Diphenyl ether structure-activity

Wang YW, Liu HX, Zhao CY, Liu HX, Cai ZW, Jiang GB. Quantitative structure-activity relationship models for prediction of the toxicity of polybrominated diphenyl ether congeners. Environ Sci Technol 2005 39 4961-6. 

Francis BM, Metcalf RL. 1984. Structure activity relationships in diphenyl ether teratogenicity. Teratology 29 29A. 

Howie L, Dickerson R. Davis D. et al. 1990. Immunosuppressive and monooxygenase induction activities of polychlorinated diphenyl ether congcrers in C57BL/6N mice quantitive structure-activity relationships. Toxicol Appl Phamiacol 105 254-263. 

Many photobleaching herbicides act by inhibiting the enzyme protoporphyrinogen oxidase (Protox), which catalyzes the last step in common between chlorophyll and heme biosynthesis. Usnic acid shares some structural features in common with these herbicides, such as the diphenyl ether scaffolding. The inhibitory activity of (-)-usnic acid on Protox was similar to that of the herbicide, acifluorfen, (I50 ca. 3 pM). However, these compounds did not displace acifluorfen from its binding site on Protox (data not shown), indicating that this natural product interacts with Protox differently than other photobleaching inhibitors. 

Polychlorinated diphenyl ethers (PCDE) are common impurities in chlorophenol formulations, which were earlier used as fungicides, slimicides, and as wood preservatives. PCDEs are structurally and by physical properties similar to polychlorinated biphenyls (PCB). They have low water solubility and are lipophilic. PCDEs are quite resistant to degradation and are persistent in the environment. In the aquatic environment, PCDEs bioaccumulate. These compounds are found in sediment, mussel, fish, bird, and seal. PCDEs show biomagnification potential, since levels of PCDEs increase in species at higher trophic levels. PCDEs are also detected in human tissue. Despite the persistence and bio accumulation, the significance of PCDEs as environmental contaminants is uncertain. The acute toxicity and Ah-receptor-me-diated (aryl hydrocarbon) activity of PCDEs is low compared to those of polychlorinated di-benzo-p-dioxins (PCDD) and dibenzofurans (PCDF). Due to structural similarity to thyroid hormone, PCDEs could bind to thyroid hormone receptor and alter thyroid function. Furthermore, PCDEs might be metabolized to toxic metabolites. In the environment, it is possible that photolysis converts PCDEs to toxic PCDDs and PCDFs. 

Marine sponges of the genus Dysidea are a rich source of structurally unique and biologically active compounds, including spiro-sesquiterpenes such as spirodysin and dehydroherbadysinolide, furanosesquiterpenes based on the furodysinin and furodysin skeletons, brominated diphenyl ethers, polychlorinated alkaloids and other compounds [99-103],... 

This skewed conformation also imparts further stereospecific characteristics to the hormone T3 which contains only a single outer ring iodine. Because of the restricted rotation about the two diphenyl ether bonds, the chemically equivalent 3 and 5 -iodines are conformationally distinct, giving rise to a distal (away) or proximal (near) conformation (Figure 3). To verify the importance of this conformational feature, numerous structural analogues of triiodothyronine were synthesized (4) in an effort to determine the biologically active conformer of T. ... 

The first nuclear magnetic resonance (NMR) studies of T3 failed to isolate two distinct spectra for the distal and proximal conformers (8). In addition, molecular orbital (MO) calculations predicted a high barrier to internal rotation about the diphenyl ether bonds (j)). These data suggested that there was only one conformer present in solution, presumably distal, since this was shown to be the active form of the hormone. However, the first crystal structure of T3 showed the 3 -I conformation to be proximal (10), inconsistent with available binding and activity data. 

Kodavanti PRS, Ward TR, McKinney JD, et al. 1996a. Increased pH]phorboI ester binding in rat cerebellar granule cells and inhibition of sequestration in rat cerebellum by polychlorinated diphenyl ether congeners and analogs Structure-activity relationships. Toxicol Appl Pharmacol 138 251-261. 

Kato and associates (1978) reported on the acaricidal activity of 4-nitro-diphenyl ethers of the general structures shown below ... 

In this chapter, a rationale of the structure-activity relationships of various series of bioactive secondary metabolites from Indo-Pacific marine invertebrates is reviewed. These include alkaloids, terpenes and polybrominated diphenyl ethers which were subjected to a series of bioassays in search for insecticidal, antibacterial, fungicidal, and cytotoxic lead compounds. From these various biotests, it was observed that the bioactivity of an analogue is not due to general toxicity but rather possesses a degree of specificity on a particular target biomolecule. The relationship between chemical structures and biological activity is related to the specific action of a compound. 

Fig. 9. Structure elucidation of the (M-COj) ion at m/z 170, generated from diphenyl carbonate A, comparing diphenyl ether B, ortho phenyl phenol C, an para phenyl phenol, respectively, by DADI/MIKE Spectrometry and linked scan (E /V = const.) upon coUisional activation - ...

Several chemistries introduced in the 1990s did not conform to the established structure-activity relationships (SARs) of previous chemistries like the diphenyl ethers and the 2,4-dihalo-5-substituted-phenyl heterocycles. Figure 3.13 shows the SARs of 2-fluoro-4-chloro-5-substituted-phenyl heterocycles [5, 64]. These newer developments impacted both the aromatic and the heterocyclic portion of N-phenyl heterocycles. 

Further st udy of the effect of various analogs of thyroxine on the swelling of mitochondria in vitro (Shaw el al., 19,59) has revealed that thyronine derivatives la( king a halogen substitution in cither ring of the diphenyl ether have little or no activity there is a similar structural requirement for... 

The advantage of this synthesis is that it provides both hormones in pure form. The modular construction of the diphenyl ether allows also introducing any substituent at the 3 - and 5 -positions, which is extraordinarily useM for exploring structure-activity relationships. 

Thyroxine and Triiodothyronine. Thyroxine is one of the earliest recognized hormones (isolation in 1915 by Kendall determination of structure and synthesis in 1925 by Harington). It is an iodine-containing aromatic amino acid. The non-iodinated parent compound of thyroxine is called thyronine. The unusual structural feature is the diphenyl ether group. Iodine atoms may be substituted at the positions 3, 5, 3, 5. A few diiodo- and triiodothyronines have physiological significance, especially 3,5,S -triiodothyronine, which is about five times as active as thyroxine itself. 

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