Oxireductases in the Enzymatic Synthesis of Water-Soluble Conducting Polymers, by E. Ochoteco and D. Mecerreyes
*

Transferases in Polymer Chemistry, by J. van der Vlist and K. Loos
*

Hydrolases Part I: Enzyme Mechanism, Selectivity and Control in the Synthesis of Well-Defined Polymers, by M.A.J. Veld and A.R.A. Palmans
*

Hydrolases in Polymer Chemistry: Chemoenzymatic Approaches to Polymeric Materials, by A. Heise and A.R.A. Palmans
*
Hydrolases in Polymer Chemistry: Part III: Synthesis and Limited Surface Hydrolysis of Polyesters and Other Polymers, by G.M. Guebitz
*

Exploiting Biocatalysis in the Synthesis of Supramolecular Polymers, by S. Roy and R. V. Ulijn

Protein folding remains one of the most exclusive problems of modern biochemistry. Structure analysis has given access to the wealth of the molecular architecture of pro teins. As architecture needs static calculations, protein structure is always related to thermodynamic factors that govern folding and stability of a particular folded protein over the non-organized polypeptide chain. During the past decades a huge amount of thermodynamic data related to protein folding and stability has been accumulated. The data are certainly of importance in dechiffring the protein folding problem. At the same time, the data can guide the con struction of modified and newly synthesized proteins with properties optimized for particular application. The intention of this book is a generation of a data collection which makes the vast amount of present data accessible for multidisciplinary research where chemistry, phy sics, biology, and medicine are involved and also pharmaceutical and food research and technology. It took several years to compile all the data and the author wishes to thank everyone who provided data, ideas or even unpublished results. The author is, in particular, indebted to Prof. Wadso (Lund, Sweden) and IUPAC's Steering Committee on Bio physical Chemistry. Furthermore, support by the Deutsche Forschungsgemeinschafi (INK 16 AI-I) is acknowledged."

Saponins are complex molecules made up of sugars linked to a triterpenoid or a steroid or a steroidal alkaloid. These natural products are attracting much attention in recent years because of the host of biological activities they exhibit. The diversity of structural features, the challenges of isolation because of their occurrence as complex mixtures, the pharmacological and biological activities still to be discovered, and the prospect of commercialization - these all are driving the study of saponins. Triterpenoid saponins are dominating constituents of this class and occur widely throughout the plant kingdom including some human foods e. g. beans, spinach, tomatoes, and potatoes, and animal feed e. g. alfalfa and clover. Saponins were initially a rather neglected. area of research primarily because of great difficulties in their isolation and characterization. With the advent of more sophisticated methods of isolation and structure elucidation through the last two decades, there has been increased interest in these natural products. Besides structure determination, research activities are now moving forward to clarify structure-activity relationships. Our previous reviews on triterpenoid saponins (l, 2) covered literature from 1979 to mid-1989. The literature on triterpenoid saponins up to 1988 has also been covered by two reviews by HILLER et at. (3, 4). This review incorporates newer trends in isolation and structure determination of triterpenoid saponins, new triterpenoid saponins isolated and biological properties of these products reported during the period late 1989-mid 1996. 2."

The Leguminosae is an economically important family in the Dicotyledonae with many cultivated species, e. g. , beans and peas. The family also contains many well-known medicinal plants. It is composed of 17,000 or more species that constitute nearly one twelfth of the world's flowering plants (1). Traditionally the family has been divided into three subfamilies, Caesalpinioideae, Mimosoideae and Papilionoi- deae, which are sometimes recognized as separate families Caesalpinia- ceae, Mimosaceae and Papilionaceae. The International Code of Botanical Nomenclature permits alternative nomenclatures, the family names being replaced by Fabaceae, Fabales and Faboideae, and this usage will be common (2). Licorice (liquorice, kanzoh in Japanese, gancao in Chinese) is the name applied to the roots and stolons of some Glycyrrhiza species (Fabaceae) and has been used by human beings for at least 4000 years. The earliest written reference to the use of licorice is contained in the Codex Hammurabi dating from 2100 B. C. , and the subsequent history in the West has been described in the earlier reviews (3-6). In the Far East, references to the effectiveness of licorice are contained in the "Shen Nong Ben Cao Jing", the first Chinese dispensatory whose original anonymous volumes probably appeared by the end of the third century (7, 8).

Phytochemists are aware that their focus of interest is receiving attention from a wider segment of society and from a greater diversity of disciplines within the scientific community than ever before. Nonetheless, they were bemused to learn three years ago that "until recently scientists didn't even know phytochemi cals existed" (Newsweek, April 24, 1994). Changing public perception of the positive contributions of phytochemicals to human well-being has foundations in scientific advances. With popular reports emphasizing the important implica tions of phytochemicals in the daily lives of people, there is a pressing need for those working in this area to explain their diverse scientific activities to the public. Chemicals from plant foods are linked through epidemiological and ex perimental studies with reduced incidence of chronic degenerative diseases. Phytomedicines, standardized according to particular constituents, are making increasing contributions to health care. Naturally occurring constituents of plants are recognized as fundamental to the appeal, quality, and marketability of food products. In light of such developments, perceptions by phytochemists of their own discipline and its applications are expanding. Until recently, food phyto chemistry largely implied food toxicants. Food plants were familiar, but seldom the source of novel economically important compounds. Increasingly sophisti cated methods of analysis, however, have opened new opportunities for under standing the nature and functions offood constituents, and for manipulating them to improve the quality, acceptability, and value of food products.

Micro-TAS '98 is the third of a series of symposia initiated by MBSA (University of Twente) in 1994, on the subject of miniaturizing, and integrating within a monolithic structure, the chemical, biochemical and biological procedures commonly used for analysis and synthesis. The primary tool used to develop micro-total analysis systems (mu- TAS) has been micro-photolithographic patterning and micromachining. These powerful tools of Micro System Technology (MST or MEMS) have been applied in highly imaginative ways to develop microchip chemical arrays, fully integrated pump and fluid manifolds, and electrokinetically driven micro-channel systems to be used for genetic analysis, clinical diagnostics and environmental monitoring, and to integrate reactions as diverse as the polymerase chain reaction (PCR) and the large volume, partial oxidation of ammonia. This text illustrates the rapid expansion of the field, the extensive industrial involvement, the increasing number of participating researchers, the expanding range of concepts and applications that utilize MST and microfluidic devices, and new MST-compatible plastic micro-machining to meet the needs of the life science community. This volume contains the proceedings of the Third International Symposium on Micro-Total Analysis Systems, mu-TAS '98, held on October 13-16 in Banff, Alberta, Canada. State-of-the-art invited and contributed papers presented by the world's leading mu- TAS research groups provide a highly informative picture of the growth since 1994 and of the promising future of this exciting and rapidly growing field.

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer Imprint ever since the series' inauguration in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer Imprint ever since the series' inauguration in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

In order to make further progress in elucidating the mechanism of NOS catalysis it will be essential to throw light on the interaction between the enzyme and its substrate. An understanding of the catalytic site will also assist the development of therapeutically important NOS inhibitors. In particular. it will be useful to uncover any differences that exist between the substrate binding sites of the three NOS isozymes which might be exploited for the development of isoform selective NOS inhibitors. A comparison of NOS to other Arg-binding proteins has shown no significant sequence homology (159). Moreover, the lack of a 3D structure and absence of significant sequence homology between the NOS oxygenase domain and known cytochromes P450 has made it difficult to identify residues and construct a model of the distal heme pocket responsible for substrate binding. However, a number of groups are currently working towards crystallisation of the separate NOS reductase and oxygenase domains of the three isoforms for X-ray diffraction studies; the first X-ray structure is likely to be forthcoming within a matter of months. * The results of these studies are expected to resolve many of the uncertainties surrounding the structure of the NOS catalytic site. Preliminary X-ray diffraction analysis of CPR from rat liver has already been reported by MASTERS et al. (524) and the future emergence of a detailed structure for this protein should throw light on the structure and function of the NOS reductase domain.

It was in 1979 when GROVE et al. isolated from pollen of rape (Brassica nap us) a highly active plant growth promoter, named it brassinolide and elucidated its structure as (22R,23R,24S)-2

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer Imprint ever since the series' inauguration in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

"The greater our knowledge increases, the more our ignorance unfolds. " U. S. President John F. Kennedy, speech, Rice University, September 12, 1962 My primary purpose for writing this book was much more than to provide another information source on Chemistry, Manufacturing & Controls (CMC) that would rapidly become out of date. My primary purpose was to provide insight and practical suggestions into a common sense business approach to manage the CMC regulatory compliance requirements for biopharmaceuticals. Such a common sense business approach would need (1) to be applicable for all types of biopharmaceutical products both present and future, (2) to address the needs of a biopharmaceutical manufacturer from the beginning to the end of the clinical development stages and including post market approval, and (3) to be adaptable to the constantly changing CMC regulatory compliance requirements and guidance. Trying to accomplish this task was a humbling experience for this author In Chapter 1, the CMC regulatory process is explained, the breadth of products included under the umbrella ofbiopharmaceuticals are identified, and the track record for the pharmaceutical and biopharmaceutical industry in meeting CMC regulatory compliance is discussed. In Chapter 2, while there are many CMC commonalities between biopharmaceuticals and chemically-synthesized pharmaceuticals, the significant differences in the way the regulatory agencies handle them are examined and the reasons for why such differences are necessary is discussed. Also, the importance of CMC FDA is stressed."

Literally thousands of papers have been published on nitric oxide over the past ten years. But there is no single monograph available that has previously attempted to summarize the important features of the roles of nitric oxide in inflammation. The voluminous literature regarding the incredible range of chemical and biological effects of nitric oxide and reactive nitrogen oxide species, RNOS, may present a tangle of confusing information to the researcher. This volume brings together experts from nitric oxide and inflammation research and presents a concise up-to-date overview as well as future aspects of this rapidly growing field.

It was a great honor for us to organize ChiCat, a symposium devoted to Chiral Reactions in Heterogeneous Catalysis and to be the hostsofmore than 120 scientists coming from everywhere in the industrialized world, to celebrate together one century of existence ofInstitut Meurice. This school was established in 1892when an industrial chemist, named Albert Meurice, decided to educate practical chemists according to the perceived needs ofthe industry ofthat time. This is exactly what we are still trying to do. It is the reason why, thirty years ago, we started a research activity in catalysis, and why we progressively devote this research to the applications of catalysis in the field of fine chemicals. In this respect, we are very close to another initiative of Albert Meurice, who started the first production of synthetic pharmaceuticals in Belgium during World War I. This business later on became a part ofthe Belgian corporation DCB, still very active in pharmaceuticals today. The school created by Albert Meurice merged in the fifties with another school that had been created to meet the same needs in the field of the food industries, mainly distilleries and breweries. This merger was done in the frame of the establishment of CERIA. For people in catalysis, ceria stands for cerium oxide, but for those who engineered the concept, CERIA stood for Center of Education and Research for the Food and Chemical Industries.

Due to the worldwide epidemic of acquired immunodeficiency syndrome (AIDS), the past ten years have witnessed a flurry of activity in the chemotherapy of viral diseases. Unprecedented scientific efforts have been made by scientists and clinicians to combat infections of human immunodeficiency virus (HIY), the causative agent. Looking back over the past ten years, we have made remarkable progress toward the treatment of the viral disease: isolation of HIV only two years after the identification of the disease, plus major strides in the areas of the molecular biology and virology of the retrovirus, etc. More remarkably, the discovery of the chemotherapeutic agent AZT (Retrovir) was made within two years after the isolation and identification of the virus, followed by unprecedented drug development efforts to culminate in the FDA approval of AZT in twenty-three months, which was a record-breaking time for approval of any drug for a major disease. The last six to seven years have particularly been an exciting and productive period for nucleoside chemists. Since the activity of AZI' was established in 1985, nucleoside chemists have had golden opportunities to discover additional anti-HIV nucleosipes, which are hoped to be less toxic and more effective than AZT, and the opportunity continues. As we all are aware, AZT possesses extremely potent anti-HIY activity, and no other nucleoside or non nucleoside has surpassed the potency of AZT in vitro."

In response to the tremendous increase in the number of protein and peptide drugs, this treatise critically reviews transport and metabolism mechanisms relating to the delivery of endogenous and recombinant proteins to mammalian organs, tissues, and cells. It will promote fruitful collaboration among academic and industrial scientists in the fields of pharmacology, cell biology, biochemistry, physiology, and immunology.

Cosmetic Science has developed greatly since the publication of the 8th edition of this textbook in 1974. Although the first part of this volume still consists of chapters about product preparations in alphabetical order, each product category has been revised and updated by a specialist. An outline of the biology, structure and function of skin, hair, teeth and nails and the reasons for the need for cosmetics are given in those dealing with the relevant preparations. Throughout, the word Cosmetics includes toiletries and thus all products which protect, cleanse, adorn, and perfume the human body, and combat body odour and perspiration. The 'f' spelling for the element 'sulfur' and its derivatives has been used following the recommendations of the International Union of Pure and Applied Chemistry (IUP AC) and the decision taken by the Royal Society of Chemistry (RSC) and the British Standards Institute (BSI) to use 'f' instead of 'ph' in all their publications. This stems from the derivation of the use of the 'f' from Latin and its use in England until the 15th century.

Trials in the treatment of the leukemias are sometimes based on a hypothesis, as in the case of exchange transfusion [33] or the use of antimetabolites [86]. Or they are conducted empirically as the results of chance observations, as in the case of the use of the nitrogen mustards, urethane, and the Vinca alkaloids. Or they lie between the two, aiming at making use of well established biological facts: examples are the use of ACTH, cortisone and, more recently, the antibiotics. What is true for bacteria may also perhaps be true, if not for elephants, at least for the malignant cells of mammals. It was this idea that lay behind the first attempts at treating cancer and leukemia with antibiotics. The results obtained by the use of certain substances extracted from micro-organisms (actinomycin, azaserine, mito mycin, rufocromomycin), although encouraging at times, were inconsistent. The action of rubidomycin appears to cover a wider spectrum and to be more consistent and more effective. As in the case of Homer and Christopher Columbus, the honor of having given birth to rubidomycin is claimed by more than one country and town. In fact, the same product was discovered in the same year, though quite independently, by a group of French workers [184] who described it under the name of rubidomycin, and by a group of Italian workers [87] who studied it under the name of daunomycin.

Like the previous nine volumes published between 1988 and 1996, "Medicinal" "and" "Aromatic" "Plants X" is unique in its approach. It comprises 22 chapters dealing with the distribution, importance, conventional propagation, micropropagation, tissue culture studies, and the in vitro production of important medicinal and pharmaceutical compounds in various species of "Actinidia," "Alkanna," "Arnebia," "Campanula," "Catharanthus," "Centella," "Chenopodium," "Cornus," "Cynara," "Ephedra," "Euglena," "Haplophyllum," "Morus," "Oenothera," "Otacanthus," "Oxalis," "Polypodium," "Rosmarinus," "Sesamum," "Solanum," "Taxus," and "Tephrosia." This book is tailored to the needs of advanced students, teachers, and research scientists in the field of pharmacy, plant tissue culture, phytochemistry, biochemical engineering and plant biotechnology.

Contents: B. Alcaide P. Almendros: Novel Aspects on the Preparation of Spirocyclic and Fused Unsual -Lactams.- S.S. Bari A. Bhalla: Spirocyclic -Lactams: Synthesis and Biological Evaluation of Novel Heterocycles.- L. Troisi C. Granito E. Pindinelli: Novel and Recent Synthesis and Applications of -Lactams.- C. Palomo M. Oiarbide: -Lactams Ring Opening: A Useful Entry to Amino Acids and Relevant Nitrogen-Containing Compounds.- B. Mandal P. Ghosh B. Basu: Recent Approaches Towards Solid Phase Synthesis of -Lactams.- A.Arrieta B. Lecea F.P. Cossio: Computational Studies on the Synthesis of -Lactams Via [ 2+2] Thermal Cycloadditions.- B. K. Banik I. Banik F. F. Becker: Novel Anticancer -Lactams

Penicillins and cephalosporins have a long history in combating bacterial infections. Despite new infectious diseases and occurring resistance, beta-lactam antibiotics will for many years to come continue to play a prominent role in our therapeutic arsenal. This book covers the industrial development of the chemical and biochemical processes used to manufacture these products, as well as looking ahead to possible future processes. The interplay between synthetic organic chemistry with the understanding and application of enzymes, modeling of fermentation processes and integration through (bio-) chemical process engineering is illustrated. In-depth scientific approaches to biocatalysis and biocatalyst development including enzyme kinetics, enzyme crystal studies and semi-rational enzyme mutations are also presented. Metabolic pathway analysis and modeling of fermentation process are treated as well as molecular precision in synthetic approaches to beta-lactams, their precursors and derivatives. Process technology studies including new reactor concepts, possible short-cut routes and improved down-stream-processing methods complete a broad view on the scope and limitations of the presently developed industrial processes including an intriguing insight into future process possibilities. This book represents an excellent case study on the transformation of traditional, stoichiometric, organic synthesis and classical fermentations into modern (bio-) catalysis and biosynthesis based on insights in metabolic pathways and enzyme actions.

Since 1994, the Phytochemical Society of North America has devoted its annual symposia to topics with biological perspectives. Our last four volumes have dealt with medicinal plants (1994), plant/insect interactions (1995), food phytochemicals (1996), and plant/microbe interactions (1997), respectively. The Symposium held in Pullman, Washington, July 26-31, 1998 brought many aspects of these previous symposia once again to the forefront. This time, however, there was greater emphasis on the potential applications of phytochemistry to the diverse topics of human health and nutrition and plant defense. As we learned about innovative uses of molecular biology as it is being applied to these topics, we were reminded once again of the biochemical th foundation on which these advances rest. On the occasion of the 75 birthday of G.H. Neal Towers, which we were privileged to celebrate, a perspective of where we began and how far we have advanced was made patently real for those in attendance. The papers assembled in this volume were presented during the Sympo- sium. Roughly grouped under three broad topics, they include: I. Drug Discov- ery and Pathway Engineering toward New MedicinallNutriceutical Targets (papers by Cragg, Croteau, Thompson, Costa, McLaughlin, Dixon, and Matern), 2. Roles for Polyphenols-Biosynthesis and Applications (Gross, Hillis, Haslam, and Ferreira), 3. New Chemical Prospects and Plant Defense (Asakawa, Selmar, Houghton, and Mizutani).

Eine grosse Anzahl heterocyclischer Naturstoffe leitet sich vom Ring- system des Piperidins (1) ab. Als Substituenten einfach oder mehrfach substituierter Piperidinbasen finden sich Methyl-, Carboxyl-, Hydroxyl- und Aminogruppen sowie aliphatische Seitenketten unterschiedlicher Lange. Die Substitution erfolgt bevorzugt an den C-Atomen 2, 3 und 6 sowie am Heteroatom. In zahlreichen Fallen ist der Piperidinring in a- oder ss-Stellung direkt oder uber eine C-Brucke mit einem weiteren Heterocyclus verbunden, z. B. einem Piperidin-, Piperidein-, Pyridin-, Indol-, Chinolizidin- oder Furanrest. Daruber hinaus kann der Piperidin- ring zum 2,6-Dioxopiperidin (Glutarimid) oxydiert oder zum Pipendein dehydriert sein. Wahrend Naturstoffe mit Pyridinstruktur im Tier- und Pflanzenreich weit verbreitet sind und einzelnen von ihnen wie NAD oder Pyridoxal- phosphat als Coenzymen des Primarstoffwechsels besondere Bedeutung zukommt, handelt es sich bei den naturlichen Piperidinverbindungen im allgemeinen um sekundare Pflanzenstoffe (vgl. I8, I9I). Dabei sind einige wie z. B. die Pipecolinsaure (7) sporadisch auf verschiedene Pflanzen- familien verteilt. Andere Piperidinbasen wie die Conium- oder Piper- Alkaloide weisen dagegen eine ausgesprochene Artspezifitat auf. Im Gegensatz zu den meisten Pyridinalkaloiden finden sich die Piperidin- basen oft mit strukturell andersartig gebauten Alkaloiden vom Chino- lizidin- oder Trepantyp vergesellschaftet, was in den meisten Fallen durch eine enge biogenetische Verwandtschaft bedingt sein durfte.

Antifolates are an important class of anticancer drugs originally developed as anti leu- kemic agents, but now used, usually in combination with other drugs, for the treatment of a wide range of tumors, notably carcinomas of the head and neck, breast, germ cell tumors, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and osteogenic sar- comas. 5-Fluorouracil and its prodrugs also target, in part, the folate-dependent enzyme, thymidylate synthase. Furthermore, folate supplementation in the form of leucovorin, modulates 5-fluororuacil activity. 5-Fluorouracil is widely used in the treatment of colorectal and gastric cancer and in combination for other solid tumors such as breast and head and neck cancers. Ongoing clinical trials with the newer antifolates suggest that the range of solid tumors where these agents will be of use may broaden further. Half a century ago, interesting scientific and clinical discoveries suggested that folie acid was a vitamin involved in vital cellular metabolic processes. The folate analogs, aminopterin and methotrexate, were synthesized by the American Cyanamid Company in an attempt to interfere with these processes and were shown to have anticancer activity by Farber and his colleagues. Hence, the principle of antimetabolite therapy for the treatment of cancer was established. Biomedical research over the following years led to a deeper understanding of the complex biochemical pharmacology of folates and antifolates. Selective antimicrobial agents were discovered, but more tumor-selective anticancer agents did not immediately emerge.