Activity biological

Biological Activity.—2-Amino-4-ethoxycarbonylthiazole and its 2-acyl derivatives possess mitodepressive and mitostatic properties 2-dichloro-acetylamino-4-ethoxycarbonylthiazole is the most effective compound of a series of analogues examined. Certain Schiff s bases derived from 2-amino-5-phenylthiazole and their reduction products show diuretic properties.  

Suzuki, M. Sato, K. Nishikawa, and T. Goto, Tetrahedron Letters, 1969, 4683. 

Henegaru, and Z. GySrfi, Arch. Pharm., 1970, 303, 102. 

Mesionic Hiiazoles.—summary and discussion of the chemistry of mesionic thiazoles has been provided by experts in this field.  

Biological Activity.—5-Ethoxy-3-(trichloromethyl)-l,2,4-thiadiazole controls root rot (caused by Phytophthora cinnamomi) in plants such as Chamaecyparis lawsoniana and Eucalyptus marginata.  

The proof of activity of a biological pesticide is typically evaluated by a standardized bioassay except in the case of microbial metabolites where the major active ingredient(s) may be measured by analytical methods. Biological activity measurements, besides serving as a parameter for quality control, are an essential tool in the product development and optimization process. It is important to define the assay procedure in order to compare production batches and experimental formulations. These assays are typically used for product release or may be designed to assess specific aspects of product activity such as mobility in soils, colonization on leaf surface, etc. 

Data have been reported on the biological activity of AMT and MTX analogues (III.28) and (III.29), as well as on the activity of the 5-Me congeners 

In assays of DHFR and TS inhibition as well as S. faecium and L. casei growth inhibition [32a], (III. 112) and (HI.l 13) proved considerably less active than (III.l 11). In the DHFR assay, potency was decreased 140-fold by 5-Me substitution and 400-fold by 5,10-Me2 substitution. Potency against S.faecium relative to (III.l 11) was decreased 4,200-fold in (III.l 12) and 330-fold in (III.l 13), whereas potency against L. casei was decreased 11-fold in (III.l 12) and 85-fold in (III.l 13). It thus appeared that modification of 

Molecular chirality is most often observed experimentally through its optical activity, which is the elfect on polarized light. The spectroscopic techniques for measuring optical activity are optical rotary dispersion (ORD), circular di-chroism (CD), and vibrational circular dichroism (VCD). 

The measurements are predicted computationally with orbital-based techniques that can compute transition dipole moments (and thus intensities) for transitions between electronic states. VCD is particularly difficult to predict due to the fact that the Born-Oppenheimer approximation is not valid for this property. Thus, there is a choice between using the wave functions computed with the Born-Oppenheimer approximation giving limited accuracy, or very computationally intensive exact computations. Further technical difficulties are encountered due to the gauge dependence of many techniques (dependence on the coordinate system origin). 

The most reliable results are obtained using ah initio methods with moderate-to large-sized polarized basis sets. The use of gauge-independent atomic orbitals (GIAO) removes gauge dependency problems. 

For transition metal complexes, techniques derived from a crystal-field theory or ligand-field theory description of the molecules have been created. These tend to be more often qualitative than quantitative. 

Recent progress in this field has been made in predicting individual atoms contribution to optical activity. This is done using a wave-functioning, partitioning technique roughly analogous to Mulliken population analysis. 

The but-2-enolide (1) and tetronic acid (2) ring systems constitute important structural features in a wide range of biologically important natural products, e.g. vitamin C (222), the cardenolide digitoxigenin (223), and strigol (224), the germination stimulant for the plant parasite Striga (192, 193). Two of the first 4-ylidenebutenolides to be found in natiu-e were protoanemonin (5) and patulin (10). These molecules aroused 

Attention has already been drawn to the desirable odoriferous properties of alkylidenephthalides (13/14) and bovolide (15) and their analogues (p. 136 .. In one isolated report the synthetic ethylidenebuten-olide (226) has been reported to possess carcinogenic properties 200). 

I thank David W. Knight for help in collecting information for this review. 

Naturally Occurring Oxygen Ring Compounds. Butterworths. 1963. 

Recent Advances in the Chemistry of Unsaturated Lactones. Chem. Rev. 76, 625 (1976) idem Chemistry of Butenolides, ibid. 64, 353 (1964). 

The highly specific morphological distribution of the homoisoflavanones in Liliaceae bulbs raised the question of their biological significance. Phenolic compounds have been shown to be widely distributed in waxy surface material of buds (77, 78, 80), leaves (77, 49, 50, 51, 79), 

Recently Ravish and Kirkiacharian 60) have analyzed the effect of a series of natural and synthetic homoisoflavanones on Phytophthora parasitica and on the activity of some of its enzymes. They have found inhibition of in vitro growth and sporogenesis of the microorganism. Enzymatic studies revealed no remarkable inhibition of a polyphenol oxidase or of a- and P-amylases, whereas P-glucosidase and five pectinolytic enzymes (endo PTE/PATE and endo PMG/PG) which are directly involved in the infection mechanism are inhibited to a varying extent. No structure-dependent effects were readily perceptible except that fully methylated compounds seemed to be relatively ineffective. 

Aqueous extracts of the heartwood of Haematoxylon braziletto and H. campechianum were shown to possess antibacterial activity (59). They are bactericidal for Salmonella typhosa and Micrococcus pyrogenes var. aureus and bacteriostatic for Escherichia coli. The active principle has not been identified unequivocally. However it has been suggested that the antibacterial activity is due to brazilin (21) or its oxidation product brazilein (104) which is the actual pigment. Neither the unpigmented sapwood nor the bark of the plant contain the active compound. The comparable hematoxylin derivatives are somewhat less active. 

So far reports of simple homoisoflavanones are restricted to the two genera Eucomis and Scilla, both belonging to the family Liliaceae, subfamily Scilloideae. A preliminary investigation of 28 species from 10 genera of this subfamily revealed that phenolic compounds occur quite commonly in the bulb waxes (Table 10). 

It is interesting to note that the inclusion of Chionodoxa in Scilla based on a close morphological relationship with Scilla bifolia (66) is 

Seawater is a living medium. It has a very high level of biological activity that also contributes to the corrosion resistance of metals (for better or worse). 

Whenever a piece of metal is immersed in seawater, within a few seconds it will be covered by a viscous, biological humour, a so-called zooglea, on which then all the marine matter built up from plants, marine animals, especially molluscs with or without a shell such as barnacles, corals, algae, sponges, etc., will develop. 

It should be recalled that this plant or animal matter would not get fixed on a metal whose salts are toxic for these organisms. This is the case of copper, mercury and tin, which is why the most efficient antifouling paints, nowadays prohibited, were organic salts of copper or mercury. 

Aluminium has no antifouling effect because its salts, including alumina (Al(OH)3), are not toxic for marine organisms. As a consequence, marine biological matter (algae and molluscs) will cover aluminium immersed in seawater very quickly if local conditions allow their growth. 

Corrosion resistance depends on the position of the metal with respect to the sea. It can be immersed, semi-immersed or placed at a certain level above the water. In each case, the environment is different, depending on the exposure, and consequently, the corrosion resistance of the metal may be different. 

Isocoumarins display a very wide range of biological activities. Many fungal isocoumarins exhibit antifungal activity (304), particularly oospolactone (23) (201), cladosporin (86) (253) and 6-methoxymellein (53) (85). 

Mellein (19) causes inhibition of growth of corn seedUngs (90) and has been found recently in several insects. The defensive secretion of termites (41) and Australian onerine ants (52), the mandibular gland secretion of carpenter ants (48) and the male hair pencils of the oriental fruit moth (19) all contain mellein (19). There is no evidence that mellein acts as a sex attractant the insect irritant or insecticidal properties of mellein are implicated (121). 8-Hydroxyisocoumarin (14) and its dihydro derivative (13) are found in the defensive secretion of the tem-brionid beetle, Aspena pubescens (175). 

Among the indolyl bacterial oxazoles 70-72, pimprinine (70) has been reported to be antiepileptic (106). It has also been shown to possess monoamine oxidase inhibitory activity (107). 

Structure-activity studies (116, 117) on virginiamycin Ml (90) have established the importance of the macrocyclic ring and the 13-OH group. Oxidation of the latter resulted in loss of activity, whereas the products of nonstereoselective reduction of the C-15 carbonyl group retained biological activity (116,117). Vir-giniamycins have been demonstrated to enhance lactation in ruminants (118) and to protect HeLa cell monolayers infected with Herpes simplex type I virus (119). 

Alkaloid name Molecular formula Melting point (solvent) (reference) UV, nm (solvent) (reference) 

Antitussive effects (tested on cats) have been reported for MGXs from Rudbeckia [147] and mahony [58]. Comparative tests performed under the same conditions with some drugs used in clinical praxis revealed a significantly higher activity than expressed by the non-narcotic synthetic drugs. 

A small set of steroids prepared from androstanes feature a spirobutyrolactone at C17. These agents act as antagonists of aldosterone, the highly oxygenated steroid that controls serum electrolytes and blood volume. The antagonist action of the spirolactones is manifested as diuretic and antihypertensive activity. 

Reference has already been made in this article to pyrazines with antibacterial, antituberculous, antidepressant, diuretic, pesticidal, and herbicidal activity. A review further illustrates the wide range of biological activities of pyrazine derivatives.432 

Department of Chemistry and Applied Chemistry, University of Salford, Salford, England 

The chemistry of iV-dialkylanilines is, for the most part, predictable. However, the presence of an ortho substituent can give rise to unexpected and interesting reactions of synthetic value. Although such reactions have been reported sporadically during the last 75 years, their usefulness is little appreciated possibly because the relevant observations are buried in the literature. In some cases incorrect structures have been assigned to products arising from such reactions simply because the effect of a /-amino group was not understood. 

The first example of a surprising reaction sequence due to a /-amino effect was observed by Pinnow as early as 1895 during his attempts to prepare the acetyl derivative (3) of o-aminodimethyl-aniline (1) by prolonged reflux in acetic anhydride. He obtained 1,2-dimethylbenzimidazole (2) instead, and on the basis of analogous observations in related reactions he suggested that the formation of 

It is the purpose of this review to collate all the available material relating to the (amino effect and to attempt a rationalization of its operative influence in a mechanistic manner. The cyclizations of ortho-sustituted (-anilines are described in two main sections. The first discusses ring closures between the ortho substituent and the (-nitrogen (4), while the second chapter deals with those ring formations which involve the a-methylene groups attached to the nitrogen (5). 

Almost nothing is known about the physiological role of cyclopeptide alkaloids in plants. The low natural abundance of these compounds (0.0002-1%) and the lack of practical synthetic methods hamper systematic studies on their biological properties. The following activity have been reported. 

In a study of toxicity of Sri Lankan traditional medicinal herbs, Arseculer-atne and co-workers evaluated 125 commonly used medicinal plants for the occurrence of hepatotoxic pyrrolizidine alkaloids (129,130). Crotolaria juncea, C. verrucosa, and Holarrhena antidysenterica were shown to contain pyrrolizidine alkaloids by TLC. When fed to rats, these plants produced hepatic lesions compatible with the action of pyrrolizidine alkaloids. 

Although the endemic species Broussonetia zeylanica (Thw.) has no claims of medicinal applications, when screened, some of its extracts exhibited significant antimicrobial activity against three common pathogenic organisms, Candida albicans, Escherichia coli, and Staphylococcus aureus (15). Bioactivity-guided fractionation led to the isolation of the major antimicrobial alkaloid, 8-hydroxyquinoline-4-carbaldehyde (1), active against C. albicans and S. aureus (17,18). 8-Hydroxyquinoline (oxine) and its derivatives are known to have an array of antimicrobial properties, and a number 

In continuing their evaluation of the medicinal claims of Tabemaemon-tana dichotoma, Perera et al. screened the tertiary alkaloid fraction derived from the stem and root bark of this plant for antimicrobial activity. These were found to have a broad spectrum of activity against Bacillus subtilis, S. aureus, E. coli, C. albicans, and Aspergillus niger (126), justifying the use of aqueous extracts of this plant to heal wounds in traditional medicine (134). Monogagaine (181), a new bisindole alkaloid isolated from T. dicho-toma stem bark, exhibited antibacterial activity against B. subtilis (104). 

Alphabetical List of the Alkaloids Encountered in Sri Lankan Flora 

Alkaloid Name Class Source Plant Part Ref. 

The binding requirements of an enzyme and substrate can be explored by finding the apparent affinity. Km, of modified substrates for the enz3nne. If the modified analog is not a substrate, but an inhibitor, the apparent affinity for the enzyme is given by the inhibitor constant, Ki. 

The series D-galactose, 6-deoxy-D-galactose, 6-deoxy-6-fluoro-D-gaIactose, 

6-chloro-6-deoxy-D-galactose, and 6-deoxy-6-iodo-D-galactose has been 

Competitive Inhibition, and Transport across Cell Membranes 

The discovery that fluorocitric acid is a powerful inhibitor of aconitase led to a search for similar inhibitors. It was in this connection that 6-deoxy- 

Symptoms of intoxication in humans caused by accidental ingestion of Kou-Wen plants have been described as follows. The effect on the digestive system starts with loss of appetite and turn of the stomach, and continues to severe abdominal pain and intestinal bleeding. The effect on the respiratory system presents as breathing difficulties which finally lead to death by respiratory failure. The effect on muscle innervation usually results in generalized muscular weakness and paralysis of the limbs. The effect on the circulatory system starts with heartbeat disorders and a drop in blood pressure, but heart failure is not a common cause of death. In addition to dilation of pupils, a drop in body temperature and proliferation of white blood cells have also been obseryed (70). 

The toxicities of gelsemicine (G), aconitine (A), and pseudoaconitine (P) have been compared (72), and it was found again that the toxicity depends on 

The toxicity of the alkaloids from G. elegans has been studied much less extensively, but it has been found that the toxicity of the principal alkaloid koumine is comparable to that of gelsemine (MLD, 180 mg/kg) (7,25,60). The later isolated compound gelsenicine (humantenmine) proves to be the most toxic of G. elegans alkaloids, the LDS0 being 185 /ig/kg (mice, intra-peritoneal injection) (20). 

Preliminary observation on 16 cancer patients who have been treated with the above-mentioned total alkaloid preparation indicates that symptoms are improved. Thus hepatic cancer patients have claimed disappearance of pain, improvement of appetite, and reduction of ascites patients suffering esophageal cancer claimed to have the self-feeling of relaxation of pain and disappearance of vomiting and upset stomach as well as the improvement of appetite. These preliminary results are quite encouraging, but certainly more extensive investigations are needed before the antitumor action of the Gelsemium alkaloids can be established. 

The order for the Gelsemium alkaloid preparation to be a practical remedy in the chemotherapy of cancers, caution must be paid to the safety problem. Thus, not only should the dosage itself be strictly controlled, but also further investigation of suitable methods of administration as well as the application of combination forms should be initiated. 

Oxazinomycin (l)5 is a 1,3-oxazine antibiotic. There are five other antileukemic antibiotic macrolides of known tetrahydro-l,3-oxazine-2-one structures. Maytansine, Maytanprine, and Maytanbutine were found by Kupchan et a/.278,278 in Maytenus ovatus and Maytenus buchananii, and in Maytenus serrata by Meyers et al.,277 and Calubrinol 

Recently Kupchan et al.219 isolated two Maytansinoids Maytanacine and Maytansinol. They differ from the previously described Maytansinoids by different substituents at C-3, both being without an amino acid residue at that position. Semisynthetic Maytansinoids have also been prepared by esterification of the 3-OH group of Maytansinol. 

Corey and Bock280 designed a synthetic route to Maytansine, and obtained a fragment of the molecule containing the 1,3-oxazine ring. 

Rice281 isolated Leucogenenol, a metabolite of Penicillium gilmanii, and attributed to it the spiro-2H-1,3-oxazine structure (123). It is also found in bovine and human liver.282 

Beginning from 1989, another interesting series of intramolecular organogermane complexes, such as Ge-substituted N-germylmethyllactames, were investigated extensively by Baukov, Pestunovich, Voronkov, Struchkov and others544,545. 

The biological activity of germanium compounds and their influence on the biosphere have been considered in detail in an excellent monograph of Latvian and Russian chemists published in 1990 (in which 767 references are cited86) as well as in earlier reviews by 

Further events in bio-organogermanium chemistry, which was bom soon after bio-organosilicon chemistry547,548, have been described in a monograph86. 

The practical application of organogermanium compounds has been developed since the last quarter of the 20th century. They were used in medicine and agriculture as drugs and biostimulants86,574 as well as in the microelectronic industry to produce thin films of elementary germanium151,152. 

The physiological effects were judged (as a result of some rather amateur experiments on white mice) similar to those of phosgene [1822], but clearly a modern detailed evaluation is required if COBr is to be used more widely. Liver microsomes from phenobarbital 

Department of Organic Chemistry, La Trobe University, Bundoora, Victoria, Australia 

From Acyl Derivatives of a-Amino Acid Esters 

From Cyanohydrins and Aldehydes (Fischer Oxazole Synthesis). 120 

The first review of the chemistry of oxazoles by R. H. Wiley1 was published in 1945 when the parent molecule was still unknown. A significant interest in the chemistry of oxazoles was revived in an effort to synthesize penicillin, when this fascinating antibiotic molecule was thought to contain an oxazole ring. In this way aspects of oxazole chemistry were studied which had received little or no attention before. An extensive coverage of this work8 appeared in 1949. The chemistry of oxazole and its derivatives 

Acheson, Introduction to the Chemistry of Heterocyclic Compounds, 2nd ed. Wiley (Interscience), New York, 1967. 

It was early discovered that ergothioneine could not replace, even partially, the dietary histidine requirement of the growing rat (Eagles and Cox, 1928). Similar negative results have been obtained with thiolhistidine 

In view of the known lipotropic effect of betaine, the activity of ergo-thioneine as a lipotropic agent is of interest. No work has been published, but Best and Ridout (1939) have mentioned that negative results were obtained in unpublished experiments. 

An implication of a different kind of effect on seminal metabolism is made by Haag and MacLeod (1959), who found that an ergothioneine-containing extract of human semen caused a marked depression of sperm motility and glycolysis. However, pure ergothioneine did not produce this 

Ergothioneine is one of several substances which show a protective effect against the degradation of insulin by beef liver enzymes (Williams and Berg, 1956). It is of interest in this connection that the ability of sulfhydryl compounds such as cysteine and glutathione to inactivate insulin in vitro is not exhibited by ergothioneine (Schock et al., 1935). 

The physiological significance of this curious effect is at present imknown. It remains to be determined whether ergothioneine is responsible for the nicotinamide-sensitivity of the DPNases of red cells, spleen, and brain. It may be noted that rat brain contains Uttle or no ergothioneine. The insensitivity of Neurospora DPNase toward inhibition by nicotinamide can be explained by the fact that the procedure used for purification of the enzyme would also remove ergothioneine. W. Feldman in the author s laboratory has found that all of the determinable ergothioneine of N. crassa is apparently present in the mycelial cytoplasm in an unbound form. 

Swainsonine (378) has been found to inhibit unusual metal-dependent cytosolic a-mannosidases found in three very different hyperthermophiHc marine bacteria. These include Thermotoga maritima, which functions best at pH 6 and 80 °C in the presence of cobalt(II) or cadmium(II) the extremely acidophilic archaebacterium Picrophilus torridus (Euryarchaea) which grows optimally at pH 0.7 and 60 and the zinc-dependent 

References to locoweed intoxication in animals have dealt with the tox-icokinetic profile and effects on serum components in sheep fed on O. sericea and other locoweeds the detection and disappearance of the alkaloid 

Some relevant results relating to the discovery of swainsonine (378) in uncommon (mainly Brazilian) plant sources as a result of observed toxicity in goats and other animals that browse on toxic plants have already been 

The neurotransmitter acetyl chohne provides an example of this phenomenon. 

Different conformations of acetylchohne bind different receptors. The gauche conformation binds the muscarinic receptor of postganglionic parasympathetic nerves the anti conformation binds nicotinic receptors at ganglia and the acetylcholine receptor at neuromuscular junctions. 

Cycloalkanes with one ring have the general formula compared with the general formula 

C H(2 2) for acyclic alkanes. Cycloalkanes have two fewer hydrogen atoms than alkanes because another carbon—carbon bond is needed to form the ring. Cycloalkanes are drawn as simple polygons in which the sides represent the carbon—carbon bonds. It is understood that each comer of the polygon is a carbon atom bonded to two hydrogen atoms. 

D-aspartate spacer inhibited adhesion by ca 50% at 10 pM [62]. In the tumor cell invasion assay, 67 slightly inhibited the invasion of A549 cells through an artificial membrane, by 64% at 10 pM. 

As an exact analog of the phytoalexin elicitor branched heptasaccharide 82 the branched SPH 83 was devised with four amide bonds replacing the 1 - 6 linkages of the pentasaccharide backbone and thus producing the same length. No elicitor activity was detected for 83, possibly because of the reduced flexibility or different conformation of the mimetic structure [56]. Mimetics of the sialyl Lewis and sialyl Lewis oligosaccharides have recently foimd increased attention. Baisch and 

Batrachotoxin is among the most toxic substances known to man (see 78 for comparison with other toxins). A lethal dose in mouse is only about 100 nanograms and it has been estimated that in man a lethal dose would be much less than 200 pg (191). Undoubtably cytotoxic effects on heart leading to arrhythmias and cardiac arrest play a dominant role in the toxicity of this 

Tetrodotoxin and saxitoxin, which block the voltage-dependent sodium channels, prevent and actually reverse batrachotoxin-elicited depolarizations. The blockade by tetrodotoxin occurs at a different channel site than that at which batrachotoxin acts. Classical anesthetics, however, would appear to antagonize the action of batrachotoxin through competition for the binding site (50 and references therein). Local anesthetics have been shown to block but perhaps not reverse the action of batrachotoxin in squid axon (79), rat diaphragm (77), eel electroplax (55), frog nerve 160, 765), synaptosomes (706, 179), and neuroblastoma cells (50, 755, 756). 

Batrachotoxin will not cause depolarization in the absence of sodium ions, consonant with its proposed mechanism of action. In denervated muscle, sodium channels develop which are not sensitive to tetrodotoxin but do retain sensitivity to batrachotoxin (8). Batrachotoxin causes a massive release of acetylcholine in neuromuscular preparations. This effect, undoubtedly due to depolarization of the presynaptic terminal, is prevented by tetrodotoxin (25, 149, 269) or by botulinus toxin (236). 

Pretreatment of lobster axons with sulfhydryl reagents such as / -chloromercuribenzene sulphonic acid and dithiothreitol prevent or reduce respectively depolarization elicited by batrachotoxin (77). Such treatment does not prevent stimulus-evoked activation of sodium channels. The results with such sulfhydryl reagents provides evidence for the importance of a protein to the action of batrachotoxin. 

The effects of batrachotoxin in nerve and muscle preparations are often relatively irreversible. This apparent irreversibility probably reflects a slow removal of the alkaloid from tissues because of lipid solubility and because only a small percentage of sodium channels ( 5%) need to be activated to cause and maintain complete depolarization in most electrogenic membranes. The effects of batrachotoxin are readily reversible in neuroblastoma cells (52). 

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CtHjCIjNS, PhC(S)NH2, a herbicide with a high level of biological activity. 

Morphine and its salts are very valuable analgesic drugs but are highly addictive. In addition to suppression of pain, morphine causes constipation, decreases pupillary size and depresses respiration. Only the (-l-)-stereoisoraer is biologically active. They appear to produce their effects on the brain by activating neuronal mechanisms normally activated by... 

Figure Bl.2.11. Biologically active centre in myoglobin or one of the subunits of haemoglobin. The bound CO molecule as well as the proximal and distal histidines are shown m addition to the protohaeme unit. From Rousseau D L and Friedman J M 1988 Biological Applications of Raman Spectroscopy vol 3, ed T G Spiro (New York Wiley). Reprinted by pennission of John Wiley and Sons Inc.

The second application of the CFTI approach described here involves calculations of the free energy differences between conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution [9, 10]. DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen, where D-Pen is the D isomer of /3,/3-dimethylcysteine) and other opioids are an interesting class of biologically active peptides which exhibit a strong correlation between conformation and affinity and selectivity for different receptors. The cyclic form of DPDPE contains a disulfide bond constraint, and is a highly specific S opioid [llj. Our simulations provide information on the cost of pre-organizing the linear peptide from its stable solution structure to a cyclic-like precursor for disulfide bond formation. Such... 

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

The protein folding problem is the task of understanding and predicting how the information coded in the amino acid sequence of proteins at the time of their formation translates into the 3-dimensional structure of the biologically active protein. A thorough recent survey of the problems involved from a mathematical point of view is given by Neumaier [22]. 

Data any observation provides data, which could be the result of a physical measurement, a yes/no answer to whether a reaction occurs or not, or the determination of a biological activity. 

Information if data are put into context with other data, we call the result information. The measurement of the biological activity of a compound gains in value if we also know the molecular structure of that compoimd. 

The work by Hammett and Taft in the 1950s had been dedicated to the separation and quantification of steric and electronic influences on chemical reactivity. Building on this, from 1964 onwards Hansch started to quantify the steric, electrostatic, and hydrophobic effects and their influences on a variety of properties, not least on the biological activity of drugs. In 1964, the Free-Wilson analysis was introduced to relate biological activity to the presence or absence of certain substructures in a molecule. 

In chemoinformatics, chirality is taken into account by many structural representation schemes, in order that a specific enantiomer can be imambiguously specified. A challenging task is the automatic detection of chirality in a molecular structure, which was solved for the case of chiral atoms, but not for chirality arising from other stereogenic units. Beyond labeling, quantitative descriptors of molecular chirahty are required for the prediction of chiral properties such as biological activity or enantioselectivity in chemical reactions) from the molecular structure. These descriptors, and how chemoinformatics can be used to automatically detect, specify, and represent molecular chirality, are described in more detail in Chapter 8. 

The real world is one of uncertainty. Suppose we are carrying out a reaction. We have obtained a product. In the beginning we observe a total uncertainty regarding the molecule. We have no information about its composition, the constitution of the skeleton, its stereochemical features, its physical properties, its biological activities, etc. Step by step, by routine experiments, we collect data. When the acquisition of the structural information is complete there is no uncertainty, at least about its structure. Well, we may not have perfect experiments, so this will require us to reserve space for the missing relevant information. However, it is rather more noise than genuine uncertainty, which, by the way, will never be eliminated. 

The first stage in data acquisition is the identification of the task that is, we have to know what kind of physical properties/biological activities we are going to model. 

Systems can possess different extents of complexity. To measure complexity, the information content of the system can be used. Application of information theory is increasingly finitful for modeling biological activities with regard to the symmetry of molecules. 

Let us outline one of our approaches with the following simple example. Suppose we have a dataset of compounds and two experimental biological activities, of which one is a target activity (TA) and the other is an undesirable side effect (USE). Naturally, those with high TA and low USE form the first subclass, those with low TA and high USE the second, and the rest go into the third, intermediate subclass. 

The most important task of modeling is prediction. The model itself is needed for evaluating the biological activities (and/or physical properties) of compounds, where it is either difficult or costly to measure the activities experimentally. 

Structurally similar molecules are expected to exhibit similar physical properties or, similar biological activities. ... 

To evaluate the performance of the descriptors one needs a database of compoimds for which the biological activities are known, e.g.. either the MDDR or the NCI databases. Queries are selected that are typical of a drug-hke molecule and from therapeutic categories that... 

After an alignment of a set of molecules known to bind to the same receptor a comparative molecular field analysis CoMFA) makes it possible to determine and visuahze molecular interaction regions involved in hgand-receptor binding [51]. Further on, statistical methods such as partial least squares regression PLS) are applied to search for a correlation between CoMFA descriptors and biological activity. The CoMFA descriptors have been one of the most widely used set of descriptors. However, their apex has been reached. 

The HYBOT descriptors were successfully applied to the prediction of the partition coefficient log P (>i--octanol/water) for small organic componnds with one acceptor group from their calculated polarizabilities and the free energy acceptor factor C, as well as properties like solubility log S, the permeability of drugs (Caco-2, human skin), and for the modeling of biological activities. 

For example, the objects may be chemical compounds. The individual components of a data vector are called features and may, for example, be molecular descriptors (see Chapter 8) specifying the chemical structure of an object. For statistical data analysis, these objects and features are represented by a matrix X which has a row for each object and a column for each feature. In addition, each object win have one or more properties that are to be investigated, e.g., a biological activity of the structure or a class membership. This property or properties are merged into a matrix Y Thus, the data matrix X contains the independent variables whereas the matrix Ycontains the dependent ones. Figure 9-3 shows a typical multivariate data matrix. 

The possibilities for the application for neural networks in chemistry arc huge [10. They can be used for various tasks for the classification of structures or reactions, for establishing spcctra-strncturc correlations, for modeling and predicting biological activities, or to map the electrostatic potential on molecular surfaces. 

GAs or other methods from evolutionary computation are applied in various fields of chemistry Its tasks include the geometry optimization of conformations of small molecules, the elaboration of models for the prediction of properties or biological activities, the design of molecules de novo, the analysis of the interaction of proteins and their ligands, or the selection of descriptors [18]. The last application is explained briefly in Section 9.7.6. 

Large data sets such as screening data or results obtained by combinatorial experiments are made up of a large number of data records. Hence a data record may represent a chemical reaction or substance, for example its corresponding variables will define the corresponding reaction conditions or biological activities. Depending on the dimensionality or data type of the information, one-, two-, multidimensional, or specific data types can be identified. 

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

The objective of this study is to show how data sets of compounds for which dif-ferent biological activities have been determined can be studied. It will be shown how the use of a counter-propagation neural networb can lead to new insights [46]. The cmpha.si.s in this example is placed on the comparison of different network architectures and not on quantitative results. 

Rather than making this statement, one should consider first whether the representation of the Y-variablc is appropriate. What wc did here was to take categorical information as a quantitative value. So if wc have, for instance, a vector of class 1 and one of c lass 9 falling into the same neuron, the weights of the output layer will be adapted to a value between 1 and 9, which docs not make much sense. Thus, it is necessary to choose another representation with one layer for each biological activity. The architecture of such a counter-propagation network is shown in Figure 10.1 -11. Each of the nine layers in the output block corresponds to a different MOA. 

However, these results illustrate that the use of a counter-propagation network can lead to new insights when several biological activities arc given. Furthermore, a CPG network can also be applied for studying selectivity between different biological activities. 

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Diverse libraries can be used for lead finding by screening against several different targets. The selected compounds should cover the biological activity space well. 

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