Nelumbo nucifera Gaertn. (Nymphaceae) has been used for various medicinal purposes as in Chinese herbal medicine. In particular, the leaves are known for diuretic and astringent properties, and are used to treat obesity. During our search for a plant-derived anti-obesity agent from natural products, we have found that a 50% ethanol (EtOH) extract prepared from the leaves of N. nucifera (NN) stimulated lipolysis in the white adipose tissue (WAT) of mice and that the beta-adrenergic receptor (beta-AR) pathway was involved in this effect. In subsequent experiments, dietary supplementation of NN resulted in a significant suppression of body weight gain in A/J mice fed a high-fat diet. Bioassay-guided fractionation and repeated chromatography of NN has led to the isolation and identification of quercetin 3-O-alpha-arabinopyranosyl-(1-->2)-beta-galactopyranoside (1), rutin (2), (+)-catechin (3), hyperoside (4), isoquercitrin (5), quercetin (6) and astragalin (7). Of these, compounds 1, 3, 4, 5 and 7 exhibited lipolytic activity, especially in visceral adipose tissue. Our results indicate that the effects of NN in preventing diet-induced obesity appear to be due to various flavonoids and that the activation of beta-AR pathway was involved, at least in part.

A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug-resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6′-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound 4 forms three hydrogen bonds (H-bonds) only with α-tubulin at the colchicine site; in contrast, 8 forms H-bonds with both α- and β-tubulin. We predict that, when a compound/ligand, such as 8, forms H-bonds to both α- and β-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules.

The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a–c and 5a–m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9–3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.

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Two new naphthopyrones, cassiasides B2 (1) and C2 (2), were isolated from the seeds (Cassiae Semen) of Cassia obtusifolia L. The structures of the two new compounds 1 and 2 were established as rubrofusarin 6-O-beta-D- glucopyranosyl-(1-->6)-O-beta-D-glucopyranosyl-(1-->3)-O-beta-D- glucopyranosyl-(1-->6)-O-beta-D-glucopyranoside and toralactone 9-O-beta-D-glucopyranosyl-(1-->6)-O-beta-D-glucopyranosyl- (1-->3)-O-beta-D-glucopyranosyl-(1-->6)-O-beta-D-glucopyranoside, respectively, on the basis of spectral and chemical evidence. Compound 2 was found to inhibit the histamine release from rat peritoneal exudate mast cells induced by antigen-antibody reaction.

Structural optimizations of the prior lead 1a led to the discovery of a series of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinoline derivatives as a novel class of tubulin polymerization inhibitors targeted at the colchicine binding site. The most active compound 6d showed extremely high cytotoxicity against a human tumor cell line panel (A549, KB, KBvin, and DU145) with GI50 values ranging from 1.5 to 1.7 nM, significantly more potent than paclitaxel, especially against the drug-resistant KBvin cell line, in the same assays. Analogues 5f, 6b, 6c, and 6e were also quite potent, with a GI50 range of 0.011–0.19 μM. In further studies, active compounds 6b–6e and 5f significantly inhibited tubulin assembly, with IC50 values of 0.92 to 1.0 μM and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75–99% (at 5 μM), comparable with or more potent than combretastatin A-4 (IC50 0.96 μM). Current studies included design, synthesis, and biological evaluations of 24 new compounds (series 3–6). Related SAR analysis, molecular modeling, and evaluation of essential drug-like properties, i.e. water solubility, log P, and in vitro metabolic stability, were also performed.

Little information has been reported on the antitumor effects of the diterpenoid alkaloid constituents of Aconitum plants, used in the herbal drug “bushi”. This study was aimed at determining the antitumor activities of Aconitum C19-and C20-diterpenoid alkaloids and synthetic derivatives against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines. Newly synthesized C20-diterpenoid alkaloid derivatives showed substantial suppressive effects against all human tumor cell lines tested. In contrast, natural and derivatized C19-diterpenoid alkaloids showed only a slight or no effect. Most of the active compounds were hetisine-type C20-diterpenoid alkaloids, specifically kobusine and pseudokobusine analogs with two different substitution patterns, C-11 and C-11,15. Notably, several C20-diterpenoid alkaloids were more potent against multidrug-resistant KB subline KB-VIN cells. Pseudokobusine 11-3′-trifluoromethylbenzoate (94) is a possible promising new lead meriting additional evaluation against multidrug-resistant tumors.

We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI50 values of 0.8–2.1 μM. In contrast, 1-analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistance cell line. We have now prepared and evaluated 1-analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI50 values of 0.06–0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC 50 value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.