Synthesis and evaluation of (Z)-2,3-diphenylacrylonitrile analogs as anti-cancer and anti-microbial agents.

In the present study, a series of (Z)-2,3-diphenylacrylonitrile analogs were synthesized and then evaluated in terms of their cytotoxic activities against four human cancer cell lines, e.g. lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), and colon cancer (HCT15), as well as anti-microbial activities against three microbes, e.g. Staphylococcus aureus, Salmonella typhi, and Aspergillus niger. The title compounds were synthesized by Knoevenagel condensation reaction of benzyl cyanide or p-nitrobenzyl cyanide with substituted benzaldehydes in good yields. Most of the compounds exhibited significant suppressive activities against the growth of all cancer cell lines. Compound 3c was most active in inhibiting the growth of A549, SK-OV-3, SK-MEL-2, and HCT15 cells lines with IC50 values of 0.57, 0.14, 0.65, and 0.34 mg/mL, respectively, followed by compounds 3f, 3i, and 3h. Compound 3c exhibited 2.4 times greater cytotoxic activity against HCT15 cells, whereas it showed similar potency against SK-OV-3 cells to that of the standard anti-cancer agent doxorubicin. Structure-activity relationship study revealed that electron-donating groups at the para-position of phenyl ring B were more favorable for improved cytotoxic activity, whereas the presence of electron-withdrawing groups was unfavorable compare to unsubstituted acrylonitrile. An optimal electron density on phenyl ring A of (Z)-2,3-diphenylacrylonitrile analogs was crucial for their cytotoxic activities against human cancer cell lines used in the present study. Qualitative structure-cytotoxic activity relationships were studied using physicochemical parameters; a good correlation between calculated polar surface area (PSA), a lipophobic parameter, and cytotoxic activity was found. Moreover, all compounds showed significant anti-bacterial activities against S. typhi, whereas compound 3k showed potent inhibition against both S. aureus and S. typhi bacterial strains.

Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-κB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells.

Several sesquiterpene lactones are the active components of several medicinal plants and have been demonstrated to perform various pharmacological functions. In this study, we investigated the anti-inflammatory effects of alantolactone, a sesquiterpene lactone isolated from the root of Aucklandia lappa, in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and peritoneal macrophages. Alantolactone inhibited inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) protein and mRNA transcription, as well as the downstream products, nitric oxide (NO), prostaglandin E(2) (PGE(2)) and tumor necrosis factor-α (TNF-α). Investigation of the effects on nuclear factor κB (NF-κB) signaling showed that alantolactone inhibits the phosphorylation of inhibitory κB (IκB)-α and IκB kinase (IKK) and the subsequent translocation of the p65 and p50 NF-κB subunits to the nucleus. Moreover, inhibition of mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 MAPK, and activator protein-1 (AP-1) was also observed. A further study indicated that alantolactone attenuated the phosphorylation of Akt and inhibited the expression of MyD88 and Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP), an upstream signaling molecule required for IKK and MAPKs activation. Taken together, these results suggest that alantolactone exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 cells by suppressing NF-κB activation and MAPKs phophorylation via downregulation of the MyD88 signaling pathway. Thus, alantolactone may provide a useful therapeutic approach for inflammation-associated diseases.

Interferon Treatment on HBeAg Positive Chronic Hepatitis B with HBV Precore Mutant in Liver Tissue / 대한내과학회지

BACKGROUND: This study investigates the prevalance of HBV precore mutant in chronic B hepatitis patients and whether HBV precore mutants affect hepatic inflammation and response to interferon alfa. METHODS: HBV DNA in liver tissue from 48 chronic hepatitis patients was amplified by polymerase chain reaction. The HBV precore mutants were detected by direct sequencing of amplified PCR products. Thirty-three HBeAg-positive patients (Group 1: wild- type, Group 2: mixed) were received 3-6 MU INF three times a week for 4-6 months. We did follow-ups for at least six months(mean : Group 1-11.3, Group 2- 13.7 months). A complete responder was defined as persistent(>6 months) normalization of transaminase and loss of HBeAg and/or seroconversion. RESULTS: The HBV precore mutants were found in 15 cases(31.2%) among 48 patients: 7 cases(21.2%) in 33 HBeAg-positive patients and 8 cases(53.3%) in 15 HBeAg-negative patients. The HBV precore mutants were more frequently found in HBeAg-negative patients(p= 0.043). Differences in severity of hepatic pathology were not observed in the wild-type versus mutant-type chronic hepatitis B patients(p =1.00). Initial response rate was not significantly different between two Groups(p= 0.228), but complete response rate had a lower tendency in Group 2 (p=0.073). CONCLUSION: There is a tendency for HBV precore mutants to be less responsive to INF therapy than wild type. Therefore the patients with chronic hepatitis B should be treated as early as possible in natural history of their liver disease before the emergence of HBV precore mutants.

Result of MAST in bronchial asthma in Pusan area / 알레르기

OBJECTIVES: Allergen is closely related with local features and cultural environment and a new approach method regarding causes triggering aggravation is especially required due to complex and variety of ordinary residence and pollution of living environment recently. We, therefore, performed this study to inspire the necessity of identification of causative afeuts in aothmatic patients in pusan area. METHODS: We measured serum specific IgE antibody by means of chemiluminescent analyzer employing MAST, classified the level from class 0 to 4 and interpreted the result in order to identify allergen on total 262 patients consisted of inpatients and outpatients who had been presumed as extrinisic asthma and treated in this hospital during 2 and a half years from June of 1994 to December of 1996. RESULTS: 1. With regard to sex and age distribution, the rate of men versus women was 1 : 1.3, while in the distribution by age, the twenties and the thirties were the most as 29% and 26% respectively. 2. The result of interpretation of the test showed positive in 75%, 78% of which showed positive reaction compounded of 2 kinds or more. 3. If we take a look at the distribution of total IgE class in the positive area, we can find that ; Class III and class II showed the highest frequency as 47% and 37% respectively. 4. If we take a look at the distribution by age and allergen, the twenties(32%) and the thirties(30%) showed the highest frequency, the fifties, the forties and the teens showed middle frequency as 10~13% and the sixties and the seventies showed the lowest frequency as about 1%. The causative allergen appeared in the order of pollen(40%), dust(20%), food(18%), fungus(13%) and epidermis(8%). 5. The distribution of allergen by season generally showed high rate of positive appearance in spring and fall as pollen appeared in spring(44%) and fall(27%), dust appeared in fall(32%) and summer(23%), food appeared in spring(34%) and fall(29%), fungus appeared in fall(30%) and spring(28%) and epidermis appeared in spring(30%) and fall(28%). 6. With regard to the allergen: (1) In pollen allergens, trees showed higher positive frequency than weeds and trees were in the order of birch(14%), alder(13%) and hazelnut mix(12%) and weeds showed similar positive values. (2) In dust allergens, mite(D. pteronyssinus and D. farinae) showed high positive rate as 39% each. (3) In epidermal allergens, it also showed relatively even positive value among which cat's halr-dandruff was the highest as 40%. (4) In food allergens, shrimp showed the highest as 22% and others were similar as evenly positive values. (5) In fungus allergens, Candida and Stemphylium showed the highest value as 19% each. CONCLUSION: The analysis of allergen by means of MAST could be used as a valuable guide post for identifing cousative antigens for active treatment of extrinsic asthma.