11 research outputs found
Constituents of an Extract of <i>Cryptocarya rubra</i> Housed in a Repository with Cytotoxic and Glucose Transport Inhibitory Effects
A new alkylated chalcone (<b>1</b>), a new 1,16-hexadecanediol
diester (<b>2</b>), and eight known compounds were isolated
from a dichloromethane-soluble repository extract of the leaves and
twigs of <i>Cryptocarya rubra</i> collected in Hawaii. The
structures of the new compounds were determined by interpretation
of their spectroscopic data, and the absolute configurations of the
two known cryptocaryanone-type flavonoid dimers, (+)-bicaryanone A
(<b>3</b>) and (+)-chalcocaryanone C (<b>4</b>), were
ascertained by analysis of their electronic circular dichroism and
NOESY NMR spectra. All compounds isolated were evaluated against HT-29
human colon cancer cells, and, of these, (+)-cryptocaryone (<b>5</b>) was found to be potently cytotoxic toward this cancer cell
line, with an IC<sub>50</sub> value of 0.32 μM. This compound
also exhibited glucose transport inhibitory activity when tested in
a glucose uptake assay
α-PGG inhibited thrombin induced rise in cytosolic calcium.
<p>Changes in cytosolic calcium were quantified in Fura2/AM loaded platelets. Platelets were incubated with α-PGG (3 or 10 µM) prior to stimulation with thrombin (0.1 U mL<sup>−1</sup>) and changes in calcium levels were recorded by fluorescence spectrometry as described in Experimental Procedures. The results are reported as means ± SE (n = 4).</p
α-PGG inhibited collagen-induced phosphorylation of Akt.
<p>Washed human platelets were stimulated with collagen (1.0 µg mL<sup>−1</sup>) in the presence or absence of α-PGG (10 µM). Lysis buffer was added to samples at 6 min to terminate reactions. Total Akt and p-Akt were visualized after PAGE and Western blotting as described in the Experimental Procedures. The β-actin was used as a loading control.</p
Administration of α-PGG inhibited <i>ex vivo</i> platelet aggregation induced by ADP or collagen.
<p>A, ADP or B, collagen was added to platelet-rich plasma, prepared from murine blood drawn at 30 min after oral administration of α-PGG (20 mg kg<sup>−1</sup>) or vehicle, to induce aggregation. The aggregation tracings are representative of three experiments.</p
Insulin or α-PGG induced phosphorylation of insulin receptors and IRS-1.
<p>Washed human platelets were incubated with insulin (100 nM) or α-PGG (10 µM) for five and ten minutes. The reactions were stopped by adding lysis buffer and the total and phosphorylated insulin receptors (A) and total IRS-1 and phosphorylated IRS-1 (B) were visualized after immuno-precipitation and Western blotting. The phosphorylation of insulin receptors and IRS-1 was quantified by densitometry.</p
α-PGG inhibited ADP- or thrombin-induced lowering of cyclic AMP.
<p>ADP (10 µM), thrombin (0.1 U ml<sup>−1</sup>) or PGE<sub>1</sub> (1 µM) induced changes in platelet cyclic AMP (pmoles/10<sup>8</sup> platelets) levels were quantified in the presence or absence of α-PGG (10 µM) using enzyme-linked assay kits as described in Experimental Procedures. ADP and thrombin decreased basal cyclic AMP levels by 24% (*p<0.03) and 22% (*p<0.02) respectively. α-PGG blocked ADP and thrombin induced decrease in cyclic AMP levels.</p
α-PGG inhibited thrombin induced secretion from the α- and dense-granules and platelet aggregation.
<p>Washed human platelets were stimulated with thrombin (0.1 U mL<sup>−1</sup>) in the presence or absence of α-PGG and expression of P-selectin (A) and secretion of ATP (B) and platelet aggregation (C) was monitored as detailed in Experimental Procedures. The results are reported as means ± SD for P-selectin expression (n = 3). ATP secretion and aggregation tracings are representative of three experiments.</p
Synthesis and Antitumor Activity of Ellagic Acid Peracetate
Ellagic acid (<b>1</b>) was synthesized for the
first time from methyl gallate through α-pentagalloylglucose
(α-PGG), and ellagic acid peracetate (3,4,3′,4′-tetra-<i>O</i>-acetylellagic acid, <b>2</b>) was derived from <b>1</b> by acetylation. Oral administration of <b>2</b> suppressed
melanoma growth significantly in C7BL/6 immunocompetent mice without
having any effect on natural killer (NK) cell activity. Comparison
of the immunoenhancing activities of <b>1</b> and <b>2</b> indicated that the latter compound increased white blood cell quantities
in peripheral blood and immune cells enriched from the bone marrow
and liver of mice. Therefore, both the antitumor efficacy and the
immunity enhancement by <b>2</b> were greater than those by <b>1</b>. In addition, on oral administration, neither <b>1</b> nor <b>2</b> resulted in whole body, liver, or spleen weight
changes of normal, tumor-free mice, indicating that these compounds
are potentially nontoxic to mice. It was shown that ellagic acid peracetate
(<b>2</b>) inhibits B16 melanoma cell growth in vitro and induces
B16 cell apoptosis, corresponding to BCL-2 down-regulation. Collectively,
the present data imply that <b>2</b> can suppress tumor growth
by enhancing mouse immunity and inducing tumor cell apoptosis without
apparent side effects
Na+/K+‑ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives
(+)-Digoxin (1) is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (2-5) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin (6) and (+)-17-epi-20,22-dihydro-21α-hydroxydigoxin (7), were synthesized from 1 and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for 1 to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic 1 and the noncytotoxic derivative 7 bind differentially to Na+/K+-ATPase. The HO-12β, HO-14β, and HO-3'aα hydroxy groups of (+)-digoxin (1) may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na+/K+-ATPase, respectively, but the altered lactone unit of 7 results in a rotation of its steroid core, which depotentiates the binding between this compound and Na+/K+-ATPase. Thus, 1 was found to inhibit Na+/K+-ATPase, but 7 did not. In addition, the cytotoxic 1 did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters
Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper
A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters