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1. |
Commonly used chiral drugs: A survey |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 573-576
Jeffrey S. Millership,
Anne Fitzpatrick,
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摘要:
AbstractInitial results of a comparative survey of commonly used chiral drugs are presented. The survey considered the differences between drugs used in 1982 with those in use in 1991. Two major conclusions were reached: the use of single isomer chiral drugs had increased from 31.1% in 1982 to 34.3% in 1991 and the proportion of synthetic single isomer chiral drugs available in 1991 was considerably greater than in 1982. © 1993 Wiley‐Liss, I
ISSN:0899-0042
DOI:10.1002/chir.530050802
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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2. |
Use of isotopically chiral [4′‐13C]famciclovir and13C NMR to identify the chiral monoacetylated intermediates in the conversion of famciclovir to penciclovir by human intestinal wall extract |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 577-582
R. Anthony Vere Hodge,
Sarah J. Darlison,
Simon A. Readshaw,
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摘要:
AbstractFamciclovir is the oral form of the potent antiherpesvirus agent, penciclovir. Hydrolysis of one of the acetyl ester groups of famciclovir creates a chiral centre leading to the possible formation of (R)‐ and (S)‐enantiomers. During its conversion to penciclovir, famciclovir forms two chiral metabolites, namely monoacetyl‐6‐deoxy‐penciclovir and monoacetyl‐penciclovir. The absolute configuration and stereospecificity of the monoacetyl metabolites of famciclovir, produced in human intestinal wall extract, were determined using isotopically chiral famciclovir and13C NMR spectroscopy of the isolated metabolites.13C NMR showed that the esterase(s), in human intestinal wall extract, hydrolysed the acetyl group preferentially from the pro‐(S)‐acetoxymethyl group of famciclovir. The specificity of esterase action in forming monoacetyl‐6‐deoxy‐penciclovir and monoacetyl‐penciclovir was about 77 and 72%, respectively.
ISSN:0899-0042
DOI:10.1002/chir.530050803
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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3. |
Use of isotopically chiral [4′‐13C]penciclovir and13C NMR to determine the specificity and absolute configuration of penciclovir phosphate esters formed in HSV‐1‐ and HSV‐2‐infected cells and by HSV‐1‐encoded thymidine kinase |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 583-588
R. Anthony Vere Hodge,
Sarah J. Darlison,
David L. Earnshaw,
Simon A. Readshaw,
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摘要:
AbstractPenciclovir is a potent antiherpesvirus agent which is highly selective due to its phosphorylation only in virus infected cells. Phosphorylation of one of the hydroxymethyl groups of penciclovir (PCV) creates a chiral centre leading to the possible formation of (R)‐ and (S)‐enantiomers. The absolute configuration and stereospecificity of the PCV‐phosphates produced in cells infected with herpes simplex viruses types 1 and 2 (HSV‐1 and HSV‐2), as well as by HSV‐1‐encoded thymidine kinase, were determined using isotopically chiral [4′‐13C]PCV precursors and13C NMR spectroscopy of the isolated metabolites. The absolute configuration of penciclovir‐triphosphate (PCV‐TP) produced in HSV‐1‐infected cells was shown to beSwith an enantiomeric purity of greater than 95%. However, in contrast to HSV‐1‐infected cells in which none of the (R) enantiomer was detected, about 10% of (R)‐PCV‐TP was produced in HSV‐2‐infected cells. Phosphorylation of PCV by HSV‐1‐encoded thymidine kinase was found to give 75% (S)‐ and 25% (R)‐PCV‐monophosphate. The proportion of the (S)‐isomer appears to be amplified in the subsequent phosphorylations le
ISSN:0899-0042
DOI:10.1002/chir.530050804
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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4. |
Stereoselective cyclooxygenase inhibition in cellular models by the enantiomers of ketoprofen |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 589-595
Nuria Suesa,
Maria Francisca Fernandez,
Marta Gutierrez,
Maria Jose Rufat,
Elisabet Rotllan,
Lidia Calvo,
David Mauleon,
Germano Carganico,
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摘要:
AbstractThe pharmacological activity ofrac‐ketoprofen and its enantiomers was investigated in vitro using different cellular models. The effect of these compounds on arachidonic acid metabolism was assessed by measuring the inhibition of prostanoid generation under the action of several agonists. Thus, we have evaluated the inhibition of (1) thromboxane B2synthesis in rabbit platelets and human polymorphonuclear leukocytes (PMNs), (2) prostaglandin E2synthesis in three cultured cells, namely human umbilical vein endothelial cells (HUVEC), human keratinocytes, and mouse macrophage‐like P388D1 cells. The IC50values found for (+)‐(S)‐ketoprofen were in the range between 0.1 nMand 0.8 μM, being slightly lower in all models than those found forrac‐ketoprofen (0.4 nM–3 μM). On the other hand, (−)‐(R)‐ketoprofen showed inhibition of cyclooxygenase only at concentrations two or three orders of magnitude higher than those required for the (+)‐(S) enantiomer. These results, obtained with cell types of relevance for inflammatory processes and with compounds of high optical purity, demonstrate that the prostanoid biosynthesis inhibition caused by the drugrac‐ketoprofen is exclusively due to its dextrorotatory enantiomer.
ISSN:0899-0042
DOI:10.1002/chir.530050805
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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5. |
Microbial metabolism of 2‐arylpropionic acids: Chiral inversion of ibuprofen and 2‐phenylpropionic acid |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 596-601
Andrew J. Hutt,
Azam Kooloobandi,
Geoffrey W. Hanlon,
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摘要:
AbstractThe metabolism of (R,S)‐ibuprofen has been investigated in 24 microbial cultures. Of theseCunninghamella elegans,Mucor hiemalis, andVerticillium lecaniicatalyzed the oxidation of the drug to 2‐[4‐(2‐hydroxy‐2‐methylpropyl)phenyl]propionic acid, a known mammalian metabolite. The extent of metabolism was greatest withV. lecanii, with some 47% of the substrate being consumed over a 7‐day incubation period. Enantiomeric analysis indicated stereoselective metabolism of (R)‐ibuprofen, the enantiomeric composition of the residual substrate being R/S = 0.25. Following a preparative scale incubation of (R,S)‐ibuprofen withV. lecanii, in which the reaction was allowed to go to completion, the metabolite was found to be predominantly of the S‐configuration (S/R = 2.1), suggesting that chiral inversion of either the drug and/or the metabolite had taken place. Analysis of extracts following incubation of (R,S)‐, (R)‐, and (S)‐2‐phenylpropionic acid withV. lecanii, for 21 days, indicated that chiral inversion of the (R)‐enantiomer to its optical antipode had taken place. The results of these investigations indicate that microorganisms, in addition to mammals, are able to mediate the chiral inversion of 2‐arylpropionic acids. This observation may have implications for the preparation of optically pure 2‐arylpropio
ISSN:0899-0042
DOI:10.1002/chir.530050806
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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6. |
Stereoselective sulfate conjugation of isoproterenol in humans: Comparison of hepatic, intestinal, and platelet activity |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 602-609
Gene R. Pesola,
Thomas Walle,
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摘要:
AbstractThe stereochemistry of sulfate conjugation of isoproterenol (ISO) was examined with human liver, intestine, and platelets as the phenolsulfotransferase (PST) enzyme source and PAP35S as the cosubstrate. With the hepatic cytosol, two distinct sulfation reactions were identified, a high affinity reaction (Km5 to 50 μM) and a low affinity reaction (Km360 to 2,900 μM). The efficiency of sulfation (Vmax/Km) for both reactions was 5‐fold higher for (+)‐ than for (−)‐ISO. When the hepatic PSTs were resolved by ionexchange chromatography, it could be shown that the high affinity reaction was catalyzed by the monoamine (M) form and the low affinity reaction by the phenol (P) form of PST. Only the high affinity (M form) sulfation was detected in the jejunal cytosol with aVmax/Kmvalue 6.1‐fold higher for (+)‐ than for (−)‐ISO. Finally the platelet, as a potentially useful model tissue, also demonstrated only the high affinity M form reaction with aVmax/Kmvalue 5.7‐fold higher for (+)‐ than for (−)‐ISO. In summary, this study has shown that sulfation of ISO by PSTs in various human tissues is stereoselective and favors the inactive (+)‐enantiomer over the active (−)‐enantiomer by about 5‐fold, a finding which should be considered in the therapeutic use of chiral drugs cleared by sulfate co
ISSN:0899-0042
DOI:10.1002/chir.530050807
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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7. |
Warfarin metabolites: Stereochemical aspects of protein binding and displacement by phenylbutazone |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 610-615
Eli Chan,
Andrew J. McLachlan,
Malcolm Rowland,
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摘要:
AbstractThe in vitro human serum albumin binding characteristics of the enantiomers of the major metabolites of warfarin [6‐hydroxywarfarin (6‐HW), 7‐hydroxywarfarin (7‐HW), (S)‐warfarin alcohols [(S,S)‐ and (S,R)‐WA], and (R,S)‐warfarin alcohol [(R,S)‐WA]]have been studied, using a stereospecific HPLC assay. Warfarin metabolites are less bound both within plasma and a 40 g/liter solution of human serum albumin than the enantiomers of warfarin. The reduced warfarin metabolites have a lower fraction unbound [1.33% for (S,R)‐WA, 2.09% for (S,S)‐WA, and 1.04% for (R,S)‐WA] than hydroxylated metabolites [3.24% for (R)‐6‐HW, 4.26% (S)‐6‐HW, 4.49% for (R)‐7‐HW and 4.27% for (S)‐7‐HW]to HSA. Phenylbutazone produced a concentration‐dependent increase in the unbound fraction of all metabolites. It was possible to predict the unbound fraction of warfarin metabolites based on the unbound fraction of war
ISSN:0899-0042
DOI:10.1002/chir.530050808
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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8. |
Resolution of enantiomers by HPLC on tris(4‐alkoxyphenylcarbamate)s of cellulose and amylose |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 616-621
Yoshio Okamoto,
Toshiaki Ohashi,
Yuriko Kaida,
Eiji Yashima,
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摘要:
AbstractTen phenylcarbamate derivatives of cellulose and amylose having alkoxy groups such as ethoxy, isopropoxy, and isobutoxy at 4‐position, and methyl groups at 3‐ and 5‐positions and methoxy group at 4‐position were synthesized and their chiral recognition abilities as stationary phases for high‐performance liquid chromatography were investigated and compared to those with tris(4‐methoxyphenylcarbamate)s of cellulose and amylose. In 4‐alkoxy derivatives of cellulose, chiral recognition ability increased as the bulkiness of 4‐alkoxy groups increased. 4‐Isopropoxy and 4‐isobutoxy derivatives showed high chiral recognition. On the other hand, chiral discrimination of amylose 4‐alkoxy derivatives scarcely depended on the bulkiness of the alkoxy group, and 4‐methoxy and 4‐isopropoxy derivatives showed high chiral recognition. 3,5‐Dimethyl‐4‐methoxyphenylcarbamates of cellulose and amylose possessed higher chiral recognition ability than the corresponding 4‐methoxy de
ISSN:0899-0042
DOI:10.1002/chir.530050809
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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9. |
Enantiomeric LC separation of calcium antagonists on protein‐based chiral stationary phases |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 622-626
Ersilia De Lorenzi,
Anthony F. Fell,
Alan L. Holmes,
Gabriele Caccialanza,
Gabriella Massolini,
Carlo Gandini,
Mikes Kitsos,
Carolina Ponci,
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摘要:
AbstractThree chiral calcium antagonist drugs, bepridil and two dihydropyridine derivatives (nicardipine and REC 15/2375), have been successfully separated within short retention times using either the α1‐acid glycoprotein chiral stationary phase (Chiral AGP) or the ovomucoid column (Ultron ES‐OVM). Aqueous buffer at defined pH is modified by the addition of an organic component (propan‐2‐ol, acetonitrile, ethanol) in order to modulate the retention properties of each system. The influence of pH and percentage of organic modifier on retention, selectivity, resolution, and column performance are discussed for bepridil analyzed on Chiral AGP and for the two dihydropyridines (nicardipine and REC 15/2375) analyzed on Ultron ES‐OVM stationary phases. © 1993 Wile
ISSN:0899-0042
DOI:10.1002/chir.530050810
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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10. |
Book review. “Chirality in Industry: The Commercial Manufacture and Applications of Optically Active Compounds,” Edited by: A. N. Collins, G. N. Sheldrake and J. Crosby, New York: John Wiley&Sons, 1992, xii, 409 pages, ISBN: 0‐471‐93595‐6, $135.00 |
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Chirality,
Volume 5,
Issue 8,
1993,
Page 627-627
Hassan Y. Aboul‐Enein,
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ISSN:0899-0042
DOI:10.1002/chir.530050811
出版商:Alan R. Liss, Inc.
年代:1993
数据来源: WILEY
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