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Publisher Summary This chapter discusses antibiotics that can be used pharmaceutically in agriculture or in basic research, including chemically related antibiotics, semisynthetic and synthetic derivatives, and analogues. Antibiotics are microbial metabolites possessing antimicrobial, cytotoxic, antitumour, antinematodal, or insecticidal properties. Antibiotics belong to very different groups of organic compounds, but until now, a classification from a chemical point of view has been virtually nonexistent. The samples of various qualities can be applied on to chromatographic columns. They include the filtrates and extracts of fermentation broths, the crude concentrates of antibiotics, partially purified substances, and pharmaceutical preparations. The classical and modern techniques of column chromatography are indispensable tools in the study and preparation of antibiotics. They are used mainly for the following purposes: (1) laboratory and commercial isolation and the purification of antibiotics, (2) the separation of the mixtures of antibiotics, (3) structural studies, (4) studies of the biogenesis and the preparation of labeled antibiotics, (5) studies of the chemical modifications and biotransformations of antibiotics, and (6) purity control.

The mutagenicity and activation requirements of purified synthetic derivatives and potential metabolites of 1-nitropyrene have been characterized in the Ames plate incorporation assay with the Salmonella tester strains TA98, TA98NR and TA98/1,8-DNP 6 , in the presence or absence of exogenous metabolic activation provided by Aroclor-induced rat liver S9. All the compounds tested (1-aminopyrene, N -acetyl-1-aminopyrene, N -hydroxy- N -acetyl-1-aminopyrene, 3-hydroxy-1-nitropyrene, 6-hydroxy-1-nitropyrene, and 8-hydroxy-1-nitropyrene) exhibited mutagenic activity under one or more assay conditions. 1-Nitropyrene was metabolized to 3-hydroxy-1-nitropyrene, 6- or 8-hydroxy-1-nitropyrene, 1-aminopyrene, N -acetyl-1-aminopyrene and other unidentified products (including some bound to protein) by an S9 preparation analogous to that used for exogenous metabolic activation in the Ames assay. 1-Nitropyrene and 3-hydroxy-1-nitropyrene were activated primarily by the ‘classical’ nitroreductase, while the other compounds, particularly in the presence of S9 metabolic activation, were dependent on transesterification for expression of their mutagenicity.

Publisher Summary Interest in studying the effects of structural modification of the naturally occurring steroid hormones upon activity has been evident ever since the elucidation of the structure of the sex hormones in the early 1930s. Emphasis on this particular field of steroid research was the result, first, of a natural curiosity to determine the chemical features essential for the complex hormonal activities of androgens, estrogens, and progestagens, and, secondly, of the very practical consideration of obtaining more desirable agents at lower cost for use in both human and veterinary medicine. Some of the features considered desirable for this purpose were, and still are, peroral effectiveness, high potency, extended duration of action, the separation of anabolic from androgenic and of gonadotropininhibiting from estrogenic activity. It soon became evident that, with the exception of the estrogens, the steroidal sex hormones are highly specific in their dependence of activity upon structure, and that only a limited number of structural variations would result in the retention of any biological activity, not to speak of increases in potency or separation of the physiological components involved.

Die Pflanze beherrscht die Synthese der zur Therapie der Herzinsuffizienz verwendeten Glykoside auch heute noch besser als die Chemiker. Das ist nicht verwunderlich, wenn man bedenkt, das schon die Auflosung einer Doppelbindung oder eine sterische Umlagerung die kardiotone Wirkung weitgehend zum Verschwinden bringen kann. Trotzdem hat es nicht an Versuchen gefehlt, der Natur ins Handwerk zu pfuschen. Ich mochte das mir gestellte Thema von der arztlichen Seite angehen und die Frage stellen, welcher Fortschritt in der Therapie durch die halbsynthetische Abwandlung kardiotoner Glykoside angestrebt werden kann und was bisher auf diesem Wege erreicht wurde.

Publisher Summary This chapter attempts to report progress in antitussive therapy achieved over the past twenty years. The chapter discusses the drugs that have a direct and specific action on the cough reflex, including the opium alkaloids, their synthetic derivatives and substitutes, and newer non-narcotic compounds. Such a classification eliminates adjuvant drugs such as expectorants and antibiotics that are generally used in the treatment of cough-accompanying respiratory disorders. The chapter states that antitussives with a selective anaesthetic activity on the stretch receptors of the lung have been developed. Morphine, codeine, and their derivatives act on central respiratory mechanisms, and codeine is generally accepted as the prototype of antitussives having a central point of attack. The chapter also reviews that the final stage in the development of a new antitussive drug is the clinical evaluation, and discusses whether to use patients suffering from pathological cough or individuals with an experimentally induced cough.

A number of synthetic derivatives of the essential amino acid leucine were tested for biological activity using the growth of rats as the main criterion. Of these, glycyl- l -leucine, acetyl- l -leucine, l -leucine ethyl ester, and l -leucine methyl ester supported growth while caproic acid, phthaloyl- l -leucine, benzoyl- dl -leucine, and carbobenzoxy- l -leucine were found to be inactive. Chloroacetyl- l -leucine actually suppressed growth to a greater degree than a leucine-deficient diet. The N-methyl derivative of leucine was only slightly active. Comparison of the N-acetyl derivatives of l - and dl -leucines indicates that N-acetyl- d -leucine is devoid of any activity.

Publisher Summary This chapter discusses the tropane alkaloids. The rich field of the tropane alkaloids has been investigated intensively in the last five years. The main features of this research work may be summarized: (I) The steric structures of the naturally occurring representatives have been elucidated; (2) the total syntheses of scopolamine, oscine, valeroidine, and dihydrometeloidine serve as conclusive evidence for their structures; (3) the structure suggested for dioscorine in 1950 seems invalidated by more recent experimental facts; (4) a number of synthetic derivatives of the tropeines involving their pharmacological essays have been presented; the problem of biogenesis of the naturally occurring tropanes has been attacked from new angles. The steric course of the reduction of tropinone using a variety of reagents has been extensively studied.

Spider silk and its synthetic derivatives have a light weight in combination with good strength and elasticity. Their high cytocompatibility and low immunogenicity make them well suited for biomaterial products such as nerve conduits. Silk proteins slowly degrade enzymatically in vivo, thus allowing for an initial therapeutic effect such as in nerve scaffolding to facilitate endogenous repair processes, and then are removed. Silks are biopolymers naturally produced by many species of arthropods including spiders, caterpillars and mites. The silk fibers are secreted by the labial gland of the larvae of some orders of Holometabola (insects with pupa) or the spinnerets of spiders. The majority of studies using silks for biomedical applications use materials from silkworms or spiders, mostly of the genus Nephila clavipes. Silk is one of the most promising biomaterials with effects not only in nerve regeneration, but in a number of regenerative applications. The development of silks for human biomedical applications is of high scientific and clinical interest. Biomaterials in use for biomedical applications have to meet a number of requirements such as biocompatibility and elicitation of no more than a minor inflammatory response, biodegradability in a reasonable time and specific structural properties. Here we present the current status in the field of silk-based conduit development for nerve repair and discuss current advances with regard to potential clinical transfer of an implantable nerve conduit for enhancement of nerve regeneration.

Review with 199 refs. Recent studies addressing vancomycin-resistance phenomena are surveyed. Besides leading semi-synthetic glycopeptides: BI-397 and LY 333328, other new synthetic derivs. are also presented. Rational design based on the known mode of action is seen in recent research from both industrial and academic groups. Thus, Biosearch Italia SpA worked on new synthetic glycopeptides with a modified binding pocket in order to find drugs active against both vancomycin-sensitive and -resistant strains. Eli Lilly & Co. and research groups at Stanford, Cambridge and Harvard synthesized covalently linked dimers in order to copy the dimerization and membrane anchoring effects. Both directions proved to be rewarding and some interesting compds. with potent in vitro activity against vancomycin-resistant enterococci (VRE) were found from these investigations. A new mechanistic proposal that can account for the bioactivity of LY 333328 against VRE was summarized. Research on new agents with modes of action different to that of glycopeptide antibiotics have also been successful and recent investigations related to RP-59500, SCH-27899 and U-100766 are presented. [on SciFinder (R)]

Monoterpenes, the major components of essential oils, belong to the group of isoprenoids containing ten carbon atoms. Being widely distributed in the plant kingdom they are extensively used in cuisine and human health care products. Studies have shown that both natural monoterpenes and their synthetic derivatives are endowed with various pharmacological properties including antifungal, antibacterial, antioxidant, anticancer, antiarrhythmic, anti-aggregating, local anesthetic, antinociceptive, anti-inflammatory, antihistaminic and anti-spasmodic activities. Monoterpenes act also as regulators of growth, heat, transpiration, tumor inhibitors, inhibitors of oxidative phosphorylation, insect repellants, feline and canine attractants and antidiabetics. These interesting activities which might be potentially used not only in pharmaceutical, but also food and cosmetic industries are discussed below.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological processes. They represent a typical example of enzyme convergent evolution, as six genetically unrelated families of such enzymes were described so far. It is more than 70 years that synthetic compounds, mainly sulfonamides, have been used in clinical practice as diuretics and systemic acting antiglaucoma drugs. Recent studies using natural product libraries and isolated constituents from natural sources (such as fungi and plants) have disclosed novel chemotypes possessing carbonic anhydrase inhibition activities. These natural sources offer new opportunities in the search for new and more effective carbonic anhydrase inhibitors, and may serve as new leads for the design and development of future drugs. This review will discuss the most recent advances in the search of naturally occurring products and their synthetic derivatives that inhibit the CAs and their mechanisms of action at molecular level. Plant extracts are not considered in the present review.

The majority of functionally important biological processes are regulated by allosteric communication within individual proteins and across protein complexes. The proteins controlling these communication networks respond to changes in the cellular environment by switching between different conformational states. Targeting the interface residues mediating these processes through the rational identification of molecules modulating or mimicking their effects holds great therapeutic potential. Protein-protein interactions (PPIs) have shown to have a high degree of plasticity since they occur through small regions, called hot spots, which are included in binding surfaces or in binding clefts of the proteins and are characterized by a high degree of complementarity. This prompted several researchers to compare the protein structure to human grammar proposing terms like "protein language". The decoding of this language represent a new paradigm not only to clarify the dynamics of many biological processes but also to improve the opportunities in drug discovery. In this review, we try to give an overview on intra-molecular and inter-molecular protein communication mechanisms describing the protein interaction domains (PIDs) and short linear motifs (SLiMs), which delineate the authentic syntactic and semantic units in a protein. Moreover, we illustrate some novel approaches performed on natural compounds and on synthetic derivatives aimed at developing new classes of potential drugs able to interfere with intra-molecular and inter-molecular protein communication.

INVESTIGATIONS of the relationships between the anti-tussive activity and other pharmacological properties of many known drugs1 led us to conclude that local anaesthetic effect was very important in order to predict the antitussive activity of new compounds, especially if this action is accompanied by other pharmacological effects such as the antispasmodic and antihistaminic ones. A systematic investigation was then carried out on new synthetic derivatives possessing local anaesthetic properties in different degrees. The compound N (2-benzoyloxy-methyl-2-phenylbutyl)-N,N dimethylamine (benzobut-amine)2 was found to have the most interesting anti-tussive activity among a series of many other related compounds. Benzobutamine displays local anaesthetic properties and, at the same time, shows antispasmodic, anticonvulsant and antihistaminic effects. In this communication a description of the pharmacological properties of this drug is given.

More than twenty synthetic derivatives of structurally established A-aromatic octahydrophenanthrenes were examined by 13C n.m.r. Empirical observations were made on the experimental chemical-shift trends at C-1, C-6, C-9, and C-10, which are sufficiently characteristic to allow probable assignment of the stereochemistry of the B/C ring junction.

FOR MANY years penicillin has been known to be neurotoxic when injected intrathecally or when applied directly to the brain. 1,2 Yet, few appear to realize that large doses of intravenously administered penicillin may, under certain circumstances, lead to epileptoid convulsions. The current trend to administer penicillin and its synthetic derivatives in ever-increasing doses for treatment of severe infections, or even for prophylactic purposes, exposes some patients receiving such therapy to the hazards of penicillin-induced epilepsy. It would, therefore, seem opportune to report such occurrences in order to increase the awareness of this dangerous complication. We present our experience with five cases in which penicillin had a toxic effect on the cerebrum. Report of Cases Case1.—A 21-year-old man underwent replacement of the mitral and aortic valves with a disposable bubble oxygenator. Total time for cardiopulmonary bypass was 234 minutes. Plasma hemoglobin value at the termination of the extracorporeal circulation