bstract Cancer has been the first lethal factor in Taiwan, and hepatitis B is also a serious problem in our country. We have identified that the extracts of Taiwanese Schisandraceous plants, including Schizandra arisanensis, Kadsura matsudai and K. japonica, have inhibitory effect on type B hepatitis surface antigen (HBsAg) and e-antigen (HBeAg). Besides, we also find that the extracts of Echinops grijsii can inhibit the growth of human cancer cell line, KB and Hela. To purify active compounds by using column chromatography and high-performance liquid chromatography, we have furnished fifty-eight compounds from above Schisandraceous plants, including thirty-seven C18 lignans composed of [6.8.6]-dibenzocyclooctadiene skeleton, nine C19 homolignans, four triterpenes, three steroids and five cyclic-aromatic compounds. In the case of Echinops grijsii, we got thirteen major compounds containing eight thiophenes, four triterpenes, and a sterol. Structural elucidation of the novel homolignan and ten lignans are based on the spectral and chemical analyses, mainly by using two-dimensional nuclear magnetic resonance (NMR) of 1H and 13C nucleus. From the anti-HBsAg and anti-HBeAg assay, we found that four of new C18 lignans and one known (+)-gomisin K3 (33) lignan exhibited the significant inhibitory effects on surface antigen of hepatitis B virus. Moreover, to modify the known lignans, kadsurarin with different halogens and functional group having nitrogen atom, as well as (+)-gomisin K3 with several kinds of phenyl compounds and sulfur functional groups are processed. The preliminary structures and bioactivity relationships (SAR) studies demonstrated that (+)-gomisin K3 with sulfuric functional group could decrease cytotoxicity and increase inhibitory effect on surface antigen and e-antigen of hepatitis B virus. In the part of studying synthesis by using inactive 5¡¦-(but-3-en-1-ynyl)-2,2¡¦ -bithiophene (1) from Echinops grijsii, the yne-ene moiety of its structure was hydrolyzed into carbonyl group and then was attached a serious of various carbon number of hydroxy groups. Besides the above experiment, £\-trithienyl (1) was served as a substrate and made it into unsaturated carbonyl group, which then was linked with a series of hydroxy groups. Cytotoxicity datum showed that the derivatives of bi-thiophene have better anticancer activity than derivatives of tri-thiophene. And the assay results also exhibited that the bi-thiophene derivatives with hydroxy group with less than three carbon numbers have better inhibitory activity against cancer cells.

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Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme following cyclooxygenase-2 (COX-2) for the production of prostaglandin E₂(PGE₂), and has been identified as a novel therapeutic target for cancers. From an in silico screen aimed at developing novel small molecule inhibitors of mPGES-1, a 2-aminothiazole compound PGE0001 was identified from 13 putative hits based on its ability to reduce cellular PGE₂ and minimal COX-2 inhibition in vitro. Utilizing drug design strategies based on a 4-point pharmacophore model, we also discovered a new series of compounds exhibiting superior potency without inhibiting COX-2, as exemplified by compound PGE0056. In multiple cancer cell lines, both PGE0001 and PGE0056 reduced cytokine-stimulated PGE₂ release with submicromolar EC₅₀ values, although the two compounds exhibited differential kinetics. Importantly, these compounds showed promising anti-tumor effects in xenograft mouse models. Mice injected with the compounds also had reduced PGE₂ in serum. Surprisingly, none of the compounds inhibited mPGES-1 in cell-free assays, except for MK-886, a reported mPGES-1 inhibitor. In order to determine the mechanisms of action of PGE0001 and PGE0056, the PGE₂ synthesis cascade was extensively examined. Immunoblotting analysis suggested that the PGE₂ reduction in a short time frame was not due to alteration of the protein level of enzymes involved in PGE₂ synthesis/metabolism. So far, we have excluded upstream COX-1/2, phospholipase A₂, and other PGE synthases (mPGES-2 & cytosolic PGES) as major targets for PGE0001 or PGE0056. Interestingly, these compounds were found to inhibit a number of kinases implicated in cancer, presumably due to their structural feature. Although these alternative kinase targets may not sufficiently explain the mechanisms responsible for PGE₂ reduction, inhibition of them may strengthen the therapeutic potential of our compounds. We also implemented a target pull-down approach using biotinylated derivatives of these compounds, followed by proteomic analysis to isolate targets to which these compounds bind. As a result, we identified a couple of other enzymes involved in the arachidonic acid metabolic pathway, which need to be further validated. In summary, we identified novel classes of anti-inflammatory compounds with anti-tumor activity, although the mechanisms of action remain to be clarified.

Doxorubicin is one of the most potent anticancer drugs used in the treatment of wide spectrum of neoplastic diseases including breast, thyroid, colon and liver cancer. However, doxorubicin use is associated with undesirable side effects including cardiomyopathy and congestive heart failure. In the present study we have established that treatment of rat cardiac myoblasts (H9c2 cells) with doxorubicin resulted in H9c2 cell injury in a dose and time dependent manner with almost 50% cell death obtained at 5 μM of doxorubicin treatment for 24 hours. We have selected about 50% cell injury as optimum doxorubicin-induced cell injury because once this threshold is reached, cells became irreversibly injured and could not respond to protective treatment. Another potent antineoplastic drug cyclophosphamide had no cardiotoxic effects on H9c2 cells even at 35 μM concentration and up to 72 hours of treatment. Pretreatment of H9c2 cells for 24 hours with dexamethasone, cortisol, corticosterone or progesterone, significantly protect H9c2 myoblasts against subsequent 5 μM doxorubicin treatment for 24 hours in a concentration dependent manner with maximum protection obtained at 100 nM dexamethasone, 100 nM progesterone, 500 nM cortisol and 500 nM corticosterone. However, testosterone or dehydroepiandrosterone had no protective effects even at 10 μM concentration. It is concluded that both glucocorticoids and progesterone protect H9c2 cells against doxorubicin-induced cell injury.

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Cancer remains the second most common cause of death worldwide affecting around 10 million patients every year. Among the therapeutic options, chemotherapeutic drugs are widely used but often associated with side effects. In addition, toxicity against immune cells may hamper anti-tumor immune responses. Some chemotherapeutic drugs, however, preserve immune functions and some can even stimulate anti-tumor immune responses through the induction of immunogenic cell death (ICD) rather than apoptosis. ICD stimulates the immune system by several mechanisms including the release of damage-associated molecular patterns (DAMPs) from dying cells. In this review, we will discuss the consequences of inducing two recently characterized forms of ICD, i.e., pyroptosis and necroptosis, in the tumor microenvironment (TME) and the perspectives they may offer to increase the immunogenicity of the so-called cold tumors and to stimulate effective anti-tumor immune responses.

The synthesis of cyclopenta[c]thiophenes has been sparsely reported in the literature owing to several difficulties involved in their synthesis. The present work involves the proposed synthesis of cyclopenta[c]thiophenes and their precursors using activated methylene. Cyclopenta[c]thiophene compounds show promise in the field of polymer and catalysis chemistry. These substituted polythiophenes are potential organic semiconductors and anti-tumor agents. The research presented shows the successful and novel conversion of 3,4-bis(chloromethyl)-2,5-dimethylthiophene and 3,4-bis(bromomethyl)-2,5-dimethylthiophene to a fused 5,5'-fused membered ring which is the precursor to cyclopenta[c]thiophene the sulfone ester, 5-carbomethoxy-5- phenylsulfonyl-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene, in just two steps as compared to four steps previously reported in the literature. This valuable precursor intermediate currently made and proven by characterization is one synthetic step away from a substituted cyclopenta[c]thiophene. A paper has been submitted to Letters in Organic Chemistry to report our work.