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Recent advances in the chemistry of β-actam antibiotics
94
BIOCHEMICAL EDUCATION
October 1978
Recent Advances in the Chemistry of ~-Iaetam Antibiotics E d i t e d by J E l k s . P p 313. S p e o a l P u b h c a U o n No t h e C h e r m c a l Society ( B u r h n g t o n H o u s e , L o n d o n 0 B N ) , 1977 £14 50 or $29 00.
28 of W1V
During World W a r I1. over 1000 scientists in the U S A and the U K were frantically workang on the elucidation of the structure of pemcillm and seeking a way to synthestsmg it Indeed, synthetic work was pushed ahead at a time when there was still not agreement on the structure itself Success was achieved in structural determination but not in synthesis The rapid development in efficiency of production by fermentation made synthetic production appear less urgent (and less financially attractive) The secret wartime work of the many groups was written up in R B Woodward's m o n u m e n t a l "The Chemistry of Penicillin" (1949) and chemical work was then fairly quiescent for a decade W h e n the synthesis of penicillin was achieved around 1960 a n d it was found that Cephalosponn C also contained a/]-lactam ring, a new upsurge of interest m this laetam field took place and research is now very active It was timely therefore for a Symposium to be held in Cambridge m 1976 on recent advances in the chemistry of fllactams, and the present book is a record of the proceedmgs As one of the original thousand but who has been rather out of touch with the field for over thirty years, it was indeed a revelation to see the dazzling virtuosity now being displayed on the synthetic side Analogues of pemcillms and cephalosporms have been produced, often by semi-synthesis, not only by alterations on the periphery of the intact nucleus but also, m pemcilhns, by opening the thtazohdme ring attached to the/]-lactam one, modifying it and recychsmg, so that new antibiotics have been produced filling gaps in the antibacterial spectrum of penicillin G New structures are turning up in nature such as the nocaxdicms which have a monocyclic fl-lactam lang or clavulanic acid with a novel fused fl-lactam ring This acid shows inhibitory action on fl-laetammase and so might be useful as a synergisUc agent in mixtures with lactammasesensitive antibiotics The thirty-two chapters in this book cover a wide range of /~-lactam chemistry Those of most biochemical relevance are " c h e m i c a l Aspects of the Biosynthesis of fl-lactam Antibiotics" by A b r a h a m and "Studies on the Biosynthesis of Penicillin G in a High-producing strain of Pemctlhum chrysogenum" by Bycroft, Wels, Corbett and Maloney It is good that the Master himself, R B Woodward, has contributed a chapter in which he describes current work in progress in the Woodward Research Institute This has led to the synthesis of unsaturated pemcilhns ("penems") m which the double bond characterlsUc of the cephalosporlns has been introduced into the five-membered ring of the penicillin nucleus, in the hope of combining the special reactivity factors present in the pemcilhns and cephalosporms The book is packed solid with Information and is a most useful guide to the state of the art as it was in June 1976 Clearly all those who are interested in the chemistry of fl-lactams, natural or synthetic, will want to possess this excellent report or have access to It B A Kilby
Biologically Active Substances: Exploration and Exploitation E d i t e d b y D A H e m s P p 309 J o h n W i l e y a n d S o n s , C h l c h e s t e r a n d N e w Y o r k 1977 £13 5 0 o r $26 00 This is a record of a symposium held in June 1976 in London to celebrate the career and the 70th birthday of Sir Ernst Chain It begins with K R L Mansford presenting a profile of Sir Ernst, reminding us that he had escaped from Nazi G e r m a n y in 1933 and, like others, had been warmly welcomed by Sir Gowland Hopkins in Cambridge He moved later to Oxford, Rome and finally to London where he became Head of the Department of Biochemistry at
Vol. 6
No. 4
l m p e n a l College with a splendid new laboratory which had been built for hirn The book naturally begins with/Llactam antibiotics and the hrst chapter, like that m the book reviewed above, is written by W P A b r a h a m on the biosynthesis of ~-lactams It seems that the evidence is consistent with the same trlpeptide 5(L-a-ammoadtpyl)L-cystemyl-D-vahne) being the common precursor of both benzyl p e m c d h n and cephalosporm C The second chapter by G N Robinson deals with the biological propertms of /3-1actam anUbtottcs and then, to hll m the large scale production side of the p e m c d h n story, R F a h m writes about biochemical e n g m e e n n g in the production of fungal metabohtes since he was involved with Chain m developmental work in Rome Until 1960, about the only source of ergot alkaloids was from the sclerota of Clavtceps purpurea, produced by infecting rye in the field Then an industrial process was developed for the production of lysergic acid derivatives in hmitless amounts by the cultivation of Clavtceps species m submerged culture This forms the basis of a chapter by F Arcamone who also described his own work on the use of the plentiful lysergic acid as the starting point for developing new drugs K D Barrow and G Mellows write about fuslcoccms, an interesting family of phytotoxic substances produced by the fungus Fus~coccum amygdah which causes cankers on almond and peach trees The complex structures have been elucidated - - they are trtcychc dtterpmotd aglucones attached to a substituted glucose - but their mode of action is still not fully understood Water balance and transpiration are affected and some seek an underyhng explanaUon in terms of changes m permabillty to K + G T Banks outlines the events which led to the discovery of mycoviruses which infect filamentous fungi and the discovery of the interferon-stimulating properties of the viral ds-RNA This antiviral activity in animals was probably more responsible for the explosion of interest in these viruses than any concern for illness in fungi lmperfectt K W Buck continues the story by discussing the biochemical and biological implications of double-stranded RNA mycoviruses which axe now known to be rather widespread Particles have been found in over 100 fungal species and indeed, it is estimated that 10--15% of randomly sampled fungal isolates contain particles With perhaps over 100,000 well defined fungal species, there should be plenty to keep fungal virologists busy for some years Five different particles have been isolated from cultivated m u s h r o o m s attacked by an epidemic die-back disease, so mycoviruses have commercial relevance The author points out that these viruses might be useful tools in RNA research since they can be obtained in gram quantities quite easily T h e n J M Dewdney concludes the mycovlrus story by discussing clinical and veterinary applications of the ds-RNA from the viruses, which display a wide spectrum of biological activity, including interferon induction, the ability to protect animals from viral diseases, amphhcatlon of i m m u n e responsiveness and antltumour activity The exploitation of these properties is still at the exploratory stage, but clearly an interesting and exciting field to be working in At this point in the book, there is a switch in direction towards problems of m a m m a l i a n metabohsm, s t a r a n g with a discussion on pathways of glucose absorption and metabolism (F Pocchlari and G D'Agnolo), the m e c h a n i s m of action of lnsuhn (A Beloff-Cham and A J M Kits van Heljmgen) and liver metabolism in diabetes (D A Hems) Metabolic approaches to myocardial infarction are then discussed by K R L Mansford and D, J Hearse The new "plague" whmh can be responsible for 40°70 of all deaths in m e n between 4 5 - 5 4 years is clearly a prime target for research The article discusses the natural history of myocardial ischaemta and Identifies some of the numerous potentially-deleterious changes The hope is that when these are understood, interventions can be designed to combat them The two last chapters deal with neurochemlstry H F Bradford discusses the metabolism and transmitter function of amino acids in the nervous system while J A Edwardson and G W Bennett write on the hypothalamlc hormones and mechanisms of neuroendocrine integration In this review It has not been possible to do m u c h more than to indicate the scope of the contributions Some closing remarks were contributed to the book by Sir Hans Krebs
BIOCHEMICAL EDUCATION
October 1978
Recent Advances in the Chemistry of ~-Iaetam Antibiotics E d i t e d by J E l k s . P p 313. S p e o a l P u b h c a U o n No t h e C h e r m c a l Society ( B u r h n g t o n H o u s e , L o n d o n 0 B N ) , 1977 £14 50 or $29 00.
28 of W1V
During World W a r I1. over 1000 scientists in the U S A and the U K were frantically workang on the elucidation of the structure of pemcillm and seeking a way to synthestsmg it Indeed, synthetic work was pushed ahead at a time when there was still not agreement on the structure itself Success was achieved in structural determination but not in synthesis The rapid development in efficiency of production by fermentation made synthetic production appear less urgent (and less financially attractive) The secret wartime work of the many groups was written up in R B Woodward's m o n u m e n t a l "The Chemistry of Penicillin" (1949) and chemical work was then fairly quiescent for a decade W h e n the synthesis of penicillin was achieved around 1960 a n d it was found that Cephalosponn C also contained a/]-lactam ring, a new upsurge of interest m this laetam field took place and research is now very active It was timely therefore for a Symposium to be held in Cambridge m 1976 on recent advances in the chemistry of fllactams, and the present book is a record of the proceedmgs As one of the original thousand but who has been rather out of touch with the field for over thirty years, it was indeed a revelation to see the dazzling virtuosity now being displayed on the synthetic side Analogues of pemcillms and cephalosporms have been produced, often by semi-synthesis, not only by alterations on the periphery of the intact nucleus but also, m pemcilhns, by opening the thtazohdme ring attached to the/]-lactam one, modifying it and recychsmg, so that new antibiotics have been produced filling gaps in the antibacterial spectrum of penicillin G New structures are turning up in nature such as the nocaxdicms which have a monocyclic fl-lactam lang or clavulanic acid with a novel fused fl-lactam ring This acid shows inhibitory action on fl-laetammase and so might be useful as a synergisUc agent in mixtures with lactammasesensitive antibiotics The thirty-two chapters in this book cover a wide range of /~-lactam chemistry Those of most biochemical relevance are " c h e m i c a l Aspects of the Biosynthesis of fl-lactam Antibiotics" by A b r a h a m and "Studies on the Biosynthesis of Penicillin G in a High-producing strain of Pemctlhum chrysogenum" by Bycroft, Wels, Corbett and Maloney It is good that the Master himself, R B Woodward, has contributed a chapter in which he describes current work in progress in the Woodward Research Institute This has led to the synthesis of unsaturated pemcilhns ("penems") m which the double bond characterlsUc of the cephalosporlns has been introduced into the five-membered ring of the penicillin nucleus, in the hope of combining the special reactivity factors present in the pemcilhns and cephalosporms The book is packed solid with Information and is a most useful guide to the state of the art as it was in June 1976 Clearly all those who are interested in the chemistry of fl-lactams, natural or synthetic, will want to possess this excellent report or have access to It B A Kilby
Biologically Active Substances: Exploration and Exploitation E d i t e d b y D A H e m s P p 309 J o h n W i l e y a n d S o n s , C h l c h e s t e r a n d N e w Y o r k 1977 £13 5 0 o r $26 00 This is a record of a symposium held in June 1976 in London to celebrate the career and the 70th birthday of Sir Ernst Chain It begins with K R L Mansford presenting a profile of Sir Ernst, reminding us that he had escaped from Nazi G e r m a n y in 1933 and, like others, had been warmly welcomed by Sir Gowland Hopkins in Cambridge He moved later to Oxford, Rome and finally to London where he became Head of the Department of Biochemistry at
Vol. 6
No. 4
l m p e n a l College with a splendid new laboratory which had been built for hirn The book naturally begins with/Llactam antibiotics and the hrst chapter, like that m the book reviewed above, is written by W P A b r a h a m on the biosynthesis of ~-lactams It seems that the evidence is consistent with the same trlpeptide 5(L-a-ammoadtpyl)L-cystemyl-D-vahne) being the common precursor of both benzyl p e m c d h n and cephalosporm C The second chapter by G N Robinson deals with the biological propertms of /3-1actam anUbtottcs and then, to hll m the large scale production side of the p e m c d h n story, R F a h m writes about biochemical e n g m e e n n g in the production of fungal metabohtes since he was involved with Chain m developmental work in Rome Until 1960, about the only source of ergot alkaloids was from the sclerota of Clavtceps purpurea, produced by infecting rye in the field Then an industrial process was developed for the production of lysergic acid derivatives in hmitless amounts by the cultivation of Clavtceps species m submerged culture This forms the basis of a chapter by F Arcamone who also described his own work on the use of the plentiful lysergic acid as the starting point for developing new drugs K D Barrow and G Mellows write about fuslcoccms, an interesting family of phytotoxic substances produced by the fungus Fus~coccum amygdah which causes cankers on almond and peach trees The complex structures have been elucidated - - they are trtcychc dtterpmotd aglucones attached to a substituted glucose - but their mode of action is still not fully understood Water balance and transpiration are affected and some seek an underyhng explanaUon in terms of changes m permabillty to K + G T Banks outlines the events which led to the discovery of mycoviruses which infect filamentous fungi and the discovery of the interferon-stimulating properties of the viral ds-RNA This antiviral activity in animals was probably more responsible for the explosion of interest in these viruses than any concern for illness in fungi lmperfectt K W Buck continues the story by discussing the biochemical and biological implications of double-stranded RNA mycoviruses which axe now known to be rather widespread Particles have been found in over 100 fungal species and indeed, it is estimated that 10--15% of randomly sampled fungal isolates contain particles With perhaps over 100,000 well defined fungal species, there should be plenty to keep fungal virologists busy for some years Five different particles have been isolated from cultivated m u s h r o o m s attacked by an epidemic die-back disease, so mycoviruses have commercial relevance The author points out that these viruses might be useful tools in RNA research since they can be obtained in gram quantities quite easily T h e n J M Dewdney concludes the mycovlrus story by discussing clinical and veterinary applications of the ds-RNA from the viruses, which display a wide spectrum of biological activity, including interferon induction, the ability to protect animals from viral diseases, amphhcatlon of i m m u n e responsiveness and antltumour activity The exploitation of these properties is still at the exploratory stage, but clearly an interesting and exciting field to be working in At this point in the book, there is a switch in direction towards problems of m a m m a l i a n metabohsm, s t a r a n g with a discussion on pathways of glucose absorption and metabolism (F Pocchlari and G D'Agnolo), the m e c h a n i s m of action of lnsuhn (A Beloff-Cham and A J M Kits van Heljmgen) and liver metabolism in diabetes (D A Hems) Metabolic approaches to myocardial infarction are then discussed by K R L Mansford and D, J Hearse The new "plague" whmh can be responsible for 40°70 of all deaths in m e n between 4 5 - 5 4 years is clearly a prime target for research The article discusses the natural history of myocardial ischaemta and Identifies some of the numerous potentially-deleterious changes The hope is that when these are understood, interventions can be designed to combat them The two last chapters deal with neurochemlstry H F Bradford discusses the metabolism and transmitter function of amino acids in the nervous system while J A Edwardson and G W Bennett write on the hypothalamlc hormones and mechanisms of neuroendocrine integration In this review It has not been possible to do m u c h more than to indicate the scope of the contributions Some closing remarks were contributed to the book by Sir Hans Krebs