Ring Conjugation Research Articles

ChemInform Abstract: Synthesis and Biochemical Studies of 7‐Substituted 4,6‐Androstadiene‐3,17‐diones as Aromatase Inhibitors.

AbstractAllylic oxidation of the protected dione (I) yields the androsten‐7‐one (II) which is treated with the organometallics (III).

Synthesis and biochemical studies of 7-substituted 4,6-androstadiene-3,17-diones as aromatase inhibitors

Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful as therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. Several 7 alpha-thio-substituted androstenediones have proven to be potent inhibitors of aromatase in vitro and in vivo. Recent research efforts have focused on designing aromatase inhibitors with both substitution at C-7 and extended linear conjugation in rings A and B of the steroid nucleus. The targeted compounds, 7-substituted 4,6-androstadiene-3,17-diones 4-10, were prepared by the addition of either Grignard or lithium reagents to 3,3:17,17-bis(ethylenedioxy)-5-androsten-7-one (3). Inhibitory activities of the compounds were evaluated in vitro by enzyme kinetic studies employing the microsomal fraction isolated from human term placenta. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-dione analogues are effective inhibitors with apparent Ki's of 60.9-174 nM, while the 7-phenyl analogue exhibited an apparent Ki of 1.424 microM. Thus, several 7-substituted 4,6-androstadiene-3,17-diones were prepared and exhibited good competitive inhibition of aromatase in vitro in human placental microsomes.

Spectroscopic analysis of chlorophyll model complexes: methyl ester ClFe(III)pheophorbides

As models for chlorophyll a (Chl a), methyl ester ClFe(III)pheophorbides (1, pheophorbide a; 2, mesopheophorbide a; and 3, mesopyropheophorbide a) were examined by Fourier transform infrared (FTIR) absorption and resonance Raman (RR) spectroscopy. The infrared (IR) chlorin band above 1600 cm-1, assigned as a Ca-Cm mode (Andersson et al. (1987) J. Am. Chem. Soc. 109, 2908-2916) is shown to be metal-sensitive and responsive to spin state and coordination number for dihydroporphyrins, as well as being diagnostic for the chlorin vs. porphyrin or bacteriochlorin macrocycle. Frequency variations for this metallochlorin IR band thus parallel those of the v10 RR mode of porphyrins in their predictive utility. Qy excitation SERRS spectra of Chl a were compared with Qy excitation RR spectra of 1 and methyl Ni(II)pyropheophorbide a. The data demonstrate that 5-coordinate ClFe(III)pheophorbides are better models for chlorophylls than are ruffled 4-coordinate Ni(II)pheophorbides. Major spectral differences between the three chlorophyll models are associated with the C-9 keto and/or C-10 carbomethoxy vibrational modes. The approx. 1700 cm-1 IR band was formerly assigned solely to v(C = O) of the C-9 keto group. However, this IR feature shifts down to approx. 1685 cm-1 and nearly doubles in intensity when the C-10 carbomethoxy is removed, as for 3. Similar frequency downshifts coupled with intensity increases in the IR are found in the literature on chlorophylls. RR spectra of pheophorbides having the C-10 carbomethoxy group (1 and 2) have bands at both approx. 1700 and approx. 1735 cm-1. However, the C-9 keto v(C = O) mode of pyrophorbins also downshifts to approx. 1685 cm-1, as in the IR spectra. The approx. 1735 cm-1 ester RR mode disappears in the case of pyrophorbins, and is never RR active for nonconjugated esters of porphyrins or chlorins. These data demonstrate an interaction between the C-10 and C-9 carbonyls of phorbins. They also indicate that phorbins tend toward conjugation of the C-10 ester. Biological examples of such conjugation effects have recently been reported, e.g., for the Chl a pi-cation radical (Heald et al. (1988) J. Phys. Chem. 92, 4820-4824). Because the phorbin E ring is the major structural feature distinguishing chlorophylls from non-photosynthetic systems, the participation of the C-10 ester in ring conjugation is suggestive of its biological importance.

Ultraviolet Difference Spectral Studies in the Gamma Radiolysis of DNA and Model Compounds. I. Aqueous Solutions of DNA Bases

Ultraviolet difference spectra of gamma-irradiated, air-saturated aqueous solutions of DNA bases vs. unirradiated solutions of the same bases are shown to be a very sensitive supplemental tool with which to investigate the yields, postirradiation kinetics, and general nature of DNA base radiation products. Irradiated pyrimidines yield difference spectra which are approximately negative mirror-images of the base absorption spectra in the near-UV, indicating loss of ring conjugation. Difference spectra of irradiated purines yield a more complex pattern containing a positive long-wavelength peak, interpreted as radiation-induced extension of conjugation of the pi electron system beyond that of the unirradiated purine. On the basis of the spectroscopic evidence from these studies, 8-hydroxyguanine appears to be the dominant UV-absorbing radiation product in air-saturated guanine solutions with a G-value of 0.3 molec (100 eV)-1. Difference spectral studies provide isosbestic points which can be used in testing proposed radiation products and their yields. Such spectral studies are a rapid, non-invasive, supplemental tool which can be employed in conjunction with other analytical techniques in radiation-chemical studies, and which is one of the few tools able to detect short-lived chemical intermediates observed in oxygenated solutions of irradiated purines.

Graphite in Kupferschiefer (Poland) and its genetic meaning

Graphite forms crystals up to 0.08 mm in size in carbonates or argillaceous carbonates directly under- and overlying black shale. Increased contents of Si, Al, Ca, and K in graphite are related to intercalations of graphite-montmorillonite and less to intercalations of graphite-illite. Quartz and gibbsite are also detected. The formation of graphite was probably a two-stage process: To a less extent the process of dehydrogenesis and conjugation of aromatic rings took place in a reaction with Al, Si, and OH of phyllosilicates producing Al(OH)3 (gibbsite), former H4SiO4 (now quartz), and H2O.

Synthesis and biological activity of some further cyclopenta[a]phenanthrenes.

16,17-Dihydro-11-methoxy-15H-cyclopenta[a]phenanthrene was synthesized by two different routes and tested for carcinogenicity in Tylers Original (TO) and SENCAR strain of mice by repeated application and initiation/promotion regime. 16,17-Dihydro-11-hydroxy-15H-cyclopenta[alpha]phenanthrene was also tested for carcinogenicity in the TO strain by repeated application. Surprisingly with both of these compounds, which lack conjugation in ring D, one of the ingredients essential for biological activity appears to be carcinogenic. It is tempting to speculate whether these compounds undergo metabolic oxidation in the skin at the benzylic C-17 position.

Dipole moment of the intramolecular hydrogen bond. 2-Nitrophenol and its derivatives

Dipole moments of substituted 2-nitrophenols VIa-VIf and substituted 2-nitroanisoles VIIa to VIIf were measured in benzene and dioxan solutions. Infrared spectroscopy confirmed that nitrophenols VI exist either solvent and at different concentrations as non-associated molecules with an intramolecular hydrogen bond. Therefore, the difference between the experimental dipole moment and that calculated from group moments can be attributed to charge redistribution raised by the hydrogen bond. Only a minute part of it may be due to electron transfer through the ring (conjugation of the functional groups) as follows particularly from he comparison with nitroanisoles VII. Nevertheless, the charge transfer, expressed as the vector μH, amounts only 1.7 . 10-30 Cm (at an angle of 138° to the H-O bond), i.e. several times less than observed previously in compounds with more powerful hydrogen acceptors. CNDO/2 and MNDO calculations agree fairly with the gross dipole moments of the compounds investigated but are unable to predict μH, not even as far as its direction is concerned.

A spectroscopic study of the structure of trimethylaroxysilanes

A number of trimethylaroxysilanes of general formula ArOSi (CH3)3 have been studied by the IR, Raman and UV spectroscopy methods and theoretical conformation analysis. The UV spectra of these compounds in the 200–300 nm region are typical for molecules containing an ArO group and consist of bands attributed to the ππ transitions of the oxygen-conjugated benzene ring. This is confirmed by higher 1600 cm−1 line intensity values in the Raman spectra compared to those for the corresponding benzene-monosubstituted compounds. The intensities of the 1600 cm−1 band in the IR spectra of trimethylaroxysilanes were used for the calculation of the OSi(CH3)3 constant as equal to −0.50 ± 0.03. This points to a donating effect of the trimethylsiloxy group on the π-electron system of the benzene ring. There are indications that the molecules of trimethylaroxysilanes in the liquid and solution states have a conformation with the ArOSi dihedral angle not so high as to prevent oxygen-benzene ring conjugation. Theoretical conformational analysis of trimethyl-p-bromophenoxysilane gave a dihedral angle value of 90°. Additional stabilisation of the conjugated conformation (ϑ < 90°) is assumed to occur in the liquid state through the internal field of the medium. A dependence of the 830, 915, and 930 cm−1 band intensities on the dielectric constants of the medium has been found. The internal rotation potential around the CO bond in trimethylaroxysilanes is suggested to have a “smoothed” appearance, that is a torsion vibration with a large amplitude.

Structure and absolute stereochemistry of the sesquiterpene alcohol (–)-myliol: X-ray analysis of the p-bromobenzoate

The structure and absolute configuration of the novel sesquiterpene alcohol, (–)-myliol (C15H22O) have been determined by X-ray analysis of its p-bromobenzoate (III). Crystals of the p-bromobenzoate (III) are triclinic, space group P1, a= 10.37(1), b= 10.20(1), c= 10.39(1)Å, α= 107.8(1), β= 71.6(1), γ= 110.3(1)°, Z= 2, with two independent molecules in an asymmetric unit. The structure was solved by the heavy-atom method, and refined by block-diagonal least-squares to R 0.085 over the 1 956 independent observed reflections. The absolute configuration was determined by the anomalous dispersion effect. The two molecules in the asymmetric unit have similar geometries, and each contains a novel fused 5,3,6,3-tetracyclic ring system. The two cyclopropane rings in this fused ring are in conjugation and the central cyclopropane ring conjugates further with an exo-double bond. The cyclopentane ring in this skeleton has an envelope conformation and the cyclohexane ring is considerably distorted by the two fused cyclopropane rings.

Conjugation of aziridine and benzene rings in a number of p-substituted N-phenylethyleneimines

p-Methyl- and p-halo-substituted N-phenylethyleneimines were synthesized, and their structures were confirmed by their IR, UV, and PMR spectra. It was concluded that the introduction of the indicated substituents into the para position relative to the aziridine ring increases conjugation of the benzene and aziridine rings as compared with unsubstituted N-phenylethyleneimine.

CONJUGATIVE EFFECT OF PYRIDAZINONE RING ON THE COPOLYMERIZABILITIES OF 3(2-SUBSTITUTED)6-METHYLPYRIDAZINONES WITH STYRENE

Abstract Radical copolymerizations of several pyridazinones (I–VI) with styrene (M1) have been carried out. It has been found that plots of log 1⁄r1, against both νc=o and νc=c in the pyridazinone ring gave straight lines, indicating that the reactivity of the double bond in the ring might be affected by the ring conjugation which involves the carbonyl group.

Para‐Conjugation in Aromatic Systems and the Correlation between Mo Bond Order and the Resonance Structures Cheng

AbstractA simple correlation between the MO bond orders and the resonance structures of a π system is proposed. Para conjugation is a resonance structure with parallel arrangement of alternating attractive and repulsive bonds. The results in C5H5−, C6H6 and C77+ clearly show that the para conjugation is very important comparing with the ordinary ring conjugation. The aromatic substitution reactions strongly demomstrates the effect of para conjugation in benzene, naphthalene and anthrance.

The5T2–1A1crossover in some iron(II)–amidine complexes: magnetic properties and Mössbauer spectra

The preparations of the new amidine, N′-(2-pyridylmethyl)picolinamidine (ppa), and two methyl-substituted derivatives (Meppa and Me2ppa) are described and their bischelate complexes with iron- and nickel-(II). Physical properties characterise the metal compounds as the hydrated salts of six-co-ordinate complex ions in which the ligands are terdentate, [M(ligand)2]X2,nH2O (X = univalent anion). Magnetic and Mossbauer measurements show that the ppa complexes of iron(II) exist in a temperature-dependent high-spin ⇌ low-spin equilibrium in accordance with a prediction based on the ligand-field spectra of the nickel(II) complexes. The iron(II) complexes of the substituted ligands are fully high-spin over the temperature range investigated.Electronic and Mossbauer spectra suggest that in the complexes the ligands are stabilised in the tautomeric form which provides for chelate ring conjugation, and that the local symmetry about the metal ion is approximately D2d

Detection of Decomposition and Analytical Interferences in Pharmaceutical Preparations Containing Corticosteroids

Since the blue tetrazolium and phenylhydrazine reagents for corticosteroids react with the intact side chain at C17, and the isonicotinic acid hydrazide method and UV spectro-photometry depend upon conjugation in Ring A at the other end of the molecule, the analytical results by the four methods give information concerning decomposition caused by oxidation of the C17 side chain and by deconjugation in Ring A. Methods are proposed which allow the detection and determination of both acidic and neutral decomposition products. Measurement of the variation of absorbance with time can be used to detect unidentified interferences in the blue tetrazolium, phenylhydrazine, and isonicotinic acid procedures. The extent of interference of several substances which interfere in at least one of the color reactions is reported. Several examples of the use of the proposed methods to detect and determine decomposition and/or interference are given.

Corticosteroid metabolism during the combined administration of ACTH and catecholamines.

Abstract Various doses of epinephrine or norepinephrine were added to ACTH infusions and administered intravenously from 8 A.M. till 4 P.M. to 94 normal men and 51 normal women. Corticosteroids in plasma, red blood cells, and urine were measured. Plasma and red blood cell corticosteroid curves were analyzed by means of an analog computer. The results were compared with those obtained with standard ACTH infusions in 42 normal men and 42 normal women. In men 2 effects were observed: a significant decrease of plasma corticosteroid concentration during and at the end of the infusion when small amounts of catecholamines were added to the ACTS solutions and a significant increase of the plasma corticosteroid concentration with doses at least 5 times larger of catecholamines. Using the analog computer analysis it could be shown that these effects were due to a constant increase in removal rate r when more than 25 ng. per minute per kilogram of catecholamines was added to the ACTH infusion and an increase in production rate p probably due to a contraction of the readily miscible pool when large doses (120 ng. per minute per kilogram) were administered. In women no effect on removal rate, but only the increase in the p factor was found. The increase in free corticosteroid removal rate observed in men is not due to an accelerated A ring hydrogenation and conjugation of the corticosteroids or to an additional storage of corticosteroids in the red blood cells. Neither is an increased conversion of cortisol to cortisone the cause of the observed phenomenon. The sex difference noted during the combined administration of ACTH and catecholamines might explain certain of the sex differences in stress-induced pathology.

Study of Organic Scintillators

The scintillation counting behavior of a group of fifty-five pure crystalline organic compounds has been extensively studied. The data obtained have been analyzed with the goal of developing a better understanding of the scintillation process and of scintillator behavior. The materials were carefully purified, and massive crystals were grown. Relative scintillation average-pulse-height efficiencies at 30°C and —70°C for cobalt-60 gamma-ray excitation, gamma-ray excited scintillation decay times, and 2537 A ultraviolet-excited reflection and transmission photofluorescence spectra have been determined. A few solutions were also studied for comparison purposes. The purification and properties of the different materials are discussed in detail. The experimental data have been analyzed on the basis of Birks' photon cascade theory of the scintillation process. The ratio of the scintillation efficiency to the integrated photofluorescence intensity is shown to be a measure of Birks' primary photon production efficiency. The primary photon efficiencies vary over a relatively narrow range, so that there is a rough general correlation between the scintillation efficiencies and the integrated photofluorescence intensities. The best phosphors are those with rigid molecular and crystal bonding so that both the primary photon production and photofluorescence efficiencies are reasonably high. There is a tendency for the best scintillators to have the simplest and most sharply defined photofluorescence spectra. The scintillation efficiencies have been correlated with molecular structures and the mobility of the π electrons (or with the resonance interactions) within the molecules. In the simpler cases, consideration of singly charged quinoid structures permits the calculation of parameters which can be directly correlated with the scintillation efficiencies. In more complex cases, steric hindrance, hyperconjugation, ``unshared'' and ``nonbonding'' electron pairs, five-membered aromatic rings, heavy atom (triplet-state) effects, and quinoid (quenching) ground states must be considered. In all cases, the effects of thermal (vibrational) perturbations are present. ``Bond density'' and ``bound valence'' values have proved to be useful in correlating scintillation phenomena and molecular structure effects. Strongly colored compounds are usually poor scintillators. Earlier predictions of high scintillation efficiency for quinquephenyl and sexiphenyl are reaffirmed, and coronene, benzo[ghi]-perylene, and 1,2,5,6-dibenzanthracene are also predicted to be significantly better than the presently known organic scintillators. The further study of compounds containing five-membered aromatic rings appears promising. A generally good correlation has been found between the scintillation efficiencies and molecular diamagnetic anisotropy values. Some relationships between the scintillation decay times and the molecular structures can also be seen. The best crystalline organic scintillators are colorless substances of high melting point possessing molecules of simple structure and low atomic number in which there is extensive resonance conjugation of rings, ethylenic double bonds, and other groups to give extended, rigidly interlocked systems.