Structure Activity Relationships and Mechanism of Action

In recent years a considerable number of streptonigrin analogs have been synthesized which are primarily on variations of the 5,8-quinoline quinone structure with different substituents at C-2, C-6, and C-7 

However, cultures of E. coli exposed to higher concentrations of streptonigrin exhibited an initial first-order decline in viability, implying that a single hit per cell was lethal and pointed to the bacterial chromosome as the site of action. 

The relevance of these observations to the lethal effect of streptonigrin in vivo on human tumors has not been established. Virtually all work reported during the past decade has focused on the in vitro interaction of streptonigrin with DNA and on the formation and identity of the putative radical(s) responsible for the single strand breaks. 

Hajdu (27) has presented spectroscopic and electrochemical evidence for the formation of 1 1 complexes of streptonigrin with Cu and Zn in each case with the release of one equivalent of proton. The pKa of streptonigrin was lowered 2.3 and 3.3 pKa units in the presence of one equivalent of Zn and Cu, respectively. In acetonitrile solution, reduction of streptonigrin was accelerated in the presence of Cu but was inhibited by Zn. Hajdu suggested that in acetonitrile structure 

The NMR spectrum of the Zn complex of streptonigrin in DMSO-de showed distinct downfield chemical shifts for the COOH, C-2, C-3, C-4, and C-4a resonances (28). The structural significance of these shifts is not clear. 

---

Structure and activity at adrenergic receptors of catecholamines and related compounds, 2, 127 Structure-activity relationships and mechanism of action of antibacterial sulphanilamides and... 

Pate DW (1999) Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Doctoral dissertation. Kuopio University Publications, Kuopio... 

The study of medicinal chemistry gives us hope for future treatment options for hypertension. Knowledge of structure-activity relationships and mechanisms of action foster the development of new medications and administration techniques. Clinicians will have to stay up to date with the new developments in the etiology of the disease state, the molecular bases of the drugs actions, and the pharmacokinetic properties of the drugs to provide the best therapeutic outcomes for patients. 

Since 1946, a series of antibiotic antimycins A (AA, 94-la 94-9) have been isolated from various Streptomyces species [77-80] (Fig. 5). Antimycin A complex, a mixture of derivatives, has been widely used for biochemical studies. As it inhibits the electron transfer of ubiquinol-cytochrome c ox-idoreductase [81], many scientists have investigated their structure-activity relationships and mechanism of action [82-89]. The related deacyl compounds, deisovalerylblastmycin (95a) [90], urauchimycins 95b and 95c [91], and kitamycins 95d and 95e [92] were isolated from Streptomyces species. In addition, the corresponding L-serine derivatives, UK-2A 2D (96a-d) [93] and UK-3A (97) [94], were added to this series. 

Aryl-1.2,4-triazine-3,5-dione are a new class of light activated membrane disrupting herbicides. They are active on both grass and broadieaf weeds at low rates. The synthesis, structure-activity relationships and mechanism of action are presented. 

Ledley, F. D., Mullin, B. R., Lee, G., Aloj, S. M., Fishman, P. H., Hunt, L. T., Dayhoff, M. O., and Kohn, L. D., 1976, Sequence similarity between cholera toxin and glycoprotein hormones. Implications for structure activity relationship and mechanism of action, Biochem. Biophys. Res. Commun. 69 852. 

Benigni, R. and Passerini, L., Carcinogenicity of the aromatic amines from structure-activity relationships to mechanisms of action and risk assessment, Mutation Res. Rev., 511, 191-206, 2002. 

Several naturally occurring triterpenes have been reported to show anti-HIV activity, e.g. betulinic acid, platanic acid, glycyrrhizin, mimusopic acid, gano-deriol and geumonoid.16 20 These active compounds hold the potential to serve as hits or leads for anti-HIV drug development.21,22 The focus of this chapter is bevirimat, the first in a new class of compounds termed HIV maturation inhibitors (Mis). Our discussion covers modification, structure-activity relationship (SAR), mechanism of action studies and clinical trials of bevirimat. 

Cationic polymerizations induced by thermally and photochemically latent N-benzyl and IV-alkoxy pyridinium salts, respectively, are reviewed. IV-Benzyl pyridinium salts with a wide range of substituents of phenyl, benzylic carbon and pyridine moiety act as thermally latent catalysts to initiate the cationic polymerization of various monomers. Their initiation activities were evaluated with the emphasis on the structure-activity relationship. The mechanisms of photoinitiation by direct and indirect sensitization of IV-alkoxy pyridinium salts are presented. The indirect action can be based on electron transfer reactions between pyridinium salt and (a) photochemically generated free radicals, (b) photoexcited sensitizer, and (c) electron rich compounds in the photoexcited charge transfer complexes. IV-Alkoxy pyridinium salts also participate in ascorbate assisted redox reactions to generate reactive species capable of initiating cationic polymerization. The application of pyridinium salts to the synthesis of block copolymers of monomers polymerizable with different mechanisms are described. 

Symposium on structure, activity and clinical applications Fed, Proc. 36, 9-1 [6 (1977). Review of mechanism of action I- Bjbrk, Lf. Lindahl, Mol Cell Biochem. 48, 161-182 (1982) of structure activity relationships and prepn of low mol wt fractions B. Casu, Advan. Carbohyd. Chem. Bio-... 

Abstract Protoberberine alkaloids and related compounds represent an important class of molecules and have attracted recent attention for their various pharmacological activities. This chapter deals with the physicochemical properties of several isoquinoline alkaloids (berberine, palmatine and coralyne) and many of their derivatives under various environmental conditions. The interaction of these compounds with polymorphic DNA structures (B-form, Z-form, H -form, protonated form, triple helical form and quadruplex form) and polymorphic RNA structures (A-form, protonated form, triple helical form and quadruplex form) reported by several research groups, employing various analytical techniques such as spectrophotometry, spectrofluorimetry, circular dichro-ism, NMR spectroscopy, viscometry as well as molecular modelling and thermodynamic analysis to elucidate their mode and mechanism of action for structure-activity relationships, are also presented. 

In this section several recently published studies on the interaction of nonionic surfactants with a variety of biological systems, including enzymes, bacteria, erythrocytes, leukocytes, membrane proteins, low density lipoproteins and membranes controlling absorption from the gastrointestinal tract, nasal and rectal cavities, will be assessed. This is a selective account, work having been reviewed that throws light on structure-activity relationships and on mechanisms of surfactant action. 

Keskin O, Bahar I, Jernigan RL et al. Characterization of anti-cancer agents by their growth inhibitory activity and relationships to mechanism of action and structure. Anti-Cancer Drug Design 2000 15 79-98. 

Trapani G et al Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Curr Med Chem 2000 7 249.[PMID 10637364]... 

The purpose of hazard identification is to evaluate the weight of evidence for adverse effects in humans based on assessment of all available data, ranging from observations in humans and animal data to an analysis of mechanisms of action and structure-activity relationships. Each source of information has its advantages and limitations, which determine the weight of that evidence collectively, the evidence permits a scientific judgement as to whether the chemical can cause adverse effects. 

Woo, Y.T. and Lai, D.Y., Mechanisms of action of chemical carcinogens and their role in structure-activity relationships (SARs) analysis and risk assessment in Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens, Benigni, R., Ed., CRC Press, Boca Raton, FL 2003, pp. 41-80. 

Both cell cultures and animal studies have shown that many of the naturally occurring mono-, sesqui-, di-, sester-, and meroterpenoids as well as retinoids possess potentially chemopreventive activities. Terpenoids are minor but ubiquitous components of our diet, and have the advantage of being non-toxic or relatively non-toxic to humans. More mechanistic-oriented basic research is needed to elucidate the mechanisms of action. Studies of derivatives of these naturally occurring terpenoids are also necessary to elucidate the structure-activity relationship and to guide the development of novel chemopreventive agents. 

ABSTRACT More than 100 abscisic acid (ABA) analogs have been reported so far. Some were synthesized to clarify structure-activity relationships, and others were developed as tools for investigating the molecular mechanism of ABA action. These analogs, especially those that can be useful tools for studying ABA reception and catabolic inactivation, are summarized together with their design concepts, structural properties and bioactivities. 

Tomasic M, Mann L S, Soma L R 1997 Effects of sedation, anesthesia and endotracheal intubation on respiratory mechanics in adult horses. American Journal of Veterinary Research 58 641-646 Trapani G, Altomare C, Liso G et al 2000 Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Current Medicinal Chemistry 7 249-271... 

Su, C-T., Tang, C-P, Chong, M., Shin, Y-S., Liu, C-Y., and Wu, M-T., Quantitative structure-activity relationships and possible mechanisms of action of bispyridinium oximes as antidotes against pinacolyl methylphophonofluori-date, Fund. Appl. Toxicol.,3,271 -277,1983. 

---