- Email: [email protected]
Comprehensive medicinal chemistry
TIBS 16 - JUNE 1991
Others in the same category are Bayer's azlocillin, Sumitomo's apalcillin and Tanabe's aspoxicillin. All these penicillins, like carbenicillin and ticarcillin, have to be injected, since they are not absorbed to a significant extent when taken by mouth. Penicillins aM other ~ a c t a m
Between 1959 and 1964 ten clinically important penicillins (8--17) were prepared for the first time in a single Beecham laboratory. Thereafter operation of the Law of Diminishing Returns became evident and the rate of innovation slowed. However, the utility of existing penicillins was boosted in the 1970s by the discovery of effective inhibitors of several ~-lactamases. The first of these to be introduced clinically, in 1981, was clavulanic acid, a ~lactam of unusual structure produced by Slreptomyces clavuligerus. Use of clavulanic acid in combination with either amoxycilfin or ticarcillin extends the effective antibacterial spectra of the penicillins to include a number of otherwise resistant organisms ~z.
As the amount of worldwide research on new peniciilins declined, that on other series of ~-lactam antibiotics increased. Details of the structures and antibacterial activities of almost all the clinically important ~-lactams, including penicillins, have been collated by Rolinson ~3. Elucidation of the structure of the naturally occurring cephalosporin C in the early 1960s was followed by an enormous amount of work on its chemical modification, which still continues, and which has produced a range of semi-synthetic cephalosporins even more numerous than the semi-synthetic penicillins. The late 1970s saw the
emergence of several further families of ~ a c t a m antibiotics. While some have been derived from one or more parent members produced by microorganisms, others are purely artificial creations. Preferred syntheses of the latter often start from penicillin G and preserve the ~-lactam ring intact through lengthy sequences of chemical manipulation. Such virtuosity would have astonished an earlier generation of scientists who
stood in awe of the fragility of the first penicillins.
References
1 Nayler,J. H. C. (1991) TrendsBiochem.Sci. 16, 195-197 2 Sakaguchi,K. and Murao,S. (1950) J. Agric. Chem.Soc.Japan23, 411 (Chem.Abs.1951, 45, 1197) 3 Rolinson,G. N., Batchelor, F. R., Butterworth, D., Cameren-Wood,J., Cole, M., Eustace,G. C., Hart, M. V., Richards,M. and Chain, E. B. (1960) Nature187, 236-237 4 Kaufmann,K. and Bauer, K. (1960) Naturwissenschaften47, 474-475 5 Claridge,C. A., Gourevitch,A. and Lein,J. (1960) Nature187, 237-238 6 Huang,H. T., English,A. R., Seto, T. A., Shull, G. M. and Sobin, B. A. (1960) J. Am. Chem. Soc. 82, 3790-3791 7 Weissenburger, H. W. O. and Van de Hoeven, M. G. (1970) Rec.Trav.Chim.89, 1081-1084 8 Sheehan,J. C. and Henery-Logan,K. R. (1959) J. Am. Chem.Soc.81, 5838-5839 9 Doyle,F. P., Nayler,J. H. C., Smith, H. and Stove, E. R. (1961) Nature191,1091-1092 10 Abraham,E. P. and Chain, E. (1940) Nature 146, 837 11 Nayler,J. H. C. (1973) Adv. DrugRes.7,1-105 12 Hunter,P. A., Coleman, K., Fisher,J. and Taylor, D. (1980) J. Antimicrob.Chemother.6, 455-470 13 Rolinson,G. N. (1986) J. Antimicrob. Chemother.17, 5-36
BOOKRE EWS Six volumes of information Comprehensive Medicinal Chemistry edited by Corwin Hansch, J, C. Emmett, P. D. KenneweU, C. A. Ramsden, P. G. Sammes and J. B. Taylor, Pergamon Press, 1990. £1145.00 (6 vols, ~6000 pages) ISBN 0 08 032530 0
The vast area covered and the size of this book means that no single reviewer has the detailed knowledge of the subject matter of volumes I-5. The editors of this set of books have organized the subject matter logically, progressing from a general volume to four specific volumes and providing a useful and extensive cumulative index in volume 6. Despite glaring omissions these volumes are a landmark in the field. They will be useful to chemists and biochemists to make their research and teaching more relevant and applied, while pharmacologists and immunologists will find the volumes invaluable for interpreting their data in structural, kinetic, thermodynamic and biochemical terms. Undergraduates and
postdoctoral fellows may use them as a first step in literature surveys, since what is not adequately covered is usually wellreferenced. However, the use of the words 'comprehensive' and 'medicinal chemistry' in the title is provocative. Can a set of six volumes be comprehensive when synthetic organic chemistry (actual syntheses) is omitted? Can it be medicinal chemistry when pharmaceutical analysis is covered in one chapter? Where does it cover the use of nuclear magnetic resonance (NMR) and mass spectroscopy - the two major tools of the natural product and synthetic chemist? Inorganic chemistry barely receives a mention, while the sections on chromatography and electrophoresis are too simple and old-fashioned. A medicinal chemist must be ..,rare not only of the nature of the pharmaceutical agent and its target macromolecule(s) and the interaction between these, but also the structure and metabolism of microorganisms, body fluids, cells and tissues. Volume I, edited by P. D. Kennewell, gives a review of these 'general principles'. The volume starts with a five-chapter 'Historical Perspective', followed by a section of
seven chapters on the targets of biologically active molecules. The next section is devoted to single chapters on sources of bioactive materials, rounding off with three chapters on genetic engineering. The volume finishes with a much needed 14-chapter section on 'socioeconomic factors in drug development'. While essentially introductory and too general, this volume does provide a framework for subsequent volumes. Volume 2, edited by P. S. Sammes covers 'Enzymes and other macromolecules' and has been repeatedly used by myself as a reference for teaching and research. The general principles of enzymology are covered in five chapters but there seems to be insufficient detail on stereochemistry, allosteric enzymes, kinetic and equilibrium isotope effects, mechanism-based drug design and threedimensional structures of enzymes. This same criticism holds for the remaining sections and chapters, with insufficient treatment given to protein engineering, carbohydrates and lipids. It is a pity that quantitative structure-activity relationships (QSAR) and computational aspects are covered in volume 4 and not
237
TIBS 16 - JUNE 1991 integrated into volume 2. However, volume 2 is a tour de force, with excellent chapters on DNA and RNA metabolizing enzymes, ribosomal-based drug design and resistance mechanisms, antibacterials and antivirals. Pharmaceutical chemists should value this volume for its excellent contents and writing but will regret the omissions. The organization is a matter of taste and opinion. I would have preferred to treat enzymes purely according to their classification (mechanisms and nomenclature) rather than their physiological functions. This volume uses both approaches (e.g. pyridoxal phosphate enzymes and cell wall inhibitory drugs are examples of both approaches). Membranes and receptors are covered in the 6 sections and 32 chapters of volume 3, edited by 3. C. Emmett. This too is timely in view of the present rapid expansion in receptor isolation, receptor cloning and sequencing and the activities of drugs that act on membrane receptors, ion channels and enzymes. All chapters are generally of a high standard and written by an impressive range of authoritative scientists. In the short time I have had this volume, it has been continuously used for advanced teaching. Nevertheless, the volume seems deficient in detail on individual receptor and ionchannel proteins. The chapters on neurotransmitters, leukotrienes, PAF and prostanoid receptors, and the chapters on drugs acting at ion channels and protein/peptide receptors are excellent, but the explosion of our knowledge of receptors for antibodies, lymphokines, cytokines and immunosuppressives is given only one small chapter. Volume 3 seems to emphasize the structures of agonists and antagonists that interact with receptors and ion-channels with only lip-service given to mechanisms. Cell surface targets for 'intracellular-acting' (steroid) hormones are largely ignored, but the chapter on prostaglandins, thromboxanes and leukotrienes more than comperlsates. Just how ion-channel gating and blocking drugs act mechanistically seems a mystery, but this reflects the literature! Recent genetic engineering attempts to pin-point the functions of each subunit or domain of a membrane protein are given insufficient coverage, perhaps due to the logistical difficulties in assembling a six-volume work. Because of rapid expansion, especially in the software and hardware available, the subject matter of volume 4 on quantitative drug design, edited by C. A. Ramsden, is difficu!t to arrange logically. Nevertheless, reasonable organization and coherence has been achieved by dividing the volume into 6 sections and 24 chapters. Section I (four chapters) gives a
238
useful introduction to computers and their use in drug design and molecular modelling, but there seems little crossreferencing to the following 20 chapters. Section II deals with quantum mechanics, molecular mechanics, dynamics and three-dimensional structures, but should the 'distance geometry' chapters of Crippen and Ghose have been located here? Also, the absence of details of onedimensional and two-dimensional NMR here (or anywhere in the six volumes) is a glaring omission. The applications to electronic and hydrophobic effects, partition coefficients, intermolecular forces and binding follow logically. The relationship of structure to bioactivity and transport is covered in a two-chapter section. As expected, the three QSAR chapters are scholarly and well-written and reflect the state-of-the-art, but as with most QSAR studies the references to and relevance to three-dimensional structures of the drugs and their macromolecular targets are inadequately treated. The final section (four chapters) on Pattern Recognition reflects the growing importance of this field. My only criticism of this chapter illustrates a major drawback of the six volumes - it is not an entity in itself and relies strongly on knowledge of mechanisms and targets in volumes 2 and 3 and techniques described in volume 5. Volume 5 is on biopharmaceutics, and it is refreshing to see this subject placed as a major component of medicinal chemistry and as a logical extension of the material covered in the previous four volumes. The organization into three sections is logical and each chapter relates to the previous chapters. The first section (Analytical Methods) is too short. Surely a whole volume on pharmaceutical
analysis was required? It gives inadequate coverage to NMR, with mass spectroscopy (actually flame ionization detection) treated as a detection system for HPLC. The chromatographic sections are clear but the subjects of ion-exchange chromatography, chromatofocusing, capillary electrophoresis etc., are not covered; did the editors consider them of little relevance? The next section covers the genetic, kinetic, dynamic, metabolic and toxicological aspects of medicinal chemistry. I found all chapters interesting, authoritative and up-to-date. The five chapters on physicochemical properties (essentially surface chemistry), formulation, routes of administration, delivery system technology and drug targeting are modern and informative. Although the price of this set is outside the realm of most individual scientists, the investment for teaching, research and as a reference for research teams is recommended. The chief editors, the editorial committee and those who wrote each chapter have performed a definite service to the field. The smallest amount of money annually given to a research area by the SERC Chemistry Committee is to medicinal chemistry. The SERC has no pharmacy or pharmaceutical science review panels - unlike the NIH. Perhaps reading these volumes will help redress this wrong and help orient government funding into medicinal chemistry!
WILLIAM A. GIBBONS University-lndust~jCentrefor Pharmaceutical Research,School~; Pharmacy,Universityof London,29/39 BrunswickSquare, LondonWCIN lAX, UK.
15th International Congressof Biochemistry: Update The Organizing Committee will arrange a special 'late poster' session for the morning of Thursday 8 August for those biochemists who, during the Gulf Crisis delayed making their decision to travel to Israel. The deadline for the submission of abstracts for this session is I July, provided that the abstracts are accompanied by registration forms and payment of the late registration fee of US$390. Each registered author may present one communication only, but may be the co-author of additional abstracts. If the special abstract form is not available, type the abstract on plain paper, without a box around the text, in a space 12.7 cm wide by 15 cm high. Special efforts will be made to include these abstracts in the/UB Abstract Book. However, abstracts received after 1 July will be included in the program, but will not be published.
!
Others in the same category are Bayer's azlocillin, Sumitomo's apalcillin and Tanabe's aspoxicillin. All these penicillins, like carbenicillin and ticarcillin, have to be injected, since they are not absorbed to a significant extent when taken by mouth. Penicillins aM other ~ a c t a m
Between 1959 and 1964 ten clinically important penicillins (8--17) were prepared for the first time in a single Beecham laboratory. Thereafter operation of the Law of Diminishing Returns became evident and the rate of innovation slowed. However, the utility of existing penicillins was boosted in the 1970s by the discovery of effective inhibitors of several ~-lactamases. The first of these to be introduced clinically, in 1981, was clavulanic acid, a ~lactam of unusual structure produced by Slreptomyces clavuligerus. Use of clavulanic acid in combination with either amoxycilfin or ticarcillin extends the effective antibacterial spectra of the penicillins to include a number of otherwise resistant organisms ~z.
As the amount of worldwide research on new peniciilins declined, that on other series of ~-lactam antibiotics increased. Details of the structures and antibacterial activities of almost all the clinically important ~-lactams, including penicillins, have been collated by Rolinson ~3. Elucidation of the structure of the naturally occurring cephalosporin C in the early 1960s was followed by an enormous amount of work on its chemical modification, which still continues, and which has produced a range of semi-synthetic cephalosporins even more numerous than the semi-synthetic penicillins. The late 1970s saw the
emergence of several further families of ~ a c t a m antibiotics. While some have been derived from one or more parent members produced by microorganisms, others are purely artificial creations. Preferred syntheses of the latter often start from penicillin G and preserve the ~-lactam ring intact through lengthy sequences of chemical manipulation. Such virtuosity would have astonished an earlier generation of scientists who
stood in awe of the fragility of the first penicillins.
References
1 Nayler,J. H. C. (1991) TrendsBiochem.Sci. 16, 195-197 2 Sakaguchi,K. and Murao,S. (1950) J. Agric. Chem.Soc.Japan23, 411 (Chem.Abs.1951, 45, 1197) 3 Rolinson,G. N., Batchelor, F. R., Butterworth, D., Cameren-Wood,J., Cole, M., Eustace,G. C., Hart, M. V., Richards,M. and Chain, E. B. (1960) Nature187, 236-237 4 Kaufmann,K. and Bauer, K. (1960) Naturwissenschaften47, 474-475 5 Claridge,C. A., Gourevitch,A. and Lein,J. (1960) Nature187, 237-238 6 Huang,H. T., English,A. R., Seto, T. A., Shull, G. M. and Sobin, B. A. (1960) J. Am. Chem. Soc. 82, 3790-3791 7 Weissenburger, H. W. O. and Van de Hoeven, M. G. (1970) Rec.Trav.Chim.89, 1081-1084 8 Sheehan,J. C. and Henery-Logan,K. R. (1959) J. Am. Chem.Soc.81, 5838-5839 9 Doyle,F. P., Nayler,J. H. C., Smith, H. and Stove, E. R. (1961) Nature191,1091-1092 10 Abraham,E. P. and Chain, E. (1940) Nature 146, 837 11 Nayler,J. H. C. (1973) Adv. DrugRes.7,1-105 12 Hunter,P. A., Coleman, K., Fisher,J. and Taylor, D. (1980) J. Antimicrob.Chemother.6, 455-470 13 Rolinson,G. N. (1986) J. Antimicrob. Chemother.17, 5-36
BOOKRE EWS Six volumes of information Comprehensive Medicinal Chemistry edited by Corwin Hansch, J, C. Emmett, P. D. KenneweU, C. A. Ramsden, P. G. Sammes and J. B. Taylor, Pergamon Press, 1990. £1145.00 (6 vols, ~6000 pages) ISBN 0 08 032530 0
The vast area covered and the size of this book means that no single reviewer has the detailed knowledge of the subject matter of volumes I-5. The editors of this set of books have organized the subject matter logically, progressing from a general volume to four specific volumes and providing a useful and extensive cumulative index in volume 6. Despite glaring omissions these volumes are a landmark in the field. They will be useful to chemists and biochemists to make their research and teaching more relevant and applied, while pharmacologists and immunologists will find the volumes invaluable for interpreting their data in structural, kinetic, thermodynamic and biochemical terms. Undergraduates and
postdoctoral fellows may use them as a first step in literature surveys, since what is not adequately covered is usually wellreferenced. However, the use of the words 'comprehensive' and 'medicinal chemistry' in the title is provocative. Can a set of six volumes be comprehensive when synthetic organic chemistry (actual syntheses) is omitted? Can it be medicinal chemistry when pharmaceutical analysis is covered in one chapter? Where does it cover the use of nuclear magnetic resonance (NMR) and mass spectroscopy - the two major tools of the natural product and synthetic chemist? Inorganic chemistry barely receives a mention, while the sections on chromatography and electrophoresis are too simple and old-fashioned. A medicinal chemist must be ..,rare not only of the nature of the pharmaceutical agent and its target macromolecule(s) and the interaction between these, but also the structure and metabolism of microorganisms, body fluids, cells and tissues. Volume I, edited by P. D. Kennewell, gives a review of these 'general principles'. The volume starts with a five-chapter 'Historical Perspective', followed by a section of
seven chapters on the targets of biologically active molecules. The next section is devoted to single chapters on sources of bioactive materials, rounding off with three chapters on genetic engineering. The volume finishes with a much needed 14-chapter section on 'socioeconomic factors in drug development'. While essentially introductory and too general, this volume does provide a framework for subsequent volumes. Volume 2, edited by P. S. Sammes covers 'Enzymes and other macromolecules' and has been repeatedly used by myself as a reference for teaching and research. The general principles of enzymology are covered in five chapters but there seems to be insufficient detail on stereochemistry, allosteric enzymes, kinetic and equilibrium isotope effects, mechanism-based drug design and threedimensional structures of enzymes. This same criticism holds for the remaining sections and chapters, with insufficient treatment given to protein engineering, carbohydrates and lipids. It is a pity that quantitative structure-activity relationships (QSAR) and computational aspects are covered in volume 4 and not
237
TIBS 16 - JUNE 1991 integrated into volume 2. However, volume 2 is a tour de force, with excellent chapters on DNA and RNA metabolizing enzymes, ribosomal-based drug design and resistance mechanisms, antibacterials and antivirals. Pharmaceutical chemists should value this volume for its excellent contents and writing but will regret the omissions. The organization is a matter of taste and opinion. I would have preferred to treat enzymes purely according to their classification (mechanisms and nomenclature) rather than their physiological functions. This volume uses both approaches (e.g. pyridoxal phosphate enzymes and cell wall inhibitory drugs are examples of both approaches). Membranes and receptors are covered in the 6 sections and 32 chapters of volume 3, edited by 3. C. Emmett. This too is timely in view of the present rapid expansion in receptor isolation, receptor cloning and sequencing and the activities of drugs that act on membrane receptors, ion channels and enzymes. All chapters are generally of a high standard and written by an impressive range of authoritative scientists. In the short time I have had this volume, it has been continuously used for advanced teaching. Nevertheless, the volume seems deficient in detail on individual receptor and ionchannel proteins. The chapters on neurotransmitters, leukotrienes, PAF and prostanoid receptors, and the chapters on drugs acting at ion channels and protein/peptide receptors are excellent, but the explosion of our knowledge of receptors for antibodies, lymphokines, cytokines and immunosuppressives is given only one small chapter. Volume 3 seems to emphasize the structures of agonists and antagonists that interact with receptors and ion-channels with only lip-service given to mechanisms. Cell surface targets for 'intracellular-acting' (steroid) hormones are largely ignored, but the chapter on prostaglandins, thromboxanes and leukotrienes more than comperlsates. Just how ion-channel gating and blocking drugs act mechanistically seems a mystery, but this reflects the literature! Recent genetic engineering attempts to pin-point the functions of each subunit or domain of a membrane protein are given insufficient coverage, perhaps due to the logistical difficulties in assembling a six-volume work. Because of rapid expansion, especially in the software and hardware available, the subject matter of volume 4 on quantitative drug design, edited by C. A. Ramsden, is difficu!t to arrange logically. Nevertheless, reasonable organization and coherence has been achieved by dividing the volume into 6 sections and 24 chapters. Section I (four chapters) gives a
238
useful introduction to computers and their use in drug design and molecular modelling, but there seems little crossreferencing to the following 20 chapters. Section II deals with quantum mechanics, molecular mechanics, dynamics and three-dimensional structures, but should the 'distance geometry' chapters of Crippen and Ghose have been located here? Also, the absence of details of onedimensional and two-dimensional NMR here (or anywhere in the six volumes) is a glaring omission. The applications to electronic and hydrophobic effects, partition coefficients, intermolecular forces and binding follow logically. The relationship of structure to bioactivity and transport is covered in a two-chapter section. As expected, the three QSAR chapters are scholarly and well-written and reflect the state-of-the-art, but as with most QSAR studies the references to and relevance to three-dimensional structures of the drugs and their macromolecular targets are inadequately treated. The final section (four chapters) on Pattern Recognition reflects the growing importance of this field. My only criticism of this chapter illustrates a major drawback of the six volumes - it is not an entity in itself and relies strongly on knowledge of mechanisms and targets in volumes 2 and 3 and techniques described in volume 5. Volume 5 is on biopharmaceutics, and it is refreshing to see this subject placed as a major component of medicinal chemistry and as a logical extension of the material covered in the previous four volumes. The organization into three sections is logical and each chapter relates to the previous chapters. The first section (Analytical Methods) is too short. Surely a whole volume on pharmaceutical
analysis was required? It gives inadequate coverage to NMR, with mass spectroscopy (actually flame ionization detection) treated as a detection system for HPLC. The chromatographic sections are clear but the subjects of ion-exchange chromatography, chromatofocusing, capillary electrophoresis etc., are not covered; did the editors consider them of little relevance? The next section covers the genetic, kinetic, dynamic, metabolic and toxicological aspects of medicinal chemistry. I found all chapters interesting, authoritative and up-to-date. The five chapters on physicochemical properties (essentially surface chemistry), formulation, routes of administration, delivery system technology and drug targeting are modern and informative. Although the price of this set is outside the realm of most individual scientists, the investment for teaching, research and as a reference for research teams is recommended. The chief editors, the editorial committee and those who wrote each chapter have performed a definite service to the field. The smallest amount of money annually given to a research area by the SERC Chemistry Committee is to medicinal chemistry. The SERC has no pharmacy or pharmaceutical science review panels - unlike the NIH. Perhaps reading these volumes will help redress this wrong and help orient government funding into medicinal chemistry!
WILLIAM A. GIBBONS University-lndust~jCentrefor Pharmaceutical Research,School~; Pharmacy,Universityof London,29/39 BrunswickSquare, LondonWCIN lAX, UK.
15th International Congressof Biochemistry: Update The Organizing Committee will arrange a special 'late poster' session for the morning of Thursday 8 August for those biochemists who, during the Gulf Crisis delayed making their decision to travel to Israel. The deadline for the submission of abstracts for this session is I July, provided that the abstracts are accompanied by registration forms and payment of the late registration fee of US$390. Each registered author may present one communication only, but may be the co-author of additional abstracts. If the special abstract form is not available, type the abstract on plain paper, without a box around the text, in a space 12.7 cm wide by 15 cm high. Special efforts will be made to include these abstracts in the/UB Abstract Book. However, abstracts received after 1 July will be included in the program, but will not be published.
!