No abstract

Inflammation and low oxygen diffusion are recognized characteristics of cardiovascular diseases such as atherosclerosis. Evodiamine, extracted from the traditional Chinese herb, Evodia rutaecarpa, is a bioactive anti-inflammatory alkaloid. The objective of this study was to investigate whether evodiamine could repress hypoxia-induced inflammatory response. We showed that evodiamine repressed not only COX-2 and iNOS expression but also prostaglandin E2 release in a concentration-dependent manner under hypoxic conditions. Furthermore, our studies indicated that COX-2 mRNA was inhibited by evodiamine, implying that transcriptional activity is involved in the mechanistic pathway. It is striking that hypoxia-inducible factor 1alpha (HIF-1alpha) inhibitor, camptothecin, suppressed hypoxia-induced COX-2 expression rather than pyrrolidine dithiocarbamate, a nuclear factor kappaB inhibitor. In addition, our studies have confirmed that evodiamine inhibited HIF-1alpha, which accounted for the transcriptional activity of COX-2, rather than nuclear factor kappaB in RAW264.7 cells. Finally, evodiamine did not affect either the level of HIF-1alpha mRNA or the degradation rate of HIF-1alpha protein, but it regulated the translational process of HIF-1alpha. We found that hypoxia-evoked phosphorylation of Akt and p70S6K was blocked after evodiamine treatment, in addition to the inhibition of phosphorylation of 4E-BP. These results suggest that the mechanism of repression of hypoxia-induced COX-2 expression by evodiamine is through the inhibition of HIF-1alpha at the translational level and is primarily mediated via dephosphorylation of Akt and p70S6K. Therefore, evodiamine could be an effective therapeutic agent against inflammatory diseases involving hypoxia.

In a continuing study, we explored how the individual rings in neo-tanshinlactone (1) influence its potent and selective in vitro anti-breast cancer activity. Accordingly, we discovered a novel class of anti-breast cancer agents, 2-(furan-2-yl) naphthalen-1-ol derivatives, based on an active C-ring opened model compound 5. Further optimization led to 18 and 21, which showed decreased cytotoxic potency, but better selectivity than neo-tanshinlactone analog 2. Interestingly, compound 20 showed broad cytotoxicity against human cancer cell lines.

Two new phenanthrenequinones, calanquinones B-C (2-3), four new 9,10-dihydrophenanthrenes, calanhydroquinones A-C (4-6), and calanphenanthrene A (7), along with five known compounds (1 and 8-11) were isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassayguided fractionation. Their structures were identified from spectroscopic data, and the compounds were tested for in vitro cytotoxic activity against human lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KBVIN) cancer cell lines. Compound 1 showed the highest potency (EC 50 < 0.5 μg/mL) against all seven cancer cell lines, with the greatest activity against breast cancer MCF-7 cells (EC 50 < 0.02 μg/mL). Generally, except for 7, compounds 2-11 also showed significant cytotoxic activity (EC 50 < 4μg/mL) against some cell lines (especially PC-3 and MCF-7) in the panel.The genus Calanthe in the Orchidaceae family contains terrestrial perennial herbs that are widely distributed from tropical Africa and Madagascar to tropical and subtropical Asia, China, Japan, southward through Malaysia and Indonesia to the Pacific islands and Australia. This genus includes more than 150 species, but only 19 are found in Taiwan. Among them, C. arisanensis Hayata (Orchidaceae) is endemic to Taiwan and grows in forests from 1000 to 2000 m throughout the island. 1 No phytochemical study of this plant has been reported to date. During cytotoxicity screening of extracts of Formosan plants, we found that an EtOAc extract of C. arisanensis was active against various human cancer cell lines, with IC 50 < 20 μg/mL. Bioassay-directed chromatographic fractionation of this extract led to isolation of two new phenanthrenequinones [calanquinones B-C (2-3)] and four new 9,10-dihydrophenanthrenes [calanhydroquinones A-C (4-6) and calanphenanthrene A (7)], as well as five known compounds (1 and 8-11). [2][3][4][5][6] Compounds 1-11 were screened for cytotoxic activity against human lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KBVIN) cancer cell lines.* To whom correspondence should be addressed. KHL Phone: (919) Results and DiscussionThe cytotoxic MeOH extract of dry roots of C. arisanensis was partitioned between EtOAc and water to give an active EtOAc extract. Column chromatography on silica gel eluting with CHCl 3 -MeOH gave thirteen fractions. Chromatographic fractionation of the active subfractions provided two new phenanthrenequinones (2-3), four new 9,10-dihydrophenanthrenes (4-7), and five known compounds (1 and 8-11). In the HMBC spectra of 2, methoxy protons at δ 3.97 and 4.06 showed 3 J interactions with carbons at δ 141.9 (C-5) and 150.2 (C-7), respectively, and the olefinic proton at δ 6.98 exhibited a 2 J interaction with a carbon at δ 150.2 (C-7) and 3 J interactions with carbons at δ 119.8 (C-4b), 140.8 (C-6), and 132.8 (C-9). These correlations led to assignment of an OCH 3 grou...

Neo-tanshinlactone (1) and its previously reported analogs, such as 2, are potent and selective in vitro anti-breast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of anti-breast agents. Several derivatives (19-21 and 24) exerted potent and selective anti-breast cancer activity with IC 50 values of 0.3, 0.2, 0.1 and 0.1 μg/ mL, respectively, against the ZR-75-1 cell lines. Compound 24 was two-to three-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analog 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.