Hsin Yi Hung

Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20(S)-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

New Betulinic Acid Derivatives as Potent Proteasome Inhibitors

In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC(50) values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.

Antitumor Agents. 280. Multidrug Resistance-Selective Desmosdumotin B Analogues

6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.

Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents.

Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.

Synthesis and biological evaluation of chalcone, dihydrochalcone, and 1,3-diarylpropane analogs as anti-inflammatory agents

Twenty-one chalcones were prepared via aldol condensation and subsequent reduction of these compound led to the corresponding dihydrochalcone and 1,3-diphenylpropane derivatives. The synthetic products were examined for their effects on NO inhibition in LPS-activated mouse peritoneal macrophages. Among the tested compounds, a 1,3-diarylpropane analog, 2-(3-(3,4-dimethoxyphenyl)propyl)-5-methoxyphenol (3p), displayed the most significant inhibitory effects against NO production. To investigate the mechanism of action, the effects of 3p on iNOS and COX-2 protein expression were studied by immunoblot. The results concluded that 3p is capable of inhibiting iNOS expression in LPS-induced RAW264.7 cells via attenuation of NF-κB signaling by ERK, p38, and JNK.

Recent progress on the traditional Chinese medicines that regulate the blood

In traditional Chinese medicine, the herbs that regulate blood play a vital role. Here, nine herbs including Typhae Pollen, Notoginseng Root, Common Bletilla Tuber, India Madder Root and Rhizome, Chinese Arborvitae Twig, Lignum Dalbergiae Oderiferae, Chuanxiong Rhizoma, Corydalis Tuber, and Motherwort Herb were selected and reviewed for their recent studies on anti-tumor, anti-inflammatory and cardiovascular effects. Besides, the analytical methods developed to qualify or quantify the active compounds of the herbs are also summarized.

YC‐1 inhibits proliferation of breast cancer cells by down‐regulating EZH2 expression via activation of c‐Cbl and ERK

YC‐1 exhibits potent anticancer activity via numerous actions in many cancer cell lines. Hence, we investigated the in vivo antitumour efficacy of YC‐1 in an MDA‐MB‐468 xenograft model and elucidated the mechanism of down‐regulation of enhancer of zeste homology 2 (EZH2) by YC‐1 in breast cancer cells.

Chemical Constituents of the Rhizomes of Bletilla formosana and Their Potential Anti-inflammatory Activity.

Nine new phenanthrenes (1-9) and a new benzyl glycoside (10) together with 45 known compounds were isolated from the rhizomes of Bletilla formosana. The structures of 1-10 were elucidated primarily on the basis of their 1D and 2D NMR spectroscopic data. Most of the isolated compounds were evaluated for their anti-inflammatory activities. The results showed that IC50 values for the inhibition of superoxide anion generation and elastase release ranged from 0.2 to 6.5 μM and 0.3 to 5.7 μM, respectively. Structure-activity relationships of the isolated compounds were also investigated. The inhibitory potencies were determined as phenanthrenes > bibenzyls > biphenanthrenes.

UV-guided isolation of polyynes and polyenes from the roots of Codonopsis pilosula

The UV-guided isolation of polyacetylenes from the crude extract of Codonopsis pilosula has successfully led to the characterization of five new polyynes, pilosulynes A–E (1–5), and two new polyenes, pilosulynes F and G (6 and 7), as well as five known analogues (8–12). Their structures were determined by spectroscopic methods, including ICD and 1D/2D NMR experiments. The absolute configurations of the 6,7-diol moiety of the isolated compounds were determined by the Snatzkes method, which revealed an induced circular dichroism after the addition of dimolybdenum tetraacetate in DMSO. Compound 6 exhibited anti-HCV activity in the HCVcc infection assay with an EC50 value of 47.2 μM.

A-ring modified betulinic acid derivatives as potent cancer preventive agents.

Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.