Spectra - Activity Relationships

The spectrum of a compound represents the molecular structure in the form of a complex code. Therefore, a relationship may be expected between spectrum and biological activity. Such a spectra-activity relationship assumes that the mechanism of biological activity is similar to the physical and chemical processes which produce spectra. This similarity is at least doubtful and the direct way of structure-activity relationships seems to be more promising. An attempt to correlate mass spectra with biological activity has led to violent replies in the literature. Controversies on this theme made many chemists very suspicious against applications of pattern recognition. 

Ting et. al. C299U reported an attempt to correlate the mass spectra of 30 sedatives and 36 tranquilizers with their biological activity. The inass spectral peak intensities at 30 mass numbers were used for the characterization of the compounds. 83 % of the compounds were classified correctly by the nearest neighbour and mapping showed well separated clusters of sedatives and tranquilizers. 

These examples show that improper use of pattern recognition methods makes it possible to obtain good classification results even for senseless questions. Normally, such effects occur if the number of spectra is a) too small, b) too different in the classes or c) does not exceed significantly the number of dimensions C251]. 

Abe et. at. C23 reported another study on the verification of correlations between mass spectra and biological activity. Several pattern recognition methods have been applied to a set of 17 analgesics and 16 antispasmodics. Predictive abilities of more than 90 % have been obtained by the KNN-method and by the learning machine. A set of 30 features and the leave-one-out-procedure was employed. 

Brent et. al. L221 used mass spectral data to predict biological activities of analogs of trimethoprim by the KNN-method. 

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The generally accepted structure-activity relationships developed in the early work in the quinolone series held that the N-1 substituent needed to be small and aliphatic. This picture was upset in a dramatic way with the discovery of the excellent potency and antimicrobial spectrum of difloxacin (45) and its congeners in which the substituent on N-1 is an aromatic ring. The synthe-... 

Effects of Sesquiterpene Lactones on Seed Germination. Sesquiterpene lactones are common constituents of the Asteraceae but are also found in other angiosperm families and in certain liverworts (31,32). These highly bitter substances exhibit a wide spectrum of biological activities (J 3) which include cytotoxicity, anti-tumor, anti-microbial, insecticidal (34) and molluscicidal (35) properties. Furthermore, they are known causes for livestock poisoning and contact dermatitis in humans (33). Structure-activity relationship studies on sesquiterpene lactones have demonstrated that biological activity frequently depend on the presence of the cr... 

The chemical diversity of pyrrolidine alkaloids indicates a broad spectrum of biological activities, which, however, does not allow, at the present time, structure-activity relationship studies. The available data are inhomogeneous, ranging from investigations of pure compounds to reports of use in folk medecine. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Many structure—activity relationship studies of host defense peptides have also focused on LL-37. Importantly, LL-37 has a broad spectrum of activities within the immune system but has also displayed cytotoxic activities that would diminish the therapeutic application of this peptide. Thus, structure—activity studies of LL-37 have focused on this cytotoxicity. A study by Nagaoka et al has demonstrated that the cytotoxic and hemolytic activities of LL-37 may reside within different regions of the peptide. Using an 18-mer... 

Colletti SL, Myers RW, Darkin-Rattray SJ, Gumett AM, Dnlski PM, Galuska S, Allocco JJ, Ayer MB, Li C, Lim J, Crumley TM, Cannova C, Schmatz DM, Wyvratt MJ, Fisher MH, Meinke PT. (2001) Broad spectrum antiprotozoal agents that inhibit histone deacetylase Strnctnre-activity relationships of apicidin. Part 2. Bioorg Med Chem Lett 11 113-117. 

Over the past few years, the heteroaryl-condensed non-natural carbazoles emerged as a rapidly growing class of compounds because of their broad spectrum of useful biological activities (8,249,873). This relatively new class of non-natural carbazoles with a great variety of heterocyclic systems has been extensively investigated in order to understand the structure activity relationships for the various biological activities (843,874—895). 

In the search for structural diversity, and novel therapeutic agents, unique ring structures like the 1,2,5-thiadiazole have always captured the imagination of chemists. Often, as in the case of timolol (4), the interest is rewarded. In the early 1990s, a simple thiadiazole was appended to a penem in the development of the structure-activity relationships for a series of ) -lactamase inhibitors. The result was enhanced penetration of the bacterial membrane and a broader spectrum of activity versus clavulanic acid <9lJAN33l>. 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

Other P-lactam antibiotics have revolutionized our understanding of the structure-activity relationships in this large group of antibiotics. Thienamycin (9.53), discovered in 1976, is a broad-spectrum antibiotic of high activity. It is lactamase resistant because of its hydroxyethyl side chain but is not absorbed orally as it is highly polar. Unfortunately,... 

Structure-activity relationships can be inferred by comparison of the antibacterial properties of the clinical agents and related compounds. Different acyl side chains can result In significant changes in the antibacterial activity, both with respect to potency and to breadth of spectrum. The highest activities are observed when the aeylaniino side chain at C-7 is a substituted acetic add. Homologation of the acetic add moiety lowers activity dramatically as exemplified by1 the naturally occurring cephalosporins, which all have weak activity. 

Because of the wide spectrum of activity shown by amines, definitive conclusions concerning structure-activity relationships cannot be made at this time. However, studies using single test systems reveal that the most active silylated amines contain the silicon atom in a y position relative to the nitrogen, as shown in partial structures 12 and 13 (55, 56). Some examples of compounds containing these groupings are found in Tables I and II. The silylated benzhydryl ethers (Section II,F) and sila-tranes (Section III,C) also contain this type of grouping. 

As you do this, I hope that you will accept a greater role in your own communities and a more active relationship with the elected public officials who will be making policies concerning hydrogen use, and to make policies with respect to a broad spectrum of other subjects involving scientific questions. 

Within each group evidence that members associate with the same receptor and/or exhibit similar modes of binding may be advanced in greater or lesser extent on the basis of comparative structure-activity relationships and direct assessments of receptor affinities by these means it may also prove possible to classify more specifically some members of the miscellaneous group. Factors governing the spectrum of activity of individual compounds and the definition of pure or mixed agonists-antagonists add a further dimension to the structure-activity analyses. 

The electronic properties of amino acid side chains are summarized in Table 3, and they represent a wide spectrum of measures. The NMR data are derived experimentally (37). The dipole (38), C mull, inductive, field, and resonance effects were derived from QM calculations (15). The VHSE5 (39) and Z3 (25) scales were developed for use in quantitative structure-activity relationship analysis of the biologic activity of natural and synthetic peptides. Both were derived from principal components analysis of assorted physico-chemical properties, which included NMR chemical shift data, electron-ion interaction potentials, charges, and isoelectric points. Therefore, these scales are composites rather than primary measures of electronic effects. The validity of these measures is indicated by their lack of overlap with hydrophobicity and steric parameters and by their ability to predict biologic activity of synthetic peptide analogs (25, 39). Finally, coefficients of electrostatic screening by amino acid side chains (ylocal and Ynon-local) were derived from an empirical data set (40), and they represent a composite of electronic effects. 

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