Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues.

Malaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mechanisms, CQ is no longer effective against most malaria cases caused by P. falciparum. The World Health Organization recommends artemisinin combination therapies for P. falciparum malaria, but resistance is emerging in Southeast Asia and some parts of Africa. Therefore, new medicines for treating malaria are urgently needed. Previously, our group identified the 4-aminoquinoline DAQ, a CQ analog containing an acetylenic bond in its side chain, which overcomes CQ resistance in K1 P. falciparum strains. In this work, the antiplasmodial profile, drug-like properties, and pharmacokinetics of DAQ were further investigated. DAQ showed no cross-resistance against standard CQ-resistant strains (e.g., Dd2, IPC 4912, RF12) nor against P. falciparum and P. vivax isolates from patients in the Brazilian Amazon. Using drug pressure assays, DAQ showed a low propensity to generate resistance. DAQ showed considerable solubility but low metabolic stability. The main metabolite was identified as a mono N-deethylated derivative (DAQM), which also showed significant inhibitory activity against CQ-resistant P. falciparum strains. Our findings indicated that the presence of a triple bond in CQ-analogues may represent a low-cost opportunity to overcome known mechanisms of resistance in the malaria parasite.

Cytotoxic Alkylynols of the Sponge Cribrochalina vasculum: Structure, Synthetic Analogs and SAR Studies.

A series of twenty-three linear and branched chain mono acetylene lipids were isolated from the Caribbean Sea sponge Cribrochalina vasculum. Seventeen of the compounds, 1-17, are new, while six, 18-23, were previously characterized from the same sponge. Some of the new acetylene-3-hydroxy alkanes 1, 6, 7, 8, 10 were tested for selective cytotoxicity in non-small cell lung carcinoma (NSCLC) cells over WI-38 normal diploid lung fibroblasts. Compound 7, presented clear tumor selective activity while, 1 and 8, showed selectivity at lower doses and 6 and 10, were not active towards NSCLC cells at all. The earlier reported selective cytotoxicity of some acetylene-3-hydroxy alkanes (scal-18 and 23), in NSCLC cells and/or other tumor cell types were also confirmed for 19, 20 and 22. To further study the structure activity relationships (SAR) of this group of compounds, we synthesized several derivatives of acetylene-3-hydroxy alkanes, rac-18, scal-S-18, R-18, rac-27, rac-32, R-32, S-32, rac-33, rac-41, rac-42, rac-43, rac-45, rac-48 and rac-49, along with other 3-substituted derivatives, rac-35, rac-36, rac-37, rac-38, rac-39 and rac-40, and assessed their cytotoxic activity against NSCLC cells and diploid fibroblasts. SAR studies revealed that the alcohol moiety at position 3 and its absolute R configuration both were essential for the tumor cell line selective activity while for its cytotoxic magnitude the alkyl chain length and branching were of less significance.

Audit of the efficacy and complications of cyanoacrylate glue embolisation to treat varicose veins in primary care.

INTRODUCTION Cyanoacrylate glue embolization (CAGE) is a non-surgical procedure that uses a proprietary medical adhesive, delivered endovenously to close truncal, varicose veins. AIM To describe CAGE administered by a New Zealand general practitioner (GP) in primary care. METHODS The procedures were performed by a single GP with a special interest and 19 years' clinical experience in procedural phlebology. The clinical records of 107 consecutive patients who underwent CAGE over a 2-year period were retrospectively reviewed. Some patients had bilateral disease and some had more than one truncal vein per leg treated. Data on 173 truncal veins were included in the audit. Clinical data, procedural details and postprocedural course were recorded and analysed for 71 females and 36 males. RESULTS In total, 173 truncal veins were treated. They included the anterior accessory saphenous vein, the great saphenous vein, the small (lesser) saphenous vein and the thigh extension with a range of clinical severity. The most commonly treated truncal vein was the great saphenous vein with an average truncal diameter of 8.8mm (2.9s.d.). Of the 173 treated truncal veins, two failed to seal with CAGE, but were sealed after adjuvant ultrasound-guided foam sclerotherapy treatment. Post CAGE, 14.5% of treated truncal veins developed a phlebitis. DISCUSSION This audit shows that varicose veins can be treated in general practice with high levels of anatomic efficacy and few adverse effects.

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.

SAR studies of gymnasterkoreayne derivatives with cancer chemopreventive activities.

We synthesized diyne triols based on gymnasterkoreayne and evaluated their cancer chemopreventive activities in terms of the chemopreventive index (CI) to reveal the structure-activity relationship, and discovered more active compounds than natural diynes.

Efficient synthesis of the first betulonic acid-acetylene hybrids and their hepatoprotective and anti-inflammatory activity.

The Sonogashira reaction can be applied for the preparation of acetylenic derivatives of betulonic acid where the triterpenoid moiety can serve as either the halo- or the acetylenic component. This reaction opened access to the first derivatives of betulonic acid containing either the arylethynyl (C[triple bond]C-Ar(Het) or the ethynyl (C[triple bond]CH) moieties. From the fundamental perspective, this work illustrates the possibility of selective Pd-catalyzed cross-coupling at terminal acetylenes in the presence of a terminal alkene. Hepatoprotective and anti-inflammatory properties of selected acetylenic derivatives of betulonic acid were investigated using the CCl4-induced hepatitis and carrageenan-induced edema models, respectively.

New evidences of antimalarial activity of Bidens pilosa roots extract correlated with polyacetylene and flavonoids.

Bidens pilosa is among the several plants used in Brazil to treat malaria. It was demonstrated that crude extracts from roots prepared with 80% ethanol by percolation are active in vitro against Plasmodium falciparum and the activity is correlated with the presence of polyacetylene and flavonoids. This extract was submitted to column chromatography with ether and ether methanol (1:1) and two fractions, enriched in polyacetylene and flavonoids, respectively, were obtained. The extract and the fractions were assessed by HPLC/DAD analysis and antimalarial tests in vivo. Ethanol extract showed by HPLC the presence of several peaks for polyacetylene and flavonoids, compounds corresponding to quercetin-3,3'-dimethoxy-7-0-rhamnoglucopyranose and the acetylene 1-phenyl-1,3-diyn-5-en-7-ol-acetate, previously identified in this extract. The peaks for flavonoids were absent in ether fraction and those ones for polyacetylene in ether:methanol. In in vivo tests, ethanol extract caused 36% of reduction of parasitaemia at fifth day, and 29% at seventh day. Ether:methanol fraction caused 38% of reduction at fifth day but was inactive at day 7. The survival of the animals treated with 80% ethanol extract was higher than in the fractions. The results showed that the in vivo activity of ethanol extract depends on the presence of polyacetylene and flavonoids.

New Polyacetylenes, DGAT inhibitors from the roots of Panax ginseng.

The petroleum ether extract of Panax ginseng showed a significant inhibition of the diacylglycerol acyltransferase (DGAT) enzyme from rat liver microsomes. Bioactivity-guided fractionation led to the isolation of two new polyacetylenic compounds, (9 R,10 S)-epoxyheptadecan-4,6-diyn-3-one ( 1) and 1-methoxy-(9 R,10 S)-epoxyheptadecan-4,6-diyn-3-one ( 2). Their chemical structures were elucidated on the basis of spectroscopic evidence and asymmetric synthesis. IC50 values of 9 microg/mL ( 1) and 32 microg/mL ( 2) were obtained.

Effect of polyacetylenes on the neurite outgrowth of neuronal culture cells and scopolamine-induced memory impairment in mice.

Polyacetylenic alcohols and their linoleates isolated from Panax ginseng C. A. MEYER and Cirsium japonicum DC., of which the lipophilic extracts had been found to affect the neuritogenesis of cultured paraneurons, were demonstrated to have a significant neuritogenic effect on PC12h and Neuro2a cells. Panaxynol and the acetylenic triol in particular were highly efficient at concentrations > or = 2 microm. Panaxynol (20 mg/kg/d, i.p., for 3 d) was confirmed to improve scopolamine-induced memory deficit in mice (Y-maze task). It is suggested that the promotion of neuritogenesis in cultured paraneurons by the addition of panaxynol is related its ability to improve memory deficits in animals.

[The evaluation of the specific activity and side effects of the m-cholinergic blocker pentifin compared to other antiparkinson agents]. / Otsenka spetsificheskoi aktivnosti i pobochnykh éffektov m-kholinoblokatora pentifina v sravnenii s drugimi antiparkinsonicheskimi sredstvami.

Experiments on rodents showed that pentifin, a muscarine antagonist belonging to the group of acetylene amines, possesses a pronounced antiparkinsonian activity. Pentifin is superior in the breadth of therapeutic action and tolerance characteristics to the conventional agents used for Parkinson's disease treatment.

Effects of the acetylene compound from Atractylodes rhizome on experimental gastric ulcers induced by active oxygen species.

This study was conducted to determine the beneficial effects of treating digestive disorders of (6E,12E)-tetradecadiene-8,10-diyne-1,3-diol diacetate (TDEYA) detected in the plasma in hydrolyzed form: (6E,12E)-tetradecadiene-8,10-diyne-1,3-diol (TDEY), following the oral administration of a decoction of Atractylodes rhizome to rats. Assessment was also made of the efficacy of TDEYA in experimental gastric disorder models. Oral administration of TDEYA at doses of 300 to 500 mg/kg suppressed the formation of gastric lesions induced by indometacin in a dose-dependent manner. TDEYA at a dose of 200 mg/kg suppressed gastric lesions induced by an ischemia-reperfusion injury model. TDEYA at doses of 100 to 300 mg/kg did not show suppressive effects on water immersion stress-induced gastric lesions. TDEYA showed no active oxygen species scavenging action, nor did it have any effect on superoxide dismutase activity in the stomach tissue. TDEYA at doses of 200 to 500 mg/kg significantly suppressed xanthine oxidase (XO) activity in the stomach tissue following its oral administration. The suppressive effects of TDEYA on lesion formation induced by indometacin and ischemia-reperfusion injury models would thus appear to be due in part to the inhibition of XO activity in the stomach tissue.