The preparation of urea by Wöhler constituted a landmark achievement in organic chemistry, and it laid the ground for the early days of target-oriented organic synthesis.1 Since then, significant progress has been achieved in this discipline; many powerful single bond forming reactions and asymmetric variants have been developed. These discoveries have paved the way for the stereoselective assembly of complex organic molecules, a task deemed inconceivable by early practitioners. A great many strategies were invented by chemists in order to facilitate the synthesis of complex natural products.2 One avenue in emulating nature’s efficiency would * To whom correspondence should be addressed. E-mail: dennis.hall@ ualberta.ca. † Novartis Institute for Biomedical Research. ‡ Department of Chemistry, University of Alberta. Chem. Rev. 2009, 109, 4439–4486 4439

Natural product synthesis using multicomponent reaction strategies.

This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzo-annelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics – some of them have been discovered and isolated from natural sources already long time ago, others have been reported very recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given. The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are formulated.

Pyrimidine as constituent of natural biologically active compounds.

Halofuginone was recently shown to inhibit the differentiation of T helper 17 (TH17) cells, which are associated with autoimmune diseases. The demonstration that halofuginone inhibits prolyl-tRNA synthetase activity explains the observed activation of the amino acid response pathway in TH17 cells and identifies amino acid restriction pathways as potential drug targets in inflammatory disease.

/pdf/halofuginone-and-other-febrifugine-derivatives-inhibit-17nl1zrfcp.pdf

Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase

Briefly stated, the operating depth of field for a bar code scanner, preferably a laser scanner, is increased by placing a cubic phase mask (CPM) in the scanning beam. The masked beam is then scanned and reflected off a bar code and received by a photodetector. The received signal is then processed to recover the original unperturbed representation of the bar code pattern. The processed signal has an increased depth of field over an unmasked scanner signal.

Method and apparatus for extending operating range of bar code scanner

Berberine (Ber) and its main metabolites were identified and quantified using liquid chromatography/electrospray ionization/ion trap mass spectrometry. Rat plasma contained the main metabolites, berberrubine, thalifendine, demethyleneberberine, and jatrorrhizine, as free and glucuronide conjugates after p.o. Ber administration. Moreover, the original drug, the four main metabolites, and their glucuronide conjugates were all detected in liver tissues after 0.5 h and in bile samples 1 h after p.o. Ber administration. Therefore, the metabolic site seemed to be the liver, and the metabolites and conjugates were evidently excreted into the duodenum as bile. The pharmacokinetics of Ber and the four metabolites were determined in conventional and pseudo germ-free rats (treated with antibiotics) after p.o. administration with 40 mg/kg Ber. The AUC0-limt and mean transit time values of the metabolites significantly differed between conventional and pseudo germ-free rats. The amounts of metabolites were remarkably reduced in the pseudo germ-free rats, whereas levels of Ber did not obviously differ between the two groups. The intestinal flora did not exert significant metabolic activity against Ber and its metabolites, but it played a significant role in the enterohepatic circulation of metabolites. In this sense, the liver and intestinal bacteria participate in the metabolism and disposition of Ber in vivo.

https://dmd.aspetjournals.org/content/dmd/early/2006/09/06/dmd.106.011361.full.pdf

Pharmacokinetics of Berberine and Its Main Metabolites in Conventional and Pseudo Germ-Free Rats Determined by Liquid Chromatography/Ion Trap Mass Spectrometry

Antimalarial alkaloids febrifugine (1) and isofebrifugine (2) were efficiently synthesized from simple achiral starting materials on the basis of the catalytic asymmetric synthesis. The first key reaction was performed using the tin(II)-mediated catalytic asymmetric aldol protocol to afford chiral aldehyde 3 in high yield with high diastereo- and enantioselectivities. The second key step, a Mannich-type reaction, did not give satisfactory results according to the conventional methods. We then developed a novel aqueous Mannich-type three-component reaction of an aldehyde, an amine, and a vinyl ether using a Lewis acid−surfactant combined catalyst (LASC), and the key intermediates 16 and 17 were obtained in high yields. The final coupling reactions of bromoacetone 14 with 4-hydroxyquinazoline were carried out using basic conditions, and successive deprotection gave 1 and 2, respectively, without any isomerization. These unambiguous total asymmetric syntheses revealed that the absolute configurations of febr...

Catalytic Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and Isofebrifugine and Their Biological Activity.

Among 42 extracts, prepared from 14 medicinal plants used in Vietnamese traditional medicine to treat malaria, 24 were found to have antiplasmodial activity by inhibiting the growth of the chloroquine-resistant Plasmodium falciparumstrain FCR-3 with EC50 values less than 10g/ml. Each medicinal plant possessed at least one active extract. The methanol extract of Coscinium fenestratumhad the strongest antiplasmodial activity with EC50 value of 0.5g/ml. Activity-guided fractionation led to identification of berberine as the major active constituent.

Short communication In vitro antiplasmodial activity of antimalarial medicinal plants used in Vietnamese traditional medicine

A simple and convenient PCR method that amplifies the 18S rRNA genes has been developed for the purpose of detecting and differentiating four species causing malaria in humans. The advantage of the assay is that the biotinylated PCR product is visualized following hybridization with specific probes which are immobilized on plate wells (microtiter plate hybridization). This method has been previously evaluated in a field study and was found to be sensitive and specific for the detection of Plasmodium falciparum and Plasmodium vivax. In the current study, the microtiter plate hybridization PCR method was evaluated by using blood specimens from malaria patients. All of 36 cases of falciparum malaria, 26 of 27 cases of vivax malaria, all of 11 cases of ovale malaria, and 2 cases of malariae malaria were diagnosed species specifically by the PCR method. There were four smear-negative, PCR-positive cases that seemed to correspond to the convalescent stage of malaria. In contrast, 30 cases for which the diagnosis of malaria has been excluded on the basis of microscopy and clinical courses showed negative PCR results. By comparing parasite densities and PCR results following antimalarial treatment of some patients, it was revealed that the PCR results largely paralleled the parasite densities and that PCR could detect as few as 10 parasites per microliter of blood. We conclude that this PCR method is highly sensitive and specific for the detection of all four parasite species and can serve as a useful supplement to microscopy for the clinical management of malaria.

Species-specific PCR detection of malaria parasites by microtiter plate hybridization: clinical study with malaria patients.

We studied DNA sequence polymorphism, expression level of pfmdr1 gene and sensitivity of major antimalarial drugs in both mefloquine sensitive and resistant strains to elucidate mechanism of mefloquine resistance. Mefloquine-resistant 523a R/24 strain exhibited decreased susceptibility to mefloquine, artemisinin and halofantrine whereas increased susceptibility to chloroquine. We found a novel point mutation in pfmdr1 gene of 523a R/24 strain. Moreover, overexpression of mRNA of pfmdr1 has been observed in this strain. In addition, functional analysis by pfmdr1 antisense revealed correlation of mefloquine sensitivity with expression level of pfmdr1. We suggest that gene mutation and overexpression of pfmdr1 may be associated with mechanism of mefloquine resistance.

Genetic analysis of mefloquine-resistant mechanism of Plasmodium falciparum

We have developed a new diagnostic method "microtiter plate-hybridization" (MPH) for the detection of human malaria parasite in which the target DNA sequence of the 18S ribosomal RNA gene is amplified by polymerase chain reaction and hybridized with the species-specific probes immobilized on a microtiter well. The PCR products bound on a well are visualized by the biotin-streptavidin system and the following chromogenic reaction. This method has allowed us to detect and identify the four species of human malaria parasites. We obtained blood samples by finger puncture from 435 donors in Japan, Solomon Island and Vietnam. The results of our method showed good correlation with the results of Giemsa staining microscopy. Furthermore, we developed a new system for the detection of new human malaria parasites. This system involves an acridine orange (AO) staining microscopic examination and "microtiter plate-hybridization". Using the system, we found a case of new variant of Plasmodium ovale whose PCR-amplified DNA did not hybridize with a probe for typical P. ovale in Vietnam. These results indicate that our new method can serve as a useful tool for the clinical management, epidemiological research of malaria, and investigation of the new type of malaria parasite.

Hye-Sook Kim

Papers

Catalytic Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and Isofebrifugine and Their Biological Activity.

Short communication In vitro antiplasmodial activity of antimalarial medicinal plants used in Vietnamese traditional medicine

Species-specific PCR detection of malaria parasites by microtiter plate hybridization: clinical study with malaria patients.

Genetic analysis of mefloquine-resistant mechanism of Plasmodium falciparum

DNA diagnosis of malaria using microtiter plate-hybridization.