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The synthesis of the gluco- and manno-stereoisomers of amphotericin B is described.
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Two sperm whale oils from the northern hemisphere and two from the southern hemisphere were fractionated. Triglyceride and wax esters were examined for fatty acids and alcohols with monoethylenic unsaturation bearing a methyl branch on an ethylenic carbon. The 7-methyl-7-hexadecenoic acid (0.37-1.37%) was accompanied by the corresponding alcohol (0.28-0.72%), but these materials were not accompanied by shorter chain homologues. The 7-methyl-6-hexadecenoic acid was relatively less important (0.23-0.68%), but was accompanied by 5-methyl-4-hexadecenoic acid (0.10-0.39%), and a partially identified C13 compound. Chromatographic properties on silver nitrate impregnated silicic acid TLC and on three GLC liquid phases are reported.
The synthetic cellulose model compounds methyl 4-O-methyl-beta-D-glucopyranoside and methyl 4-O-methyl-beta-D-glucopyranosyl-(1-->4)-beta-D-glucopyranoside and related 6-O-protected intermediates were oxidized in good to fair yields using Swern-conditions or bromine/bis(tributyltin) oxide, respectively, to afford compounds containing 6-aldehyde, 3-keto, and 2,3-diketo groups. Cellobiose and oxidized monosaccharides were then labeled with the carbonyl-selective fluorescence marker 9-(7-amino-1,4,7-trioxaheptyl)-9H-carbazolecarboxamide (CCOA). The labeled derivatives serve as model compounds for the determination of minute amounts of carbonyl groups in cellulosic polysaccharides.
The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), which has been chosen for clinical evaluation. This compound exhibited a Ki of 0.42 nM for displacement of [3H]LTD4 on guinea pig lung membranes, a pKB of 10.13 +/- 0.14 versus LTE4 on guinea pig trachea, and an oral ED50 of 1.14 mumol/kg opposite LTD4-induced bronchoconstriction in guinea pigs. The R enantiomer was found to be modestly more potent than the S enantiomer 38o. Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity. Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist. The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.
To provide deep insight into the polycyclization reaction of squalene, some analogs were synthesized and incubated with the cell-free homogenates of the recombinant Escherichia coli encoding the wild-type squalene cyclase. The presence of C6-Me leads to an efficient polycyclization cascade. Substitution of the C14-H and the C18-H with a methyl group halted the polycylization reaction at the tricyclic ring stage having a 6/6/6-fused ring system and the tetracycle with a 6/6/6/6-fused ring, respectively, both of which were produced according to a Markovnikov closure. Replacement of the C7-H and the C11-H with a methyl group led to no cyclization. These results, in conjunction with our previous reports, indicated that the methyl positions are important for bringing to completion of the normal polycylization reaction and further demonstrated that the precise steric bulk size at the methyl positions of squalene is critical to the correct folding and the strong binding of the substrate to the squalene cyclase.
The cDNA for human MGMT was transfected into and expressed in CHO cells and the post-replication repair deficient mutant CHO-UV-1 cell, both of which are devoid of endogenous MGMT activity. Expression of MGMT activity was demonstrated by measurement of activity and by immunoblot analysis. The mutant phenotype of UV-1 is characterized by extreme hypersensitivity to killing by methylating and ethylating agents as well as the antitumor antibiotic mitomycin C (MMC). MGMT expression conferred equivalent, supra-normal levels of resistance to killing by MNNG (N-methyl-N'-nitro-nitrosoguanidine) or EMS (ethyl methanesulfonate) on CHO and UV-1, but had no effect on the lethality of MMC. So, even though a mutated gene other than MGMT is known to underlie the pleiotropic phenotype of UV-1, expression of MGMT compensates for part of this phenotype. This result indicates that attempts to concordance map and clone the gene(s) responsible for the UV-1 phenotype can be complicated when using MNNG selection due to compensation by the MGMT gene. These results also indicate that the post-replication repair deficient phenotype characterized in CHO-UV-1 cells, will be masked in cells normally expressing MGMT due to MGMT-mediated resistance to methylating and ethylating agents.
Methyl n-butyl ketone (MnBK), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and acetone are widely used industrial solvents to which certain groups of workers are exposed. Pharmacological and metabolic interactions between these solvents and ethanol were explored in male CD-1 mice. The effects of these solvents on the duration of ethanol-induced loss of righting reflex and on ethanol elimination in mice were studied. The solvents were dissolved in corn oil and injected intraperitoneally 30 min before ethanol 4 g/kg ip. The four solvents prolonged significantly the duration of ethanol-induced loss of righting reflex when given in the following doses (mmol/kg): MnBK, 3.75 and 5; MIBK, 5; MEK, 5 and 10, acetone, 20 and 40. This prolongation was dose related and increased as the dose of the solvent was increased. The concentrations of ethanol in blood or brain on return of the righting reflex were similar in solvent-treated and control animals, with the exception of the group of mice treated with 40 mmol/kg acetone in which the ethanol concentrations were significantly lower than in control animals. The mean elimination rate of ethanol was markedly reduced in mice treated with MnBK 5 mmol/kg, MEK 15 mmol/kg, and acetone 40 mmol/kg. All four solvents reduced the activity of mouse liver alcohol dehydrogenase in vitro. It is concluded that enhancement of the ethanol-induced loss of righting reflex by these solvents in mice is well correlated to reduced elimination rate of ethanol.
An N-methyl-N-nitrosourea (MNU) moiety [CH3N(N=O)C(=O)NH-] linked to the C4'-position of the 5-substituted phenyl ring of phenyl neutral red (PNR), 2-methyl-3-amino-5-[p-[[2-[(N-nitroso-N-methylcarbamoyl)amino]ethy l] carbamoyl]phenyl]-7-(dimethylamino)phenazenium chloride (MNU-PNR), has been synthesized as an approach to design a molecule that will deliver alkylating agents with some preference to guanine (Gua) in the major groove of DNA. The PNR nucleus was chosen because previous studies suggested the following: (1) PNR binds with a slight preference for G/C rich sequences; and (2) PNR intercalates into DNA from the major groove with the 5-phenyl ring pointing out into the major groove (Müller, W., Bünemann, H., and Dattagupta, N. (1975) Eur. J. Biochem. 54, 279-291). It is demonstrated that MNU-PNR yields 2.6 and 6.0 times more N7-methylguanine (7-MeGua) than MNU at low salt (10 mM Tris buffer) and high salt (10 mM Tris buffer + 200 mM NaCl), respectively. It is also shown that the ratio of 7-MeGua (a major groove adduct) to N3-methyladenine (a minor groove adduct) is approximately 5 times higher for MNU-PNR than for MNU. The yield of the 7-MeGua adduct is decreased by the coaddition of a nonmethylating analogue of MNU-PNR or NaCl, but increased in the presence of the minor groove intercalator, ethidium bromide. Using a 32P-end-labeled restriction fragment, the enhanced methylation by MNU-PNR at 7-Gua is confirmed, and it is demonstrated that the sequence-dependent formation of 7-MeGua from MNU-PNR is the same as that seen with MNU. UV, circular dichrosism, and viscosity studies are consistent with MNU-PNR binding to DNA via an intercalation-based process.
Hypermethylation of CpG island (CGI) sequences is a nearly universal somatic genome alteration in cancer. Rapid and sensitive detection of DNA hypermethylation would aid in cancer diagnosis and risk stratification. We present a novel technique, called COMPARE-MS, that can rapidly and quantitatively detect CGI hypermethylation with high sensitivity and specificity in hundreds of samples simultaneously. To quantitate CGI hypermethylation, COMPARE-MS uses real-time PCR of DNA that was first digested by methylation-sensitive restriction enzymes and then precipitated by methyl-binding domain polypeptides immobilized on a magnetic solid matrix. We show that COMPARE-MS could detect five genome equivalents of methylated CGIs in a 1000- to 10,000-fold excess of unmethylated DNA. COMPARE-MS was used to rapidly quantitate hypermethylation at multiple CGIs in >155 prostate tissues, including benign and malignant prostate specimens, and prostate cell lines. This analysis showed that GSTP1, MDR1 and PTGS2 CGI hypermethylation as determined by COMPARE-MS could differentiate between malignant and benign prostate with sensitivities >95% and specificities approaching 100%. This novel technology could significantly improve our ability to detect CGI hypermethylation.
The effect of selective group I metabotropic glutamate receptor subtype 5 (mGluR5) antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. Treatment with MPEP and SIB-1893 showed significant neuroprotective effects in rat cortical neuronal cultures subjected to mechanical injury. Application of the antagonists also attenuated glutamate- and N-methyl-D-aspartate (NMDA)-induced neuronal cell death in vitro. Intracerebroventricular administration of MPEP to rats markedly improved motor recovery and reduced deficits of spatial learning after lateral fluid percussion-induced traumatic brain injury. Lesion volumes as assessed by magnetic resonance imaging were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it completely blocks agonist-induced phosphoinositide hydrolysis, electrophysiological and pharmacological studies indicate that MPEP and SIB-1893 also inhibit NMDA receptor activity at higher concentrations that are neuroprotective. Taken together, these data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.
A single dose (0.8 mmole/kg) of N-methyl-N-nitrosourea (MNUA) causes significantly more chromosome damage in the bone marrow of mice than a dose of equal toxicity to the animals, (1.1 mmole/kg) of methyl methanesulphonate (MMS) 6, 24 and 48 h after treatment. At these doses both agents alkylate bone-marrow DNA to similar extents, but only MNUA induces thymic lymphomata. The greater chromosome-damaging effects of MNUA are ascribed to the known differences in the pattern of DNA alkylation by each agent, in particular the much higher levels of O-6 methylguanine and phosphotriesters produced by MNUA. The greater chromosome-damaging effect of MNUA may account for its higher toxicity to the bone marrow which in turn may be a significant factor in the induction of thymomata. The enhancement by caffeine of chromosome damage seen particularly 48 h after MMS-treatment suggests that post-replication repair protects cells from the effects of DNA-methylation in vivo.
A potent anti-herpetic compound was identified and purified to homogeneity from the leaves of Sapium sebiferum by plaque reduction assay using herpes simplex virus type 2. The chemical structure of the purified compound was determined by mass spectroscopy and proton and carbon-13 nuclear magnetic resonance as methyl gallate, methyl-3,4,5-trihydroxybenzoate. This is the first demonstration that methyl gallate is a potent anti-herpetic compound in vitro, present in high concentration in the leaves of S. sebiferum, a Chinese folk medicine for shingles.
Methyl gallate (MG), methyl-3,4,5-trihydroxybenzoate, was highly active against herpes viruses as determined by plaque reduction assay. Herpes simplex virus type 2, MS strain, was sensitive to MG at a mean 50% inhibitory concentration (IC50) of 0.224 micrograms/ml in monkey kidney cells. MG was specific for herpes viruses with the relative sensitivity HSV-2 greater than HSV-1 greater than CMV. Two RNA viruses tested were significantly less sensitive to MG. The structural components of MG which modulate the anti-herpetic activity were identified by analysis of chemical analogues. Our structural analyses indicated that three hydroxyl groups were required but were not sufficient for the anti-herpetic action of MG. The presence and chain length of the alkyl ester were also important to the anti-herpetic activity of MG. Methyl gallate may interact with virus proteins and alter the adsorption and penetration of the virion.