Diastereoselective synthesis of polysubstituted pyrrolidinone as a key intermediate for the anticancer agents by palladium(II)-catalyzed carboxylation

Palladium(II)-catalyzed carboxylation of chiral olefins 6a-d has been examined under various conditions. In the weak basic condition (K2CO3), 7a-d were obtained in good yields. Alternatively, in the strong basic condition, pyrrolidinones 8a-d were obtained resulting in excellent yields and with high diastereoselectivity.     

A stereoselective asymmetric synthesis of antibiotic (-)-Fumagillol using claisen rearrangement and intramolecular ester enolate alkylation as key steps

(-)-Fumagillol (1), a hydrolysis product of fumagillin, has been synthesized by several group from commercially available 1,2:5,6-di-O-isopropylidene-alpha-D-allofuranose in a highly stereoselective manner. Chiral centers on C5 and C6 came from D-allofuranose and the asymmetric center on C4 was accomplished by 1,3-chirality transfer using the Claisen rearrangement on a chiral allyl alcohol. Chirality, which is necessary on an epoxide consisting of the spiro-ring system, was diastereoselectively constructed by the well-known reaction, intramolecular ester enolate alkylation (IEEA), which showed that this reaction can be applied to the alpha-alkoxy ester system. The epoxide on the side chain was regioselectively introduced by the difference between the number of substituents on the vinyl groups. This accomplishment proved that IEEA can be a useful tool for the synthesis of complex molecules.     

Stereoselective synthesis and in vitro antifungal evaluation of (E)- and (Z)-imidazolylchromanone oxime ethers

A series of (E)- and (Z)-2, 3-dihydro-3-(1H-imidazol-1-yl)-4H-1-benzopyran-4-one oxime ethers have been synthesized and tested for antifungal activity. Most compounds showed moderate to potent in vitro antifungal activity. Among the tested compounds, compound (E)-3d was the most active agent against Candida albicans and Aspergillus niger, and compounds (Z)-(3a) and (E)-3a were the most potent compounds against Microsporum gypseum. Detailed stereoselective synthesis, spectroscopic, and biological data are reported.     

Kinetics of reaction of cis-diamminedichloroplatinum(II) with DNA

A method based on cation exchange chromatography was developed to determine the adducts formed in the reaction of cis-diamminedichloroplatinum(II) (cis-Pt) with DNA. DNA was incubated with various concentrations of cis-Pt for various periods of time, ethanol precipitated, and enzymatically digested to nucleosides and Pt-containing oligonucleotides. The unmodified nucleosides were separated from the positively charged intra- and interstrand cis Pt adducts with a weak cation exchanger, CM-Sephadex C-25, and the adducts were further purified by HPLC. The main adduct was shown to be an intrastrand cross-link of cis-Pt bound to the N-7 atoms of two neighboring guanines. The minor adducts were intra- and interstrand cross-links of cis-Pt with adenine and guanine and an interstrand cross-link of cis-Pt with two guanines. At low levels of DNA-modification (cis-Pt:nucleotide = 1:50-1:1000) the intrastrand cross-link of cis-Pt with two guanines consisted of 60-70% of the total platination of DNA. At higher levels of DNA-modification (greater than 1:20), the amount of undigested products increased, indicating shielding of DNA by cis-Pt from nucleolytic enzymes.     

Synthesis of benz[f] indole-4,9-dione Derivativesvia intramolecular cyclization (II)

The new N-aryl-benz[f]-indole-4,9-dione derivatives were synthesizedvia intramolecular cyclization when triethylamine was employed as a base for the reaction of 2-chloro-3-(α-cyano-α-ethoxycarbonyl-methyl)-1,4-naphthoquinone and arylamines.     

Development of intramolecular oxidative phenolic coupling reactions using hypervalent iodine (III) reagents and their application to the synthesis of Amaryllidaceae alkaloids

Hypervalent iodine (III) reagents nowadays are used extensively in the field of organic chemistry. Especially, phenyliodine (III) diacetate (PIDA) or phenyliodine (III) bis(trifluoroacetate) (PIFA) have received much attention because of their reactivities similar to heavy metal reagents or anodic oxidation, low toxicity, ready availability and easy handling. In the continuous study of our oxidative phenolic coupling reactions using a hypervalent iodine (III) reagents, a versatile synthetic procedure for the galanthamine-type Amaryllidaceae alkaloids was accomplished. The first total synthesis of (+/-)-sanguinine and the total syntheses of (+/-)-galanthamine, (+/-)-narwedine, (+/-)-lycoramine, and (+/-)-norgalanthamine were also successfully carried out.     

Tetraoxane antimalarials and their reaction with Fe(II)

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.     

Chiral mixed ligand Co(II) and Ni(II) complexes: synthesis and biological activity

Chiral mixed ligand (CML) transition metal complexes of the type MQL.2H2O, where M is Co(II)/Ni(II), Q is deprotonated 8-hydroxyquinoline and L is a deprotonated chiral saccharide such as (+)-glucose and (-)-fructose, have been synthesized. The metal complexes have been characterized on the basis of elemental analysis and various physicochemical techniques such as molar conductance, specific rotation measurements, magnetic, spectral and thermal studies. The cup-plate method has been used to study the antibacterial activity of the compounds against some of the pathogenic bacteria such as C. diphtheriae, E. coli, S. typhi, S. dysenteriae, S. aureus and V. cholerae. The antifungal activity of the complexes against some of the pathogenic fungi such as Candida albicans and Aspergillus niger has been studied by the tube dilution method. The results have been compared against those of controls, which were screened simultaneously. The complexes have been screened for acute oral toxicity in albino rats. The method of Litchfield and Wilcoxon has been used to determine the LD50 values.     

Stereoselective antitumor properties in the Lewis lung carcinoma model using bis(morpholinomethyl) derivatives of tricyclic bis(dioxopiperazines)

Geometric isomers of 2,11-bis(morpholinomethyl)tetrahydrodipyrazino[1,2-a:2',1'-c]pyraz ine-1, 3,10,12-(2H,4H,9H,11H)-tetrone (3 and 4) and the parent bisimides (1 and 2) were studied for their stereoselective antimetastatic activity in the Lewis Lung carcinoma model. The morpholinomethyl cis-syn-trans isomer 4 was more effective as an inhibitor of metastasis than the other three analogues. Using a postamputation protocol, the order of decreasing activity was cis morpholinomethyl analogue 4 greater than trans morpholinomethyl analogue 3 greater than parent cis imide 2 greater than parent trans imide 1. Increased activity observed for the morpholinomethyl derivatives may reflect differences in solubility and delivery (prodrug) or an intrinsic antitumor activity of the morpholinomethyl-N functionality.     

不对称亨利反应在(R)-沙美特罗合成中的应用

目的 使用不对称亨利反应合成沙美特罗。方法 以4-苯基丁醇为起始原料合成长链脂肪醛,同时由对羟基苯甲醛出发经3步反应制备前手性苯甲醛,继而通过不对称亨利反应制得手性硝基醇化合物,随后用氢化方法合成(R)-沙美特罗。结果与结论 通过不对称亨利反应制得硝基醇化合物,产物的对映选择性较好(60% ee),新路线省去了原文献中制备三级胺和脱苄基两步反应,合成路线未见报道。     

Colorimetric determination of penicillins and related compounds in intravenous solutions by nickel (II)-catalyzed hydroxamic acid formation

Solutions of ampicillin, carbenicillin, methicillin, oxacillin, penicillin G, and cephalothin in 5% dextrose were analyzed by nickel(II)-catalyzed hydroxylaminolysis. The reactions of these antibiotics were complete within 20 min at room temperature. Under the analytical conditions, molar absorptivities of the ferric-hydroxamate complexes ranged from 830 to 1005 liters/mole/cm. Coefficients of variation for the analysis of these antibiotics in 5% dextrose were typically less than 3% at concentrations of 1 mg/ml. Oxacillin was analyzed by the same method in normal saline and/or lactated Ringer solutions. The method also was applied to the analysis of chloramphenicol in aqueous solutions. Only ampicillin showed a significant decrease in concentration in 48 hr.     

Suppression of epimerization by cupric (II) salts in peptide synthesis using free amino acids as amino components

An epimerization-free system for coupling N-protected peptides with free amino acids was developed. A number of inorganic substances were tested as epimerization suppressant additives during the coupling by various methods (carbodiimide plus additives, uronium salts, Woodward’s reagent-K, isobutyl-chloroformate, etc.). Some of them (ZnCl₂, RbClO₄, LiCl, SnCl₄, AlCl₃, etc.) in combination with some coupling methods can guarantee coupling with minimal epimerization (D -epimer < 1%). But only a simultaneous use of 1-hydroxybenzotriazole and Cu²⁺ ions as additives in carbodiimide-mediated peptide couplings appeared to give a standard result (D -epimer < 0.1%). There was no epimerization even in the case when N-methyl amino acid (sarcosine) was used as an amino component, while in the absence of Cu²⁺ ions an unacceptable level of epimerization was observed (D -epimer, 22% for carbodiimide with the 1-hydroxybenzotriazole method). So far it has been considered that Cu²⁺ ions prevent obtaining peptides in high yields (< 90%) by various coupling methods. We have found that the use of 1-hydroxybenzotriazole, CuCl₂ and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide instead of dicyclohexylcarbodiimide provides a possible method for obtaining the desired peptides in 90–99% yields without epimerization. All these results were shown by employing several model peptide couplings with free amino acids as amino components dissolved in an effective solvent system which readily dissolved them.     

Zn(OTf)2-catalyzed three component, one-pot cyclocondensation reaction of some new octahydroquinazolinone derivatives and access their bio-potential

An efficient synthesis of some new octahydroquinazolinone derivatives 4a–x by the cyclocondensation reaction of corresponding 2-thi(oxo)-1,2-dihydroquinoline-3-carbaldehyde 1a–e, 1,3-dicarbonyl compounds 2a–b, and substituted urea 3a–c using zinc triflate as a catalyst in refluxing ethanol in high yield is described. The structures of new compounds have been characterized on the basis of elemental analysis, FT- IR, ¹H NMR, ¹³C NMR, and mass spectral data. All the synthesized compounds were evaluated for their antimicrobial activities against various microbes. Minimum inhibitory concentration values of all the 24 synthesized compounds were also determined. Some of the synthesized compounds exhibited excellent antimicrobial activity.     

The synthesis and antimicrobial activities of some 1,4-naphthoquinones (II)

In order to evaluate the antimicrobial effect of 2,3-disubstituted-1,4-naphthoquinone derivatives we newly synthesized several 2-chloro and 2-bromo-3-(substituted)-1,4-naphthoquninones. Amination reaction of 2,3-dihalo-1,4-naphthoquinones with aryl and aliphatic amines in ethanol gave 2-halo-3-(N-alkyl or N-aryl)-1,4-naphthoquinone derivatives (1a,b–10a,b) in 60%–90% yield. These derivatives subjected to antibacterial and antifungal activities,in vitro, againstBacillus subtilis ATCC 6633, Candida albicans 10231 and local, Pseudomonas aeruginosa NCTC10490, Staphylococcus aureus ATCC 6538p, Escherichia coli NIHJ, Aspergillus niger KCTC 1231. Tricophyton mentagrophytes KCTC 6085. Among these derivatives,1b, 6b and7a showed the potent antibacterial activities.1b, 8b and9b have the antifungal activities.1b is most effective in preventing the growth ofBacillus subtilis and Pseudomonas aeruginosa, Candida albicans, Aspergillus niger. Tricophyton mentagrophytes. The several of these compounds demonstrated a broad spectrum of activitiesin vitro.     

Stereoselective synthesis of natural N-(1-Deoxy-D-beta-fructos-1-yl)-L-amino acids and their effect on lead decorporation

N-(1-Deoxy-D-fructos-1-yl)-l-amino acids isolated from hog liver are endogenous lead decorporation substances with low toxicity and cell membrane crossing ability. To simulate the effect of the natural N-(1-deoxy-D-fructos-1-yl)-l-amino acids on lead decorporation, a series of the epimerically pure N-(1-deoxy-D-fructos-1-yl)-l-amino acids (6a-e beta) were synthesized, and their usefulness as antagonists of lead intoxication was investigated. The results suggest that after treatment with 6a-e beta the liver, kidney, bone, and brain, lead levels of mice were significantly reduced in comparison with the control group. Except for bone and brain lead levels of the mice after chelating treatment with 6d beta, all of the other tissue lead levels of mice after chelating treatment with 6a-e beta are significantly lower than those of mice after treatment with dl-penicillamine (p < 0.05). All fecal lead levels of mice after treatment with 6a-e beta are significantly higher than those of mice after treatment with 0.9% saline (controls) and dl-penicillamine (p < 0.05-0.01). The effects of all chelating agents on urinary excretion of lead in mice are clearly superior to the control (p < 0.05-0.01). The results of the present studies on repeated lead exposure indicated that at tested levels of i.p. injections, the fructose-amino acids were effective antagonists of lead poisoning under the experimental conditions. After treatment with the chelators, the concentration of essential metals in mice did not exhibit change as compared to the control. The effects of the compounds on cadmium decorporation were also investigated, and similar results were observed.