Design, synthesis, and evaluation of novel ursolic acid derivatives as HIF-1α inhibitors with anticancer potential.

Hypoxia-inducible factor-1α (HIF-1α), a key mediator in tumor metastasis and angiogenesis, is associated with poor patient prognosis and has been recognized as an important cancer drug target. In this work, four novel series of ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were designed, synthesized, and evaluated for anti-tumor activity as HIF-1α inhibitors. The majority of the compounds showed an excellent ability to inhibit the expression of HIF-1α. In particular, 11b inhibited HIF-1α transcriptional activity under hypoxic conditions with IC50=36.9µM. The cytotoxicity of these compounds was also assessed in human colon cancer cell HCT116 cells by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50>100µmol/L), which was lower than that of ursolic acid (IC50=23.8µmol/L). The mechanism of action of the representative compound 11b was also investigated.

Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 µM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.

Novel arylhydrazone derivatives bearing a rhodanine moiety: synthesis and evaluation of their antibacterial activities.

A series of arylhydrazone derivatives bearing a rhodanine moiety have been synthesized, characterized, and evaluated as antibacterial agents. Some of these compounds showed potent antibacterial activities against several different strains of Gram-positive bacteria, including multidrug-resistant clinical isolates. Of the compounds tested, IIk and IIIk were identified as the most effective, with minimum inhibitory concentration values of 2-4 µg/mL against multidrug-resistant Gram-positive organisms, including methicillin-resistant and quinolone-resistant Staphylococcus aureus. None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 µg/mL.

Novel dammarane-type sapogenins from Panax ginseng berry and their biological activities.

Three new dammarane-type sapogenins (1, 3, and 5) together with two known ones (2 and 4) were isolated from the total hydrolyzed saponins extracted from Panax ginseng berry. Their structures were elucidated using a combination of 1D and 2D (1)H and (13)C NMR spectra and mass spectroscopy as 20(R)-25-methoxyl-dammarane-3ß,12ß,20-triol (1), 20(R)-25-methoxyl-dammarane-3ß,6α,12ß,20-tetrol (2), 20(R)-20-methoxyl-dammarane-3ß,12ß,25-triol (3), 20(R)-20,25-dimethoxyl-dammarane-3ß,12ß-diol (4), and (12R,20S,24S)-20,24-; 12,24-diepoxy-dammarane-3ß-ol (5). Their antitumor activities were evaluated in six human cancer cell lines. The novel compounds 1 and 3 showed significant cytotoxic activity against the six cell lines. The IC(50) values of 3 against HepG2, Colon205, and HL-60 were the lowest (8.78, 8.64, and 3.98 µM, respectively). Compounds 1 and 20(S)-25-OCH(3)-PPD, which are a pair of configuration isomers, showed a 10- to 100-fold greater growth inhibition than ginsenoside-Rg(3) (an anti-cancer clinical agent in China). The data presented here may be useful for the development of novel anti-cancer agents.

[Preparation and isolation on the rare ginsenoside derivatives with anti-cancer activity].

OBJECTIVE: To prepare and isolate the rare ginsenoside derivatives of anti-cancer activity. METHODS: Acid-degradation products of ginsenosides were isolated and purified by various chromatographic techniques such as silica gel and so on; compounds were identified and elucidated by spectral and chemical methods. RESULTS: Eleven compounds were obtained from the products of Acid-degradation. CONCLUSION: Compound I, II are discoverd from the roots, stems, leaves, fruits and alabastrums of Panax quinquefolium L. for the first time. Compound IX of derivate of the aglycone of protopanoxadiol ginsenoside was discovered and reported, having the conspicuous anti-cancer activity for the first time from the fruits of Panax ginseng.

Synthesis and anticonvulsant activity of N-(2-hydroxy-ethyl)amide derivatives.

A series novel of N-(2-hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N-(2-hydroxyethyl)decanamide 1g, N-(2-hydroxyethyl)palmitamide 1l, and N-(2-hydroxyeth-yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti-epileptic drug valproate. In the anti-MES potency test, these compounds exhibited median effective doses (ED50) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD50) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti-epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g, 1l, and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3-mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.

Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones.

To further investigate anticonvulsant activity of quinoline derivatives, a series of 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one derivatives was synthesized starting from 7-hydroxyl-3,4-dihydro-2(1H)-quinoline. In initial (phase I) screening and quantitative (phase II) evaluation, compound 7-benzyloxyl-4,5-dihydro-[1,2,4]thiazolo[4,3-a]quinoline-1(2H)-one (3f) was among the most active but also has the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 12.3 mg/kg, median toxicity dose (TD(50)) of 547.5 mg/kg, and the protective index (PI) of 44.5, which is much greater than PI of the prototype drugs phenytoin, phenobarbital, carbamazepin, and valproate. Compound 3f was chosen for further evaluation. In phase III pharmacological test, the compound had median hypnotic dose (HD(50)) and median lethal dose (LD(50)) of 1204 mg/kg and >3000 mg/kg, respectively, thus demonstrating much greater margin of safety compared to prototype drugs. The compound 3f also showed significant oral activity against MES-induced seizures and low oral neurotoxicity in mice in phase IV pharmacological test. Possible structure-activity relationship was discussed.