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1. |
1993 Syntex Award Lecture Photomedicine and photodynamic therapy |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1005-1013
David Dolphin,
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摘要:
Photodynamic therapy (PDT) involves the treatment of diseased tissue and cells using a photosensitizer and visible light. Such photomedical treatments have been known since the time of the ancient Egyptians but it was only just this year that this therapeutic modality was made available to modern medicine with the approval, in Canada, of Photofrin® for the treatment of bladder cancer. This paper reviews PDT with an emphasis on drug development, particulary for the second generation drugs, especially BPDMA (benzoporphyrin derivative-mono acid), which is now in human clinical trials.
ISSN:0008-4042
DOI:10.1139/v94-129
出版商:NRC Research Press
年代:1994
数据来源: NRC
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2. |
1992 Lemieux Award Lecture Studies related to the penicillin receptor |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1014-1032
Saul Wolfe,
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摘要:
The relative antibacterial activities of penicillins and cephalosporins are discussed in terms of their differing abilities to complex to and react with penicillin-binding proteins. The insights gained from such an analysis are being used to attempt the design of new kinds of structures targeted to the penicillin receptor. Details of such design, and examples of several new classes of compounds suggested by this work, are described. Some of these compounds exhibit interesting antibacterial activity.
ISSN:0008-4042
DOI:10.1139/v94-130
出版商:NRC Research Press
年代:1994
数据来源: NRC
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3. |
Ab initio molecular orbital calculations on the neutral hydrolysis and methanolysis of azetidinones, including catalysis by water. Relationship to the mechanism of action of β-lactam antibiotics |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1033-1043
Saul Wolfe,
Chan-Kyung Kim,
Kiyull Yang,
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摘要:
The docking of penicillins to a computer model of the active site of the penicillin-binding protein ofStreptomycesR61 produces structures that exhibit a four-centred interaction between the O-H of a serine residue and the (O)C-N of the β-lactam ring. If such a structure is a stationary point on the reaction coordinate for the acylation of the serine OH by the β-lactam carbonyl group, the acylation mechanism would appear to consist of O—C and H—N bond formation, concerted with the cleavage of the C—N bond. The existence of this "N-protonation" mechanism, and the energetics of this mechanism in comparison to the usual "O-protonation" pathway in which proton transfer to oxygen and addition to the carbonyl groupprecedeC—N bond fission, have been examined by ab initio MO calculations on the neutral hydrolysis and methanolysis ofN-methylazetidinone, penam, and penam-3α-carboxylate. The geometries of reactants and transition structures have been optimized fully at the 3-21G or 3-21G* levels, the existence of transition structures has been confirmed by vibrational analysis, thermochemical data have been computed, and the one-point energies of all structures have been determined at the MP2/6-31G* level. The N-protonation mechanism is found to exist with all substrates, and to be preferred over the O-protonation mechanism by over 5 kcal/mol. The activation energies are 5 kcal/mol lower in the bicyclic penam than in the monocyclicN-methylazetidinone, and attack from the convex face is preferred over attack from the concave face. The introduction of a 3α-carboxylate group, as in penicillin itself, results in an additional 5 kcal/mol decrease in activation energy. The origins of these trends are discussed. Since the active sites of some penicillin-recognizing enzymes contain at least one water molecule, catalysis of the foregoing reactions by one water molecule has also been examined. The catalysis amounts to over 10 kcal/mol in both the N- and O-protonation mechanisms, and the preference for the N-protonation mechanism is maintained. It is concluded that penicillin complexes to its receptor in such a manner as to allow acylation of the active site serine residue to proceed via the energetically most favourable mechanism.
ISSN:0008-4042
DOI:10.1139/v94-131
出版商:NRC Research Press
年代:1994
数据来源: NRC
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4. |
A semiempirical molecular orbital study of the methanolysis of complex azetidinones. A combined MM and QM analysis of the interaction of Δ2- and Δ3-cephems with the penicillin receptor |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1044-1050
Saul Wolfe,
Tova Hoz,
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摘要:
The semiempirical molecular orbital procedures MINDO/3, MNDO, MNDO/M, AM1, and PM3 have been used to examine possible mechanisms and modes of attack of methanol on penam, the bicyclic ring system of penicillin. These mechanisms include a one-step process in which C—O bond formation from the convex face of the molecule and proton transfer to the β-lactam nitrogen are concerted with the cleavage of the N—C(O) bond (the N-protonated pathway), and two O-protonated pathways, viz., addition to the β-lactam carbonyl group from the convex face and from the concave face of the bicyclic ring system. Only MINDO/3 reproduces the ab initio MP2/6-31G*//3-21G* trends, that the N-protonated pathway is energetically preferred over either O-protonated pathway, and, in the latter, attack from the convex face is slightly preferred over attack from the concave face. MINDO/3 has, therefore, been used for a systematic examination of the reactions of many substituted and unsubstituted β-lactam-containing ring systems with methanol. The N-protonated structure created by attack of the alcohol from the convex face of the molecule is always preferred, and structure–reactivity relationships are observed that parallel structure–activity relationships of β-lactam antibiotics. MINDO/3 has also been used to compute a scaled quantum mechanical force field for Δ2- and Δ3-cephems. This has allowed parameters to be proposed for Δ2- and Δ3-cephems in the force field of Allinger's MMP2(85) programme that complement earlier parameterizations of the program for penicillins and peptides. The availability of these parameters has led to the development of a protocol for the analysis of the differences in the antibacterial activities of penicillins and cephalosporins. The analysis is based on a combination of "fit" and "reactivity" at the site of action. Fit is determined from the geometry that results when the β-lactam compound is complexed to a hexapeptide model of the penicillin receptor, in particular, the four-centred interaction between C-O-H of the active site serine residue and (O)C-N of the azetidinone ring. Reactivity is derived from MINDO/3 calculations of ΔE≠for the reaction of methanol with the different ring systems via the N-protonated pathway. Δ3-Cephalosporins are suggested to be inherently less active than penicillins because they are inherently lessreactive. Δ2-Cephalosporins containing a 4α-oriented carboxyl group are much less active than Δ3-cephalosporins because they have a much poorerfit. The 4β epimers of these Δ2-cephalosporins are much less active than Δ3-cephalosporins because they are much lessreactive.
ISSN:0008-4042
DOI:10.1139/v94-132
出版商:NRC Research Press
年代:1994
数据来源: NRC
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5. |
Interactive design and synthesis of a novel antibacterial agent |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1051-1065
Saul Wolfe,
Haolun Jin,
Kiyull Yang,
Chan-Kyung Kim,
Ernest McEachern,
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摘要:
β-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e,fit) and catalytic (i.e.reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP fromStreptomycesR61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (G1) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme–substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the β-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the β-lactam nitrogen. Molecular orbital calculations of structure–reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the β-lactam N-C(=O), comparable to a β-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (−ΔE > 10 kcal/mol). Accordingly, structures containing aG1and aG2separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-1,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropyl)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, fromD- andL-serine. The compound derived fromL-serine is not active. The compound derived fromD-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be carried out if modification of the lead structure leads to compounds with improved chemical stability.
ISSN:0008-4042
DOI:10.1139/v94-133
出版商:NRC Research Press
年代:1994
数据来源: NRC
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6. |
Synthesis of the stereoisomers of a novel antibacterial agent and interpretation of their relative activities in terms of a theoretical model of the penicillin receptor |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1066-1075
Saul Wolfe,
Caijun Zhang,
Blair D. Johnston,
Chan-Kyung Kim,
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摘要:
2,2-Dimethyl-3-(2′-hydroxypropyl)-5-carboxy-Δ3-1,4-thiazine (1) is a designed antibacterial agent. Based on an analysis of how penicillin complexes to and reacts with a model of a penicillin-binding protein,1contains a functional group (C=N) that can react with a serine hydroxyl group of the receptor according to the putative reaction Enz-OH + C = N → Enz-O-C-NH. Compound1also contains additional substituents that are designed to position the O-H and C=N groups relative to one another in the enzyme–substrate complex in a geometry that attempts to reproduce the optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. In a first preparation of1, (±)-5-methyl-4-hexene-2-ol (2) was converted to the lithium salt of (±)-2-mercapto-2-methyl-5-tert-butyldimethylsiloxy-3- hexanone (7), which was condensed with theN-tert-butoxycarbonyl-D- andL-serine-β-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. TheRandSenantiomers of2have now been obtained, and the absolute configuration of the alcohol established, by reaction of theR- andS-propylene oxides with an organometallic reagent prepared from β,β-dimethylvinyl bromide. TheRalcohol has also been secured by lipase-catalyzed transesterification with trifluoroethyl butyrate, and chemical hydrolysis of the trifluoroethyl ester. TheRandSenantiomers of2were converted to theRandSenantiomers of7, and these were condensed with theRandSenantiomers of3to yield each of the stereoisomers of the chemically unstable1in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8Rand 5S,8Sisomers. These findings are shown to be consistent with the theoretical model. It is hoped that the stability of the lead structure1can be improved, to allow binding experiments with penicillin recognizing enzymes to proceed.
ISSN:0008-4042
DOI:10.1139/v94-134
出版商:NRC Research Press
年代:1994
数据来源: NRC
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7. |
Partial molar volumes of some drugs in water and ethanol at 35 °C |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1076-1079
M. Iqbal,
M. Asghar Jamal,
Maqsood Ahmed,
Bashir Ahmed,
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摘要:
Partial molar volumes,V0, of six drugs, mostly anaesthetics, viz., cinchocaine HCl, lidocaine HCl, mepivacaine HCl, procaine HCl, propranolol HCl, tetracaine HCl, in water and ethanol, calculated from precision densities obtained at 35 °C from a vibrating tube densitometer, are reported in this work. The data represent the smaller volumes of drug molecules in ethanol than in water. Volume contribution of hydrochloride part were calculated and excluded fromV0to assess the volume of free base component of the solutes. Volumes of free bases were also found smaller in ethanol, although much closer to those in water. The differences in volumes are interpreted as due to hydrophobicity of solutes. Relative hydrophobicities were estimated from volumes of transfer from aqueous to organic media. Correlation ofV0with van der Waal volumes are also reported. The hydrophobicity of these compounds is proposed to play a key role in the resulting drug action. Possible mechanism of drug binding with the membrane structure is also discussed.
ISSN:0008-4042
DOI:10.1139/v94-135
出版商:NRC Research Press
年代:1994
数据来源: NRC
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8. |
Activities of dilute NiO in Na2O•2SiO2by electromotive force measurements |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1080-1082
P.J. Tumidajski,
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摘要:
The thermodynamic properties of dilute NiO in Na2O•2SiO2forXNiO < 0.0125 have been investigated in the temperature range 1073–1173 K by emf measurements using the electrochemical cellwhereNiOdenotes a solution with Na2O•2SiO2. It was found that forXNiO < 0.003 the solutions obey Henry's law. The Henrian activity coefficients and the related dilute solution thermodynamic properties based on the solid NiO standard state are reported.
ISSN:0008-4042
DOI:10.1139/v94-136
出版商:NRC Research Press
年代:1994
数据来源: NRC
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9. |
Solvent effects on the reactivity of solvated electrons with ions in isobutanol/water mixed solvents |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1083-1093
Ruzhong Chen,
Yuris Avotinsh,
Gordon R. Freeman,
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摘要:
The effective reaction radii KRr, whereRris the reactive encounter radius and K is the probability of reaction per encounter, forwith, are all 0.7 ± 0.1 nm in isobutanol containing 10–20 mol% water. The value remains at 0.7 ± 0.1 nm forin pure isobutanol, and for the two transition metal ions in pure water solvent. The value forreduces to 0.35 nm in pure isobutanol and pure water solvents, whereas forin pure water solvent it is only 0.14 nm and 2.6 × 10−5 nm, respectively. The low reactivity ofwithin water is attributed to the symmetry of the hydrogen-bonded solvation structure ofin water, and the higher reactivity ofis attributed to the lower symmetry of its hydrogen-bonded solvation structure. Theions have no low-lying orbital for an electron to occupy, so either reaction occurs by proton transfer to the electron site or the neutral species must decompose. We suggest that the proton transfer or the decomposition of the neutral species is facilitated by an unsymmetrical solvation structure.Reaction ofin Al(ClO4)3solutions in water is due mainly tofrom hydrolysis ofand partly to partially hydroxylated aluminum(III) species. Reaction ofwithitself appears to be negligible in water. The reactivity of the solutions of Al(ClO4)3in isobutanol-rich solvents is 3–5 times greater than that in water.In pure C1to C41-alcanol solvents the value ofincreases linearly with the dielectric relaxation time τ1of the solvent. In these solvents the probability of permanent capture per encounter increases approximately as the square of the encounter duration.
ISSN:0008-4042
DOI:10.1139/v94-137
出版商:NRC Research Press
年代:1994
数据来源: NRC
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10. |
Déplacements homolytiques intramoléculaires: 20. Influence de la nature de la fonction peroxyde sur la décomposition induite de peroxydes δ-insaturés |
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Canadian Journal of Chemistry,
Volume 72,
Issue 4,
1994,
Page 1094-1098
B. Maillard,
X. Lubeigt,
M-J. Bourgeois,
E. Montaudon,
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摘要:
Induced decomposition of δ-unsaturated peroxidic derivatives CH2=CH(CH2)3OY (Y = OtBu, OCMe2Ph, OCOEt, OCMe2OMe) in various solvents yields a heterocycle and, in some cases, a peroxidic adduct. Intramolecular homolytic substitution (SHi) leading to the cyclic ether is highly dependent on the thermal stability of the peroxidic linkage. The rate constant was determined at 60 °C for Y = OtBu, OCMe2Ph.
ISSN:0008-4042
DOI:10.1139/v94-138
出版商:NRC Research Press
年代:1994
数据来源: NRC
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