Hala N. ElSohly

Effects of the administration of coca alkaloids on the primary immune responses of mice: Interaction with Δ9-tetrahydrocannabinol and ethanol

The effects of cocaine, its metabolites, and other alkaloids from Erythroxylon coca on the primary immune responses of ICR mice to sheep red blood cells (sRBC) and dinitrofluorobenzene (DNFB) were studied. The Jerne hemolytic plaque assay (PFC) was used to evaluate the humoral immune response to sheep red blood cells, and the delayed type hypersensitivity (DTH) response to DNFB was used to study cellular immune responsiveness. Drugs were given in single daily po doses for 5 consecutive days beginning on the day of immunization or 3 days prior to and on Days 3 and 4 after immunization. Inhibition of both PFC and DTH responses occurred at doses of 15 to 60 mg/kg of cocaine and was greatest when fed during immunization. Five other alkaloids also suppressed the PFC and/or DTH response. Cocaine was more suppressive than the six other alkaloids tested. Ethanol (5 g/kg) did not suppress the DTH response and only marginally suppressed the PFC response. delta 9-THC inhibited the PFC response at doses of 10 mg/kg and marginally suppressed the DTH response at doses of 30 mg/kg, but not at other doses ranging from 10 to 90 mg/kg. Coadministration of 5 g/kg ethanol and 15 mg/kg cocaine resulted in 50% antagonism of effects of cocaine on the PFC response and complete antagonism of the suppression of the DTH response, but only if these substances were given during the period of immunization. Like ethanol, delta 9-THC also abolished the inhibitory effects of cocaine on the PFC and DTH response but only if coadministered during the period of immunization. Coadministration of ethanol and delta 9-THC resulted in synergistic inhibition of both DTH and PFC responses.

NMR ASSIGNMENTS OF ELLAGIC ACID DERIVATIVES

HMBC spectroscopy optimized for small couplings was employed to determine the four‐bond and two‐bond proton carbon correlations on the aromatic rings of ellagic acid derivatives. Complete 13C NMR assignments of 3′‐O‐methyl‐3,4‐methylenedioxyellagic acid 4′‐O‐β‐D‐glucopyranoside (1), 3,3′‐di‐O‐methylellagic acid 4′‐O‐β‐D‐xylopyranoside (2), 3,3′,4‐tri‐O‐methylellagic acid 4′‐O‐β‐D‐glucopyranoside (3) and ellagic acid (4) were achieved using this technique. This study indicates that optimization of the delay time in the HMBC spectrum is crucial in assigning the 13C NMR signals of phenolic compounds with highly oxygenated quaternary carbons. Copyright

Constituents of Nelumbo nucifera leaves and their antimalarial and antifungal activity

From the leaves of Nelumbo nucifera (an aquatic plant), one new compound, 24(R)-ethylcholest-6-ene-5α-ol-3-O-β-D-glucopyranoside (1), along with 11 known metabolites (2-12), were isolated and identified by spectroscopic methods including 1D- and 2D NMR. Antifungal activity for (R)-roemerine (3) (IC50/MIC = 4.5/10 μg/mL against Candida albicans) and antimalarial activity for (R)-roemerine (3) and N-methylasimilobine (5) (IC50 = 0.2 and 4.8 μg/mL for the D6 clone, respectively, and 0.4 and 4.8 μg/mL for the W2 clone, respectively) was observed. None of the compounds were cytotoxic to Vero cells up to a concentration of 23.8 μg/mL. NMR data for 10-eicosanol (7) and 7,11,15-trimethyl-2-hexadecanone (10) are presented for the first time. An analysis of the structure-activity relationship shows that the substituents in position C-1 and C-2 of aporphine alkaloids are crucial for the antimalarial activity.

A short and stereospecific synthesis of (+)-deoxoartemisinin and (−)-deoxodesoxyartemisinin

Abstract The synthesis of (+)-deoxoartemisinin and (−)-deoxodesoxyartemisinin was achieved either from artemisinic acid or from artemisinin.

Absolute configuration, conformation, and chiral properties of flavanone-(3→8″)-flavone biflavonoids from Rheedia acuminata

Abstract The absolute configurations of three flavanone-(3→8″)-flavone type biflavonoids, (+)-morelloflavone ( 1 ), (+)-morelloflavone-7-sulfate ( 2 ) and (+)-volkensiflavone-7-sulfate ( 3 ) isolated from Rheedia acuminata were confirmed by circular dichroism as 2 R ,3 S , hence clarifying the literature confusion of 2 S ,3 R absolute configuration for (+)-morelloflavone. The conformations of this class of biflavonoids were studied for the first time by variable temperature NMR, NOESY, and computational calculations using a semi-empirical AM1 method. The coexistence of two conformers for morelloflavone ( 1 ) in solution at room temperature was confirmed by variable temperature NMR experiments. NOESY and computational calculations indicated that in the major and minor conformers 1a and 1b , respectively, the flavone DEF moiety is extended above and below the plane of the A/C-ring of the flavanone ABC unit, respectively. The C-3 proton of the C-ring of morelloflavone ( 1 ) is exchangeable by deuterium in acetone- d 6 /D 2 O at ambient temperature with retention of configuration, indicating considerable chiral stability of this class of biflavonoids.

Potent in vitro antifungal activities of naturally occurring acetylenic acids.

ABSTRACT Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C16 to C20: 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 μM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 μmol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.

Structure elucidation and thermospray high-performance liquid chromatography/mass spectroscopy (HPLC/MS) of the microbial and mammalian metabolites of the antimalarial arteether

Microbial metabolism studies of the antimalarial drug arteether (1) have shown that arteether is metabolized to six new metabolites in addition to those previously reported (3). Large-scale fermentations with Cunninghamella elegans (ATCC 9245) and Streptomyces lavendulae (L-105) have resulted in the characterization of these metabolites primarily by two-dimensional nuclear magnetic resonance (2D-NMR) methods as 9β-hydroxyarteether (2), a ring rearrangement metabolite (3), 3α-hydroxy-11-epi-deoxydihydroartemisinin (4), 9α-hydroxyarteether (5), 2α-hydroxyarteether (6), and 14-hydroxyarteether (7). Thermospray mass spectroscopy/high-performance liquid chromatographic analyses have shown that four of these metabolites (2, 5, 6, 7) are also present in rat liver microsome preparations.

Fatty Acids of Cannabis Seeds

The chemical composition of the fatty acids in twenty four different samples of cannabis seeds was determined by gas liquid chromatography with flame ionization detector and coupled with a mass spectrometer. The identification of twenty fatty acids was based on comparison with authentic samples. In addition six other components were detected in some samples and shown to be oxygenated acids. The data showed that the seeds could be divided broadly into two groups, one with saturated and unsaturated fatty acids averaging 9.5±1.7% and 89.4±1.9% respectively, and the other with averages of 60.1±4.1% and 21.9±6.1% of the respective fatty acids. Examination of the effect of seed maturity on the fatty acid composition showed that the more mature the seeds are, the higher is the percentage of unsaturated fatty acids and the lower the percentage of saturated ones. Detection of oxygenated low molecular weight acids in the second group could be attributed to ageing. Comparison of the fatty acid composition of seeds of drug and fibre types showed no significant difference among mature seeds. In addition, there was no correlation between the fatty acid composition of the seeds and their geographical origin.

New labdane diterpenes from Leonurus cardiaca.

Leonurus cardiaca L. has been used in oriental medicine against several types of disorders. The ethanolic extract of leaves of Leonurus cardiaca yielded three new labdane-type diterpenes: 15- O-ethylleopersin C (1), 15- O-methylleopersin C (2), and 15- EPI- O-methylleopersin C (3). Their structures were determined using 1 D and 2 D NMR including 1H-1H COSY, HMQC, HMBC, and ROESY spectroscopic techniques. Compounds (1 - 3) were evaluated for in vitro antiplasmodial activity (D6 and W2 clones) and cytotoxicity (Vero cells).

Microbial Metabolism Studies of the Antimalarial Drug Arteether

Microbial metabolism studies of the antimalarial drug arteether (1) have shown that arteether is metabolized by a number of microorganisms. Large-scale fermentation with Aspergillus niger (ATCC 10549) and Nocardia corallina (ATCC 19070) have resulted in the isolation of four microbial metabolites which have been characterized using two-dimensional nuclear magnetic resonance (2D-NMR) techniques. These metabolites have been identified as “AEM1” (2), 3α-hydroxydeoxyarteether (3), 3α-hydroxydeoxydihydroartemisinin (4), and deoxydihydroartemisinin (5).