Biomedical subjects

F R Fronczek

Publications and source records attributed to F R Fronczek.

At least 37 records · Page 2Linked to original sources

PubMed1999

Synthesis of a reaction intermediate analogue of biotin-dependent carboxylases via a selective derivatization of biotin.

[formula: see text] An efficient and practical synthesis of 1, a unique reaction intermediate analogue of biotin-dependent carboxylases, is described. The synthesis features a selective acylation of the 1'-N of biotin. Target 1 inhibits the activity of the biotin carboxylase component of acetyl CoA carboxylase. It is the first known biotin-derived inhibitor of biotin carboxylase and should promote new kinetic and structural studies of the biotin-dependent carboxylases.

Avidin↗

PubMed1999

The molecular structure of 2alpha-hydroxyneoanisatin and structure-activity relationships among convulsant sesquiterpenes of the seco-prezizaane and picrotoxane types.

The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural types with respect to the mode of cyclisation, did not induce anisatin/picrotoxinin-like convulsions in mice. Based on these results and literature data for other seco-prezizaanes, structural requirements for convulsant activity are discussed. Comparison of the three dimensional molecular shape and electrostatic properties of active and inactive seco-prezizaane type lactones with compounds of the picrotoxane type resulted in the identification of a common pharmacophore structure for these different skeletal classes of convulsant natural products.

Animals↗

PubMed1999

Antimycobacterial eudesmanolides from Inula helenium and Rudbeckia subtomentosa.

In a bioassay guided search for antimycobacterial compounds from higher plants, the root extracts of Elecampane (Inula helenium L.; Asteraceae) and Sweet Coneflower (Rudbeckia subtomentosa Pursh.; Asteraceae) were chemically investigated for their active constituents. Chromatographic fractions of root extracts of l. helenium, which exhibited significant activity against Mycobacterium tuberculosis, provided the known eudesmanolides alantolactone, isoalantolactone, and 11 alpha H, 13-dihydroisoalantolactone. Peracid epoxidation of alantolactone and isoalantolactone provided 5 alpha-epoxyalantolactone and 4(15) alpha-epoxyisoalantolactone, respectively and oxidation of alantolactone with OsO4 gave 11,13-dihydroxyalantolactone. Active fractions from R subtomentosa contained the known alloalantolactone and 3-oxoalloalantolactone. The structures of the above compounds were established by spectroscopic methods including 1D and 2D NMR techniques as well as spectral comparison with previously reported data. The molecular structure of 5 alpha-epoxyalantolactone was determined by single crystal X-ray diffraction. Eleven natural and semisynthetic eudesmanolides were tested in a radiorespirometric bioassay for activity against M. tuberculosis. 5 alpha-Epoxyalantolactone and encelin from Montanoa speciosa showed minimum inhibitory concentrations (MICs) of 8 and 16 micrograms ml-1, respectively. Alantolactone, isoalantolactone and its 4 alpha, 15-epoxide, 1,2-dehydro-3-epi-isotelekin and alloalantolactone gave MICs of 32 micrograms ml-1. All other compounds showed MIC values of 128 micrograms ml-1 or higher.

Antitubercular Agents↗

PubMed1999

Antimycobacterial ergosterol-5,8-endoperoxide from Ajuga remota.

In a bioassay-guided search for antimycobacterial natural products from higher plants, we have chemically investigated the methanol extract of aerial parts of Ajuga remota Benth. (Labiatae) for its active constituent(s). Bioactive chromatographic fractions of the crude extract provided the known triterpene ergosterol-5,8-endoperoxide plus the diterpenes clerodin, ajugarin-I, and ajugarin-II, which had been previously isolated from A. remota. This is the first report on the isolation of ergosterol-5,8-endoperoxide from this plant. The above compounds were tested in a radiorespirometric bioassay for activity against Mycobacterium tuberculosis. Ergosterol-5,8-endoperoxide showed a minimum inhibitory concentration (MIC) of 1 microgram/ml, while ergosterol-5,8-endoperoxide acetate, ergosterol, and ergosta-5,7,9(11),22-tetraen-3 beta-ol gave MICs of 8 micrograms/ml, > 128 micrograms/ml, and 128 micrograms/ml, respectively. Clerodin, ajugarin-I, and ajugarin-II were inactive with MICs of > 128 micrograms/ml.

Antitubercular Agents↗

PubMed1998

9-Hydroxy-9-(3-methylbut-3-en-1-ynyl)-9H-fluorene-1-carbonitrile.

The N atom in the title compound, C19H13NO, lies -0.0365 (14) A from the plane formed by the fluorene system, and the C [symbol: see text] N distance is 1.143 (2) A. The C [symbol: see text] C distance is 1.191 (2) A, and the ethynyl group deviates slightly from linearity, with C-C [symbol: see text] C-C bond angles of 172.0 (1) and 176.1 (2) degrees. Terminal CH2 and CH3 groups are 50:50 disordered, with equal C-C distances of 1.408 (3) and 1.406 (3) A.

Crystallography, X-Ray↗

PubMed1998

endo-endo-anti Diels-Alder diadduct of hexachlorocyclopentadiene with 1,6-dioxacyclodeca-3,8-diene.

There are two independent molecules of endo-endo-anti-1,7,8,9,10,16,17,18,19,19,20,20-dodecachloro-4,13- dioxapentacyclo[14.2.1.1(7,10).0(2,15).0(6,11)]icosa-8,17-di ene, C18H12Cl12O2, in the unit cell with different conformations. In one, the ten-membered ring adopts a chair-chair conformation, and in the other, it adopts a distorted chair-chair conformation. There are near-zero torsion angles at the ring-fusion bonds in both forms [1.5 (6) and 8.1 (5) degrees in the chair-chair molecule, and 2.9 (5) and 2.5 (5) degrees in the distorted chair-chair molecule]. The torsion angles about the bonds comprising the sides of the chair-chair are 158.5 (3), -160.7 (3), -146.8 (4) and 155.7 (3) degrees, and those of the distorted chair-chair are 148.0 (3), -146.8 (3), 175.7 (3) and -52.3 (4) degrees. The norbornene C=C bonds have lengths of 1.314 (6) and 1.305 (6) A in the chair-chair molecule, and 1.309 (6) and 1.318 (6) A in the other. The four dioxolane-system O-C bonds have average lengths of 1.411 (5) and 1.421 (5) A in the two independent molecules.

Crystallography, X-Ray↗

PubMed1998

4-Nitro-1-(trimethylsilylethynyl)benzene.

The title molecule, C11H13NO2Si, lies on a mirror plane, with only one methyl group lying out of plane. The C[symbol: see text]C triple bond has a length of 1.199 (4) A. Bond angles Si-C[symbol: see text]C and C[symbol: see text]C-C(Ar) are 177.9 (3) and 178.0 (3) degrees, respectively. The Si-Csp3 bond lengths are 1.831 (4) and 1.838 (3) A, while the Si-Csp distance is 1.839 (3) A.

Crystallography, X-Ray↗

PubMed1998

(Z)-3-benzylidene-1-ethynyl-1-phenyl-1,3-dihydroisobenzofuran.

The title compound, C23H16O, has two independent molecules in the asymmetric unit. The bond lengths and angles of the two molecules are identical. The conformation of the isobenzofuran ring systems of the molecules, however, differ slightly; in molecule A, the sp2-C atom of the five-membered ring deviates the greatest distance [0.034(2)A] from the benzo plane, while in molecule B, it is the sp3-C atom of the five-membered ring which has the greatest deviation [0.027(2)A] from the benzo plane.

Benzofurans↗

PubMed1998

Antimycobacterial activities of dehydrocostus lactone and its oxidation products.

In an attempt to study the structural dependence of antimycobacterial activity of the guaianolide dehydrocostus lactone and its derivatives, m-chloroperoxybenzoic acid oxidations of dehydrocostus lactone (1a) were performed. Three new monoepoxides, one previously synthesized diepoxide, and two new diepoxides were obtained. Two of the monoepoxides are C-10 epimers (3a, 3b), while the 4(15)-monoepoxide (2) has the 4alpha-O-configuration. The known diepoxide (4a) contains a C-10 alpha-epoxide and a beta-epoxide at C-4. The diepoxides 4b and 4c, each with a C-4 alpha-epoxy group, differ in the configuration of the epoxide ring at C-10. Allylic oxidation of dehydrocostus lactone (1a) with selenium dioxide/tert-butyl hydroperoxide afforded the known 3-epizaluzanin C (1b). The relative configurations of compounds 1b-4c were established by 1D and 2D NMR techniques (1H, 13C, COSY, NOESY, HMQC, and HMBC) as well as comparison with literature data. The molecular structures of lactones 1b, 4a, and 4c were determined by single-crystal X-ray diffraction. In radiorespirometric bioassays against Mycobacterium tuberculosis and Mycobacterium avium, dehydrocostus lactone (1a) exhibited minimum inhibitory concentrations of 2 and 16 microgram/mL, respectively. In contrast, its monoepoxides (2, 3a, and 3b) and diepoxides (4a-c), as well as its hydrogenated derivatives and other analogues (1b, 1c, 5, and 6), showed significantly lower activities against M. tuberculosis.

Antitubercular Agents↗

PubMed1998

Change in the mode of inhibition of acetylcholinesterase by (4-nitrophenyl)sulfonoxyl derivatives of conformationally constrained choline analogues.

A chiral, five-step synthesis of 2-(hydroxymethyl)-2,4-dimethylmorpholine (12) from (R)- and (S)-2-methylglycidols gives an overall yield of 63%. Morpholines (R)- and (S)-12 are converted into 2-(azidomethyl)-2,4-dimethylmorpholine (15) via 2,4-dimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholine (14). The tertiary morpholines 12, 14, and 15 are quaternarized to afford 2-(hydroxymethyl)-2,4,4-trimethylmorpholinum iodide (2), 2,4,4-trimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholinium iodide (3), and 2-(azidomethyl)-2,4,4-trimethylmorpholinium iodide (4), respectively, which all inhibit acetylcholinesterase (AChE). These morpholinium inhibitors are compared with conformationally constrained aryl hemicholinium AChE inhibitors. Enantiomers of 2 and 4 are reversible competitive inhibitors of AChE, with values of Ki = 360 +/- 30 microM for (S)-2, 650 +/- 90 microM for (R)-2, 450 +/- 70 microM for (S)-4, and 560 +/- 30 microM for (R)-4, respectively. Enantiomers of 3 are noncompetitive inhibitors of AChE with values of Ki = 19.0 +/- 0.9 microM for (S)-3 and 50 +/- 2 microM for (R)-3, respectively. AChE shows a 2-fold chiral discrimination in the case of inhibition by 2 and 3. Inhibition also changes from competitive to noncompetitive when (3-hydroxyphenyl)-N,N,N-trimethylammonium iodide (18) [Ki = 0.21 +/- 0.06 microM; Lee, B. H., Stelly, T. C., Colucci, W. J., Garcia, J. G., Gandour, R. D., and Quinn, D. M. (1992) Chem. Res. Toxicol. 5, 411-418] is converted into [3-[(4-nitrophenyl)sulfonoxy]phenyl]-N,N,N-trimethylammonium iodide (5), Ki = 6.0 +/- 0.5 microM. These results indicate that the 4-nitrobenzenesulfonyl group controls the mode of inhibition.

Acetylcholinesterase↗

PubMed1997

Two cyclohexanespiro-5'-hydantoin monohydrates.

Cyclohexanespiro-5'-hydantoin monohydrate, C8H12N2O2.H2O, has a chair-shaped cyclohexane ring with endocyclic torsion-angle magnitudes in the range 54.4 (2)-56.3 (2) degrees. All potential hydrogen-bond donors are involved in intermolecular hydrogen bonding, with lengths in the range 2.760 (2)-2.908 (2) A. In its indolyl adduct, 2-(3-indolyl)cyclohexanespiro-5'-hydantoin monohydrate, C16H17N3O2.H2O, the cyclohexane moiety adopts a chair conformation with the indolyl substituent in an equatorial position. The N-H portion of the hydantoin ring is cis to indolyl, while the C=O of the hydantoin is trans. Endocyclic torsion-angle magnitudes of the cyclohexane ring are in the range 54.2 (2)-56.7 (2) degrees. All potential hydrogen-bond donors are involved in intermolecular hydrogen bonds, with lengths 2.828 (2)-3.187 (2) A.

Crystallography, X-Ray↗

PubMed1997

A diiodo-substituted 9-anthracenone.

The central ring of the anthrone system in 1,8-diiodo-10-hydroxy-10-(3-methylbut-3-en-1-ynyl)anthrac en-9(10H)-one, C19H12I2O2, has a boat conformation and the two outer rings form a dihedral angle of 41.1 (2) degrees. The I-C bond lengths are 2.094 (4) and 2.083 (4) A. The hydroxyl and carbonyl groups form an intermolecular hydrogen bond having an O...O distance of 2.853 (4) A.

Anthracenes↗

PubMed1997

N-phenylsulfonyl-3-methylbenz[f]indole.

In the title compound, C19H15NO2S, the benz[f]indole ring system is essentially planar, with maximum and mean deviations for the 13 ring atoms of 0.051 (2) and 0.023 (4) A. The N atom lies 0.199 (1) A out of the plane of the three atoms bonded to it. The phenyl group forms a dihedral angle of 82.83 (5) degrees with the benz[f]indole plane. The S--N distance is 1.646 (1) A and the S = O distances average 1.426 (1) A.

Indoles↗

PubMed1996

2,3,4,5-Tetra-O-acetyl-1,6-di-O-(triphenylmethyl)-D-mannitol.

The central six-C-atom chain of the title compound, C52H50O10, adopts a nearly planar extended conformation free from C parallel C, C parallel O and O parallel O 1,3-parallel interactions. The three torsion angles formed by these atoms have values of 177.4 (2), 174.2 (2) and -178.0 (2) degrees. The bulky triphenylmethyl groups, which are oriented gauche to their neighboring acetoxy groups with O--C--C--O torsion angles of -69.8 (2) and -63.0 (2) degrees, cause no distortion of the bond lengths and bond angles of the sugar moiety.

Crystallography, X-Ray↗

PubMed1996

Antimycobacterial cycloartanes from Borrichia frutescens.

In a bioassay-guided search for antimycobacterial compounds from higher plants of the southeastern United States, we have chemically investigated the sea daisy (Borrichia frutescens) from coastal marshes of Louisiana for their active constituents. Bioactive chromatographic fractions provided two new triterpenes, (24R)-24,25-epoxycycloartan-3-one (1) and (23R)-3-oxolanosta-8,24-dien-23-ol (4), and (3 alpha H, 24R)-24,25-epoxycycloartan-3-ol (3a). Compound 3a had been previously isolated as a mixture of C-24 epimers. The structures of 1, 3a, and 4 were established by spectroscopic methods and chemical transformations, and the molecular structures of 1 and 4 were determined by single-crystal X-ray diffraction. In a radiorespirometric bioassay against Mycobacterium tuberculosis, the epoxycycloartanes 1 and 3a exhibited minimum inhibitory concentrations of 8 micrograms/mL. In contrast, the lanostadiene-type triterpene 4 showed no significant inhibition at 128 micrograms/mL, as did the acetate 3b. Cytotoxicity for Vero cells gave IC50 values of 71.8, 39.8, and 103.6 micrograms/mL for triterpenes 1, 3a, and 4, respectively.

Acetylation↗

PubMed1995

3,4-di-O-acetyl-2,5-anhydro-1,6-di-O-(p-tolylsulfonyl)-D-mannitol.

The title compound, 2,5-bis(4-methylphenylsulfonyloxy-methyl)oxolane-3,4-diyl diacetate, C24H28O11S2, lies on a crystallographic twofold axis. It adopts a perfect twist 3(4)T conformation in the solid state. The puckering parameters of the tetrahydrofuran ring are q = 0.32 (8) A and rho = 92.3 (5) degrees. The acetyl groups are planar, with the non-H atoms deviating less than 0.002 (3) A from their mean plane. They have an (S)-cis conformation with the C-O and C = O bonds eclipsed, and each acetyl group is orientated with the C = O group syndiaxial to the C-H bond at the ring C atom to which the group is attached.

Binding Sites↗

PubMed1995

2,6,6-Trimethyl-2-oxo-1,3-dioxa-6-azonia-2-phosphocyclooctane iodide.

The eight-membered ring in the title compound, C7H17NO3P+.I-, has a boat-chair conformation, with the local mirror plane passing through the cyclic O atom and methylene C atom adjacent to the N atom. The P = O bond is pseudo-axial and the P-CH3 bond is pseudo-equatorial. The P-N distance is 3.821 (2) A.

Carnitine Acyltransferases↗

PubMed1995

Methyl (2S,6S:2R,6R)-6-(2-cyanoethyl)-4,6-dimethyl-2-morpholineacetate.

The morpholine ring of the title compound, C12H20N2O3, adopts a chair conformation with an equatorial (methoxycarbonyl)methyl group. The cyanoethyl and (methoxycarbonyl)methyl groups are trans with respect to each other. The global minimum conformation, as computed by PCMODEL [Gajewski & Gilbert (1992). Molecular Modeling Package. Version 4.0], of the title compound agrees with that observed in the crystal. In the crystal, the torsion angles (N identical to)C-CH2-CH2-C(O), (N identical to C)CH2-CH2-C-O, O-CH-CH2-C(OOCH3) and (O)CH-CH2-C(O)-O(CH3) have values -170.0 (1), -45.9 (2), -71.6 (2) and 142.8 (1) degrees, respectively.

Chemical Phenomena↗