Shivaji V. More

Cerium (IV) ammonium nitrate (CAN) as a catalyst in tap water: A simple, proficient and green approach for the synthesis of quinoxalines

Various biologically important quinoxaline derivatives have been efficiently synthesized in excellent yields using catalytic amounts of cerium (IV) ammonium nitrate (CAN) in water. This inexpensive, nontoxic, and readily available catalytic system (5 mol%) in water efficiently catalyzes the condensation reaction of various 1,2-diketones and 1,2-diamines. Several aromatic as well as aliphatic 1,2-diketones and aromatic 1,2-diamines such as substituted phenylene diamines, and tetra amines were further subjected to condensation using catalytic amounts of CAN to yield the products in excellent yield. Besides this, ambient conditions, excellent product yields and water as a universal solvent display both economic and environmental advantages.

A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling

Aberrant sialylation catalyzed by sialyltransferases (STs) is frequently found in cancer cells and is associated with increased cancer metastasis. However, ST inhibitors developed till now are not applicable for clinical use because of their poor cell permeability. In this study, a novel ST inhibitor AL10 derived from the lead compound lithocholic acid identified in our previous study is synthesized and the anti‐cancer effect of this compound is studied. AL10 is cell‐permeable and effectively attenuates total sialylation on cell surface. This inhibitor shows no cytotoxicity but inhibits adhesion, migration, actin polymerization and invasion of α‐2,3‐ST‐overexpressing A549 and CL1.5 human lung cells. Inhibition of adhesion and migration by AL10 is associated with reduced sialylation of various integrin molecules and attenuated activation of the integrin downstream signaling mediator focal adhesion kinase. More importantly, AL10 significantly suppresses experimental lung metastasis in vivo without affecting liver and kidney function of experimental animals as determined by serum biochemical assays. Taken together, AL10 is the first ST inhibitor, which exhibits potent anti‐metastatic activity in vivo and may be useful for clinical cancer treatment. J. Cell. Physiol. 223: 492–499, 2010.

Isomalyngamide A, A-1 and their analogs suppress cancer cell migration in vitro

Isomalyngamide A (1) and A-1 (2) were isolated from the Taiwanese Lyngbya majuscule and the latter structure was elucidated by a combination of NMR spectroscopic analysis and HRESIMS measurement. We report the isolation of isomalyngamide A (1), discovery of isomalyngamide A-1 (2) and their synthetic analogs (3-9), which are further demonstrated to have therapeutic potential against tumor cell migration at the level of nanomolar to micromolar ranges, perhaps, by inactivating the expression of p-FAK, FAK, p-Akt and Akt through β1 integrin-mediated antimetastatic pathway.

Polyfluorinated bipyridine cisplatins manipulate cytotoxicity through the induction of S-G2/M arrest and partial intercalation mechanism.

A series of polyfluorinated bipyridine cisplatins 2-6 were prepared, characterized, and evaluated for their in vitro cytotoxicities against a panel of human cancer cell lines, MCF7 (breast adenocarcinoma), MDA-MB-231 (breast adenocarcinoma) and A549 (lung adenocarcinoma). The results show that a correlation between the relative order of lipophilicity of complexes 2-4 and their cytotoxicity is established by following the trend: 4>2>3. Complex 4, which is the most active compound in the series, was found to be a more effective and selective anticancer agent than cisplatin. Complex 4 inhibited cancer cell proliferation by partial intercalation to DNA, which subsequently resulted in induction of S-G2/M arrest and apoptosis.

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub‐micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase‐3 and ‐9 without affecting caspase‐8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL‐2 family regulators were also affected. Moreover, low‐dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F‐actin cytoskeleton was disrupted after low‐dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228‐induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase‐3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell‐specific cytotoxicity by inducing mitochondria‐mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.

The Tetraindole SK228 Reverses the Epithelial-to-Mesenchymal Transition of Breast Cancer Cells by Up-Regulating Members of the miR-200 Family

The results of recent studies have shown that metastasis, the most common malignancy and primary cause of mortality promoted by breast cancer in women, is associated with the epithelial-to-mesenchymal transition (EMT). The results of the current study show that SK228, a novel indole containing substance, exhibits anti-cancer activity. In addition, the effects of SK228 on the regulation of EMT in breast cancer cells as well as the underlying mechanism have been explored. SK228 was observed to induce a fibroblastoid to epithelial-like change in the appearance of various breast cancer cell lines and to suppress the migration and invasion of these cancer cells in vitro. Moreover, expression of E-cadherin was found to increase following SK228 treatment whereas ZEB1 expression was repressed. Expression of other major EMT inducers, including ZEB2, Slug and Twist1, is also repressed by SK228 as a consequence of up-regulation of members of the miR-200 family, especially miR-200c. The results of animal studies demonstrate that SK228 treatment leads to effective suppression of breast cancer growth and metastasis in vivo. The observations made in this investigation show that SK228 reverses the EMT process in breast cancer cells via an effect on the miR-200c/ZEB1/E-cadherin signalling pathway. In addition, the results of a detailed analysis of the in vivo anti-cancer activities of SK228, carried out using a breast cancer xenograft animal model, show that this substance is a potential chemotherapeutic agent for the treatment of breast cancer.

Synthesis and Evaluation of the Cytotoxicities of Tetraindoles: Observation that the 5-Hydroxy Tetraindole (SK228) Induces G2 Arrest and Apoptosis in Human Breast Cancer Cells

Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G(2)-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.

Synthesis and structure-activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents

This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.