The convulsant and anesthetic properties of cis-trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethylene.

UNLABELLED: The differences in potencies of optical isomers of anesthetics support the hypothesis that anesthetics act by specific receptor interactions. Diastereoisomerism and geometrical isomerism offer further tests of this hypothesis but have not been explored. They are the subject of this report. We quantified the nonimmobilizing and convulsant properties of the cis and trans diastereomers of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane). Although the lipophilicity of the diastereomers predicts complete anesthesia at the partial pressures applied, neither diastereomer had anesthetic activity alone, and the cis form may have a small (10%) capacity to antagonize anesthesia, as defined by additive effects on the MAC (the minimum alveolar concentration required to suppress movement to a noxious stimulus in 50% of rats) of desflurane. Both diastereomers produced convulsions, the cis form being nearly twice as potent as the trans form: convulsant 50% effective dose (mean +/- SD) was 0.039 +/- 0.009 atmospheres (atm) for the purified cis and 0.064 +/- 0.009 atm for the purified trans isomer. The MAC value for cis-1,2-dichloroethylene equaled 0.0071 +/- 0.0006 atm, and MAC for trans-1,2-dichloroethylene equaled 0.0183 +/- 0.0031 atm. In qualitative accord with the Meyer-Overton hypothesis, the greater cis potency was associated with a greater lipophilicity. However, the product of MAC x solubility differed between the cis and trans isomers by 40%-50%. We conclude that neither the cis nor trans isomers of 2N have anesthetic properties, but isomerism does influence 2N's convulsant properties and the anesthetic properties of dichloroethylene. These isomeric effects may be as useful in defining receptor-anesthetic interactions as those found with optical isomers. IMPLICATIONS: Cis-trans isomerism can influence the convulsant properties of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) and the anesthetic properties of dichloroethylene. Such isomeric effects may be as useful as those found with optical isomers in defining receptor-anesthetic interactions.

Synthesis of 2',3'-dideoxy-2',3'-didehydro nucleosides via a serendipitous route.

This paper describes a "green" synthesis of 2',3'-unsaturated 2',3'-dideoxynucleosides via an electrochemical reaction. Using this approach d4T, d4U, ddA and ddI can be synthesized in high yields.

The development of new carboxylic acid-based MMP inhibitors derived from a cyclohexylglycine scaffold.

A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7.

Chemoenzymatic synthesis of functionalized cyclohexylglycines and alpha-methylcyclohexylglycines via Kazmaier-Claisen rearrangement.

The synthesis of homochiral functionalized cyclohexylglycines and alpha-methylcyclohexylglycines via chelated Kazmaier-Claisen rearrangement is described. These were shown to be potent scaffolds for the development of MMP inhibitors.

A short, stereoselective synthesis of neo-inositol.

A practical synthesis of neo-inositol is described in which the target is prepared on a multigram scale in six operations from bromobenzene.

Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties.

UNLABELLED: The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers. In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82+/-0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF2OCCIFCF3 and CCIF2OCF2CClF2) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act. IMPLICATIONS: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act.

Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: relevance to theories of narcosis.

UNLABELLED: The Meyer-Overton hypothesis predicts that the potency of conventional inhaled anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) x the olive oil/gas partition coefficient equals a constant of approximately 1.82 +/- 0.56 atm (mean +/- SD), whereas MAC x the octanol/gas partition coefficient equals a constant of approximately 2.55 +/- 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC x the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 +/- 0.072 atm) is one-tenth that found for conventional anesthetics, whereas the product for MAC x the octanol/gas partition coefficient (1.72 +/- 1.19) is similar to that for conventional anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC x olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 +/- 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC x the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. IMPLICATIONS: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity--i.e., a greater polarity.

Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms.

UNLABELLED: Some inhaled compounds cause convulsions. To better appreciate the physical basis for this property, we correlated the partial pressures that produced convulsions in rats with the lipophilicity (nonpolarity) and hydrophilicity (polarity) of 45 compounds: 3 n-alkanes, 18 n-haloalkanes, 3 halogenated aromatic compounds, 3 cycloalkanes and 3 halocycloalkanes, 13 halogenated ethers, and 2 noble gases (He and Ne). In most cases, convulsions were quantified by averaging the alveolar partial pressures just below the pressures that caused and slightly higher pressures that did cause clonic convulsions (ED50). The ED50 did not correlate with hydrophilicity (the saline/gas partition coefficient), nor was there an obvious correlation with molecular structure. For 80% of compounds (36 of 45), the ED50 correlated closely (r2 = 0.99) with lipophilicity (the olive oil/gas partition coefficient). Perhaps because they block the effect of GABA on GABA(A) receptors, five compounds were more potent than would be predicted from their lipophilicity. Conversely, four compounds may have been less potent than would be predicted because they (like conventional inhaled anesthetics) enhance the effect of GABA on GABA(A) receptors. IMPLICATIONS: Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. One correlates with lipophilicity (nonpolarity), and the other correlates with an action on GABA(A) receptors.

Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.

Molecular properties of the "ideal" inhaled anesthetic: studies of fluorinated methanes, ethanes, propanes, and butanes.

We examined 35 unfluorinated, partially fluorinated, and perfluorinated methanes, ethanes, propanes, and butanes to define those molecular properties that best correlated with optimum solubility (low) and potency (high). Limited additional data were obtained on longer-chained alkanes. Using standard techniques, we assessed anesthetic potency (minimum alveolar anesthetic concentration [MAC] in rats); vapor pressure; stability in soda lime; and solubility in saline, human blood, and oil. If nonflammability, stability, low solubility in blood, clinically useful vapor pressures, and potency permitting delivery of high concentrations of oxygen are essential components of an anesthetic that might supplant those presently available, our data indicate that such a drug would have three or four carbon atoms with single or dual hydrogenation of two carbons, especially terminal carbons. We conclude that: 1) smaller and larger molecules and lesser hydrogenation provide insufficient potency; 2) high vapor pressures of smaller molecules do not permit the use of variable bypass vaporizers; 3) greater hydrogenation enhances flammability, and complete hydrogenation decreases potency; 4) internal hydrogenation decreases stability; and 5) greater hydrogenation increases blood solubility.

Oxidation of 2-methoxynaphthalene by toluene, naphthalene and biphenyl dioxygenases:structure and absolute stereochemistry of metabolites.

2-Methoxynaphthalene was subjected to biooxidation by whole cells of six organisms: Pseudomonas putida F39/D containing toluene dioxygenase, Escherichia coli JM109(pDTG601), containing recombinant toluene dioxygenase from Pp F39/D, Pseudomonas sp. NCIB 9816/11, containing naphthalene dioxygenase. E. coli JM109(pDTG141), containing recombinant naphthalene dioxygenase from NCIB 98161/11, E. coli C534(ProR/Sac) containing recombinant naphthalene dioxygenase from Pp G7, and Beijerinckia sp. B8/36, containing biphenyl dioxygenase. The major product of oxidation by the naphthalene and biphenyl dioxygenases has been isolated and identified as (1R,2S)-dihydroxy-7-methoxy-1,2-dihydronaphthalene, 2c. A minor product, (1R,2S)-dihydroxy-6-methoxy-1,2-dihydronaphthalene, 3c, has also been detected. Oxidation by the toluene dioxygenase-containing organisms led to the isolation of 3c as the major product. Minor products detected in these reactions were 2c, and a third compound, (1S,2S)-dihydroxy-3-methoxy-1,2-dihydronaphthalene, 4c. Structural studies and dehydration of the diols to a mixture of naphthols are described. The absolute stereochemistry of these new diols has been established by correlation with known compounds. The organisms' potential in the production of new metabolites as useful chiral synthons by biooxidation of 2-substituted naphthalenes is indicated.

Microbial oxidation of aromatics in enantiocontrolled synthesis. 2. Rational design of aza sugars (endo-nitrogenous). Total synthesis of +-kifunensine, mannojirimycin, and other glycosidase inhibitors.

A general method of synthesis for lactones and lactams related to carbohydrates has been developed that relies on the biocatalyticgeneration of 1-chloro-2,3-dihydroxycyclohexa-4,6-diene (l), obtained in excellent yield by fermentation of chlorobenzene with Pseudomonasputida 39D, followed by further functionalization to nitrogen-substituted cyclitols. These amino or azido cyclitols of type 15 are then subjected to controlled ozonolysis, which yields either lactones such as 27 or lactams containing five-membered (28) or six-membered (20 and 23) rings. Such compounds are useful intermediates for the preparation of aza sugars. Mannojirimycin (84 has been synthesized in seven steps from chlorobenzene. Kifunensine (7) has been prepared in 11 steps from chlorobenzene following an intersection with Hashimoto's procedure. Full experimental and spectral details are provided for all compounds. The potential of this general method and implications of the disclosed design features in the field of amino sugar and aza sugar synthesis are indicated.

General method of synthesis for natural long-chain beta-diketones.

Two general methods of synthesis have been developed for the preparation of long-chain beta-diketones. The first relies on malonate-type alkylation of acid chlorides derived from fatty acids, while the second, more direct method, involves coupling and subsequent hydrolysis of long-chain acetylenes with acid chlorides of fatty acids.