Firoj Ahmed

Antinociceptive and sedative effects of the bark of Cerbera odollam Gaertn.

The crude methanolic extract of the bark of Cerbera odollam Gaertn. was evaluated for its possible antinociceptive and neuropharmacological activities in animal models. At the dose of 250 and 500 mg/kg body weight, the extract showed a significant antinociceptive effect in acetic acid induced writhing in mice comparable to that produced by aspirin, used as standard drug (P

Tyrosine derivatives isolated from Streptomyces sp. IFM 10937 in a screening program for TRAIL-resistance-overcoming activity.

Exploration of actinomycetes for isolation of natural products for abrogating TRAIL resistance led to the isolation of two new tyrosine derivatives (1 and 2) along with novobiocin (3). The structures of 1 and 2 were determined by spectroscopic methods, while the absolute configuration was determined by analyzing CD spectra and by a modified Marfeys method. Compounds 1 (150 μM) and 3 (37.5 and 75 μM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells.

Bioactivity of Excoecaria agallocha

The results of neuropharmacological, microbiological and toxicological studies on the ethanol extract of the bark of Excoecaria agallocha are reported. The extract (100 and 200 mg/kg dosages) was found to produce a profound decrease in exploratory activity in a dose-dependent manner. It also showed a marked sedative effect as evidenced by a significant reduction in gross behaviour and potentiation of sodium thiopental-induced sleeping time. The totality of these effects showed that the extract possesses depressant action on the central nervous system (CNS). The extract of E. agallocha exhibited significant in vitro antibacterial activity against Staphylococcus aureus, Shigella dysenteriae, Shigella sonnei and Enterococci with the zones of inhibition ranging from 11 to 15 mm. While the extract showed considerable brine shrimp toxicity (LD50 = 20 mg/mL), it displayed only low level of toxicity in mice.

New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha.

The inhibition of the Hedgehog (Hh) signaling pathway has emerged as an anti-cancer strategy. Three flavonoid glycosides including 2 new compounds (1-2) were isolated from Excoecaria agallocha as Hedgehog/GLI1-mediated transcriptional inhibitors and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compound 1 clearly inhibited the expression of GLI-related proteins (PTCH and BCL-2) and blocked the translocation of GLI1 transcription factors into the nucleus in PANC1. Deleting the Smoothened (Smo) function in PANC1 treated with 1 led to downregulation of the mRNA expression of Ptch. This study describes the first Hh signaling inhibitor which blocks GLI1 movement into the nucleus without interfering with Smo.

Flavonoids from Sonneratia caseolaris

According to the traditional medicinal usage of Sonneratia caseolaris, we tested the extract of S. caseolaris for antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect on thin-layer chromatography. Following activity-oriented separation, two flavonoids, luteolin (1) and luteolin 7-O-β-glucoside (2), were isolated. Both of the compounds were found to possess antioxidant activity.

Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2–3). Compound 1 showed strong activity in overcoming TRAIL‐resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 μm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL‐induced apoptosis at the aforementioned concentrations. Copyright

Constituents of Amoora cucullata with TRAIL resistance-overcoming activity

In search of bioactive natural products for overcoming TRAIL resistance from natural resources, we previously reported a number of active compounds. Bioassay-guided fractionation of mangrove, Amoora cucullata, collected from Sundarbans Mangrove Forest, Bangladesh, led to the isolation of four new compounds (1-4), along with seven known compounds (5-11). Of the isolates, compounds 1, 5, 8, and 9 showed TRAIL resistance-overcoming activity, among which 8 showed the most potent activity and enhanced TRAIL-induced apoptosis in TRAIL-resistant human gastric adenocarcinoma (AGS) cells through the activation of caspase-3/7, enhancing the expression of DR4 and DR5 mRNA in AGS cells. Cell death caused by the combined treatment of 8 and TRAIL was inhibited by human recombinant DR5/Fc and DR4/Fc chimera proteins, indicating that 8 sensitizes TRAIL-resistant AGS cells to TRAIL through the induction of DR4 and DR5.

Calotropin: A Cardenolide from Calotropis gigantea that Inhibits Wnt Signaling by Increasing Casein Kinase 1α in Colon Cancer Cells

Wnt signaling plays key roles in embryonic development and various human diseases. Activity‐guided testing to isolate Wnt signaling inhibitors from the methanol extract of Calotropis gigantea (Asclepiadaceae) exudutes identified six Wnt inhibitory cardenolides (1–6), of which 1, 3, 5, and 6 exhibited potent TCF/β‐catenin inhibitory activities (IC50 0.7–3.6 nM). Calotropin (1) inhibited Wnt signaling by decreasing both nuclear and cytosolic β‐catenin in a dose‐dependent manner, and promoted degradation of β‐catenin by increasing the phosphorylation of β‐catenin at Ser45 through casein kinase 1α (CK1α). Moreover, 1 significantly increased CK1α protein and mRNA levels. The results suggest that 1 inhibits the Wnt signaling pathway by increasing CK1α protein levels. To the best of our knowledge, calotropin is the first small molecule to increase CK1α levels.

Xylogranin B: A Potent Wnt Signal Inhibitory Limonoid from Xylocarpus granatum

Xylogranin B (2) was isolated from Xylocarpus granatum (Meliaceae) leaves, by use of a cell-based luciferase screening system targeting a Wnt signaling pathway. Compound 2 inhibited TCF/β-catenin transcriptional activity (IC50 48.9 nM) and exhibited strong cytotoxicity against colon cancer cell lines. Compound 2 significantly decreased β-catenin protein levels in nuclei but not in the cytosol. These results indicated that a decrease in β-catenin levels in nuclei by 2 resulted in the Wnt signal inhibitory effects of 2.

GLYCOSIDES FROM VALLARIS SOLANACEAE WITH TRAIL-RESISTANCE-OVERCOMING ACTIVITY

A new cardenolide glycoside, vallarisoside (1), and a known one, 3β-O-(α-acofriosyl)-16-anhydrogitoxigenin (2) along with a new glycoside, benzyl 2-O-β-apiofuranosyl-(1→2)-β-D-glucopyranosyl-2, 6-dihydroxy-benzoate (3) were isolated from Vallaris solanaceae. Structures of the isolates were elucidated by ID and 2D NMR and mass spectroscopic analysis. Of the isolates, vallarisoside (1) showed potent TRAIL-resistance-overcoming activity in human gastric adenocarcinoma (AGS) cells and cell-growth-inhibitory activity against HeLa and SW480 cells.