with specific mutational genotypes, and these compounds were clustered into six different classes of mutation-oriented sensitivity. The present analysis provides new insights into the relationship between somatic mutations and selectivity response of chemicals, and these results should have applications related to predicting and optimizing therapeutic windows for anti-cancer agents. [BMB Reports 2013; 46(2): 97-102]     

Photochemical synthesis and anticancer activity of barbituric acid,thiobarbituric acid,thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives

2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines.     

Synthesis,Cytotoxicity and Antimicrobial Evaluation of New Coumarin‐Tagged β‐Lactam Triazole Hybrid

A series of coumarin‐tagged β‐lactam triazole hybrids ( 10a – 10o ) were synthesized and tested for their cytotoxic activity against MDA‐MB‐231 (triple negative breast cancer), MCF‐7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK‐293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF‐7 cancer cell lines with IC₅₀ values of 53.55 and 58.62 μm , respectively. More importantly, compounds 10b and 10d were non‐cytotoxic against HEK‐293 cell lines. Structure–activity relationship (SAR) studies suggested that the nitro and chloro group at the C‐3 position of phenyl ring are favorable for anticancer activity, particularly against MCF‐7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.     

Design and synthesis of 7-alkoxy-4-heteroarylamino-3-quinolinecarbonitriles as dual inhibitors of c-Src kinase and nitric oxide synthase

Because both c-Src and iNOS are key regulatory enzymes in tumorigenesis, a new series of 4-heteroarylamino-3-quinolinecarbonitriles as potent dual inhibitors of both enzymes were designed, prepared, and evaluated for blocking multiple signaling pathways in cancer therapy. All compounds were evaluated by two related enzyme inhibition assays and an anti-proliferation assay in vitro. The results showed that most compounds could inhibit both enzymes, and several of them showed potent inhibition activity against different cancer cell lines. The best compound 20 (CPU-Y020) showed the IC(50) values of 6.58 and 7.61microM toward colon cancer HT-29 and liver cancer HepG2 cell lines.     

Synthesis and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3-yl-amides for prostate cancer

We have previously described serine amide phosphates (SAPs) as a novel class of cytotoxic agents for prostate cancer. Several of them showed potent cytotoxicity against human prostate cancer cell lines, but were not selective in non-tumor cells. To improve the selectivity and further enhance the potency, we designed a new series of 2-aryl-4-oxo-thiazolidin-3-yl amides. The current work describes synthesis, SAR, and biological evaluation of these compounds for their ability to inhibit the growth of prostate cancer cells. The antiproliferative effects of synthesized compounds were examined in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, and TSU), and in RH7777 cells (negative controls). From this study, three potent compounds (8, 20, and 21) have been detected, which are effective in killing prostate cancer cells with improved selectivity compared to SAPs.     

Synthesis,docking studies,in vitro cytotoxicity evaluation and DNA damage mechanism of new tyrosine-based tripeptides

Peptides are one of the leading groups of compounds that have been the subject of a great deal of biological research and still continue to attract researchers' attention. In this study, a series of tripeptides based on tyrosine amino acids were synthesized by the triazine method. The cytotoxicity properties of all compounds against human cancer cell lines (MCF-7), ovarian (A2780), prostate (PC-3), and colon cancer cell lines (Caco-2) were determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay method, and % cell viability and logIC50 values of the compounds were calculated. Significant decreases in cell viability were observed in all cells (p < 0.05). The comet assay method was used to understand that the compounds that showed a significant decrease in cell viability had this effect through DNA damage. Most of the compounds exhibited cytotoxicity by DNA damage mechanism. Besides, their interactions between investigated molecule groups with PDB ID: 3VHE, 3C0R, 2ZCL, and 2HQ6 target proteins corresponding to cancer cell lines, respectively, were investigated by docking studies. Finally, molecules with high biological activity against biological receptors were determined by ADME analysis.     

Chemical composition and biological activity of triterpenes and steroids of chaga mushroom

Data on the chemical composition of triterpenic and steroid compounds, isolated from the chaga mushroom grown in natural environment or in a synthetic culture have been summarized. Special attention has been paid to the biological activity of chaga mushroom extracts and these particular compounds against various cancer cell lines in vitro and in vivo. This analysis has demonstrated some common features in inhibition of growth of various cell lines by chaga mushroom components. In this context, the most active are triterpene compounds containing OH group at C-22 and a side chain unsaturated bond.     

Triterpenoid saponins from Xanthoceras sorbifolia Bunge and their inhibitory activity on human cancer cell lines

Xanthoceras sorbifolia Bunge is widely used as healthy food material and folk medicine in China. Phytochemical investigation on its seeds oil leavings has led to the isolation and identification of seven new oleanane-type triterpenoid saponins named sorbifoliasides A-F (1-6) and bunkankasaponin F (7), along with five known ones (8-12). The structures of the new compounds were elucidated through spectroscopic analysis and chemical derivatization. Among the isolated compounds, 16-oxo-3, 28-O-bidesmosidic triterpenoid saponins (2, 3, 5) were isolated from this plant for the first time. The cytotoxicity of all compounds against the ten selected human cancer cell lines was assayed. Compounds 7 and 9 showed significant activity against all the ten cancer cell lines (IC(50) <10μM), while compounds 8, 10 and 11 exhibited moderate activity against most of these cancer cell lines.     

Synthesis,Characterization, and Biological Study of 3-Trifluoromethylpyrazole Tethered Chalcone-Pyrrole and Pyrazoline-Pyrrole Derivatives

The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All compounds were further screened for in vitro cytostatic activities on full NCI 60 cancer cell lines at National Cancer Institute, USA. Compounds (2E)-3-(1H-pyrrol-2-yl)-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}prop-2-en-1-one ( 5a ) and (2E)-1-{3-methyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-(1H-pyrrol-2-yl)prop-2-en-1-one ( 5c ) displayed significant antiproliferative activity (Growth Percentage: −77.10 and −92.13, respectively at 10 μM concentration) against the UO-31 cell lines from renal cancer and were further selected for assay at 10-fold dilutions of five different concentrations (10⁻⁴ to 10⁻⁸ M). Both compounds 5a and 5c exhibited promising antiproliferative activity (GI₅₀: 1.36 to 0.27 μM) against leukemia cancer cell lines HL-60 and RPMI-8226, colon cancer cell lines KM-12; breast cancer cell lines BT-549. Moreover, both compounds 5a and 5c were found to be non-cytotoxic (LC₅₀>100) against HL-60, RPMI-8226, and KM-12 cell lines. Remarkably, GI₅₀ values of compounds 5a and 5c were identified as more promising than sunitinib against most cancer cell lines. In silico study of compounds 5a and 5c exemplified the desired ADME properties for drug-likeness as well as tighter interactions with VEGFR-2. Hence, compounds 5a and 5c would be good cytotoxic agents after further clinical study.     

Cytotoxic effect of 2,3-disubstituted chromanones in human cancer cell lines

Four different synthetic compounds [3-aryl-2-(3-pyridyl)chromanones] were prepared and screened for cytotoxicity against a panel of 29 human cancer cell lines in five different concentrations separately. All compounds displayed cytotoxicity against cancer cell lines and one of them possessed cell type selectivity also.     

Design, synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC(50) range of 5.0-9.7 μg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).     

Design, synthesis of symmetrical bivalent mimetics of annonaceous acetogenins and their cytotoxicities

A new series of linear dimeric compounds mimicking naturally occurring annonaceous acetogenins have been synthesized by bivalent analogue design, and their cytotoxicities have been evaluated against the growth of cancer cells by MTT method. Most of these compounds show selective action favored to human cancer cell lines over normal cell lines, and compound 9 with bis-terminal benzoquinone functionality exhibits an IC₅₀ = 0.40 μM against MCF7 cell lines. This work mentions that appropriate conformational constraints might be a useful optimizing tool for this unique class of anticancer compounds.     

MicroRNA-1280 Inhibits Invasion and Metastasis by Targeting ROCK1 in Bladder Cancer

MicroRNAs (miRNAs) are non-protein-coding sequences that can function as oncogenes or tumor suppressor genes. This study documents the tumor suppressor role of miR-1280 in bladder cancer. Quantitative real-time PCR and in situ hybridization analyses showed that miR-1280 is significantly down-regulated in bladder cancer cell lines and tumors compared to a non-malignant cell line or normal tissue samples. To decipher the functional significance of miR-1280 in bladder cancer, we ectopically over-expressed miR-1280 in bladder cancer cell lines. Over-expression of miR-1280 had antiproliferative effects and impaired colony formation of bladder cancer cell lines. FACS (fluorescence activated cell sorting) analysis revealed that re-expression of miR-1280 in bladder cancer cells induced G2-M cell cycle arrest and apoptosis. Our results demonstrate that miR-1280 inhibited migration and invasion of bladder cancer cell lines. miR-1280 also attenuated ROCK1 and RhoC protein expression. Luciferase reporter assays demonstrated that oncogene ROCK1 is a direct target of miR-1280 in bladder cancer. This study also indicates that miR-1280 may be of diagnostic and prognostic importance in bladder cancer. For instance, ROC analysis showed that miR-1280 expression can distinguish between malignant and normal bladder cancer cases and Kaplan-Meier analysis revealed that patients with miR-1280 high expression had higher overall survival compared to those with low miR-1280 expression. In conclusion, this is the first study to document that miR-1280 functions as a tumor suppressor by targeting oncogene ROCK1 to invasion/migration and metastasis. Various compounds are currently being used as ROCK1 inhibitors; therefore restoration of tumor suppressor miR-1280 might be therapeutically useful either alone or in combination with these compounds in the treatment of bladder cancer.     

Synthesis and evaluation of the antiproliferative activity of novel isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives

A novel series of isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives was synthesized and evaluated in vitro against various human cancer cell lines for antiproliferative activity. These new compounds displayed activity against leukemia and breast cancer cell lines in the 3- to 18-μM concentration range.     

Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells

Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic options. Highly substituted ansa-titanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives of this study are to examine the effects of these titanocene compounds on prostate cancer cells. Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin. Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal microscopy. These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent apoptosis following treatment with all the titanocene compounds. This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer.