Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway.

Isolation, cytotoxicity evaluation and HPLC-quantification of the chemical constituents from Prangos pabularia.

Phytochemical analysis of the dichloromethane:methanol (1:1) extract of root parts of Prangos pabularia led to the isolation of twelve cytotoxic constituents, viz., 6-hydroxycoumarin (1), 7-hydroxycoumarin (2), heraclenol-glycoside (3), xanthotoxol (4), heraclenol (5), oxypeucedanin hydrate (6), 8-((3,3-dimethyloxiran-2-yl)methyl)-7-methoxy-2H-chromen-2-one (7), oxypeucedanin hydrate monoacetate (8), xanthotoxin (9), 4-((2-hydroxy-3-methylbut-3-en-1-yl)oxy)-7H-furo[3,2-g]chromen-7-one (10), imperatorin (11) and osthol (12). The isolates were identified using spectral techniques in the light of literature. 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity screening of the isolated constituents was carried out against six human cancer cell lines including lung (A549 and NCI-H322), epidermoid carcinoma (A431), melanoma (A375), prostate (PC-3) and Colon (HCT-116) cell lines. Osthol (12) exhibited the highest cytotoxicity with IC50 values of 3.2, 6.2, 10.9, 14.5, 24.8, and 30.2 µM against epidermoid carcinoma (A431), melanoma (A375), lung (NCI-H322), lung (A549), prostate (PC-3) and colon (HCT-116) cell lines respectively. Epidermoid carcinoma cell line A431 was sensitive to most of the compounds followed by lung (A549) cancer cell line. Finally a simple and reliable HPLC method was developed (RP-HPLC-DAD) and validated for the simultaneous quantification of these cytotoxic constituents in Prangos pabularia. The extract was analyzed using a reversed-phase Agilent ZORBAX eclipse plus column C18 (4.6×250 mm, 5 µm) at 250 nm wavelength using a gradient water-methanol solvent system at a flow rate of 0.8 ml/min. The RP-HPLC method is validated in terms of recovery, linearity, accuracy and precision (intra and inter-day validation). This method, because of shorter analysis time, makes it valuable for the commercial quality control of Prangos pabularia extracts and its future pharmaceutical preparations.

Evaluation of antioxidant and antimicrobial activities of Bergenin and its derivatives obtained by chemoenzymatic synthesis.

Bergenin pentacetate (2), a peracetate derivative of biologically active lead compound Bergenin (1) isolated from Bergenia stracheyi was subjected to lipase catalyzed regioselective alcoholysis to obtain 3,4,10,11-tetracetate of Bergenin (3). The free hydroxyl group of 3 was derivatised using higher carboxylic acids to obtain acyl derivatives (4-7). These compounds synthesized via chemoenzymatic route were characterized using 1H NMR, 13C NMR and mass spectral data and evaluated for DPPH radical scavenging, antimicrobial and xanthine oxidase inhibitory activities. The studies revealed that biological activity of Bergenin can be optimized by selective modification of its structure.

Immunomodulatory activity of isoflavones isolated from Iris germanica (Iridaceae) on T-lymphocytes and cytokines.

The immunomodulatory activities of two isoflavones, 5,7-dihydroxy-6,4'-dimethoxyisoflavone (irisolidone) (1) and 5,4'-dihydroxy-6,7-methylenedioxyisoflavone (irilone) (2) isolated from Iris germanica (Iridaceae) is reported. Their influence on production of T-lymphocytes (CD4+ and CD8+ cells) and T-cell cytokines, namely Th1: IL-2, IFN-gamma and Th2: IL-4 and IL-5 in a dose-dependent manner was studied by flow cytometric method in Balb/c mice. Oral administration of drugs at doses of 0.1-0.8 mg/kg per oral dose showed 1 to possess stimulatory activity on T-cells and Th1 cytokine production, while as 2 acted as an immunosuppressant for both cells and cytokines. The methylated products of 1 and 2 showed a similar trend to that of their parent compounds but their activity was drastically decreased revealing the importance of free phenolic groups for their immunomodulating activities.

New isoflavones from Iris kashmiriana.

Phytochemical investigation of the rhizomes of Iris kashmiriana (Iridaceae) led to the isolation of three isoflavones characterized by 1D and 2D NMR, IR, UV, and MS as 4'-hydroxy-8-methoxy-6,7-methylenedioxyisoflavone (isonigricin, 1), 5,6-dihydroxy-4',7-dimethoxyisoflavone (isoirisolidone, 2), and 5,7-dihydroxy-4',6-dimethoxyisoflavone (irisolidone, 3). Compound 1 is a new isoflavone, while 2 is reported for the first time from a natural source.