Biomedical subjects
Publications and source records attributed to Hugo E Gottlieb.
A molecular mechanics force field has been developed which accurately reproduces experimental solid state structures and conformer interconversion barriers for a series of sterically congested diaryl and triaryl phosphines and some of their chalcogenide and Cr(CO)5 derivatives.
Fig fruit has been a typical component in the health-promoting Mediterranean diet for millennia. To study the potential health-promoting constituents of fig fruits, six commercial fig varieties differing in color (black, red, yellow, and green) were analyzed for total polyphenols, total flavonoids, antioxidant capacity, and amount and profile of anthocyanins. Using reversed-phase liquid chromatography (RP-LC), various concentrations of anthocyanins but a similar profile was found in all varieties studied. Hydrolysis revealed cyanidin as the major aglycon. Proton and carbon NMR confirmed cyanidin-3-O-rhamnoglucoside (cyanidin-3-O-rutinoside; C3R) as the main anthocyanin in all fruits. Color appearance of fig extract correlated well with total polyphenols, flavonoids, anthocyanins, and antioxidant capacity. Extracts of darker varieties showed higher contents of phytochemicals compared to lighter colored varieties. Fruit skins contributed most of the above phytochemicals and antioxidant activity compared to the fruit pulp. Antioxidant capacity correlated well with the amounts of polyphenols and anthocyanins (R2 = 0.985 and 0.992, respectively). In the dark-colored Mission and the red Brown-Turkey varieties, the anthocyanin fraction contributed 36 and 28% of the total antioxidant capacity, respectively. C3R contributed 92% of the total antioxidant capacity of the anthocyanin fraction. Fruits of the Mission variety contained the highest levels of polyphenols, flavonoids, and anthocyanins and exhibited the highest antioxidant capacity.
Our aim was to study the effects of cucurbitacin glucosides extracted from Citrullus colocynthis leaves on human breast cancer cell growth. Leaves were extracted, resulting in the identification of cucurbitacin B/E glucosides. The cucurbitacin glucoside combination (1:1) inhibited growth of ER(+) MCF-7 and ER(-) MDA-MB-231 human breast cancer cell lines. Cell-cycle analysis showed that treatment with isolated cucurbitacin glucoside combination resulted in accumulation of cells at the G(2)/M phase of the cell cycle. Treated cells showed rapid reduction in the level of the key protein complex necessary to the regulation of G(2) exit and initiation of mitosis, namely the p34(CDC2)/cyclin B1 complex. cucurbitacin glucoside treatment also caused changes in the overall cell morphology from an elongated form to a round-shaped cell, which indicates that cucurbitacin treatment caused impairment of actin filament organization. This profound morphological change might also influence intracellular signaling by molecules such as PKB, resulting in inhibition in the transmission of survival signals. Reduction in PKB phosphorylation and inhibition of survivin, an anti-apoptosis family member, was observed. The treatment caused elevation in p-STAT3 and in p21(WAF), proven to be a STAT3 positive target in absence of survival signals. Cucurbitacin glucoside treatment also induced apoptosis, as measured by Annexin V/propidium iodide staining and by changes in mitochondrial membrane potential (DeltaPsi) using a fluorescent dye, JC-1. We suggest that cucurbitacin glucosides exhibit pleiotropic effects on cells, causing both cell cycle arrest and apoptosis. These results suggest that cucurbitacin glucosides might have therapeutic value against breast cancer cells.
5-Dimethylamino-1-aminoindan undergoes thermal decomposition and reacts with 6-chlorouracil to give 5-indanyl-6-chlorouracil derivative 9. The formation of 9 may be rationalized by a putative mechanism based on the intermediacy of the imminium methide species 8a.
The chemical stability and reactivity of hydroxy-1-aminoindans and their N-propargyl derivatives are strongly affected by the position of the OH group and its orientation relative to that of the amino moiety. Thus, the 4- and 6-OH regioisomers were found to be stable, while the 5-OH analogues were found to be inherently unstable as the free bases. The latter, having a para orientation between the OH and the amino moieties, could be isolated only as their hydrochloride salts. 7-Hydroxy-1-aminoindans and 7-hydroxy-1-propargylaminoindans represent an intermediate case; while sufficiently stable even as free bases, they exhibit, under certain experimental conditions, unexpected reactivity. The instability of the 5- and 7-hydroxy-aminoindans is attributed to their facile conversion to the corresponding, reactive quinone methide (QM) intermediates. The o-QM obtained from 7-hydroxy-aminoindans was successfully trapped with ethyl vinyl ether via a Diels-Alder reaction to give tricyclic acetals 32a,b.
[reaction: see text] In a recent article, we reported on the base-catalyzed rearrangements of dipropargyl selenides, -sulfides, -sulfoxides, and -sulfones that eventually lead to polycyclic aromatic products. In the present work, we report on the first isolation and characterization of the thiophene dioxide intermediates 5b,c from a mild tandem isomerization/cyclization/aromatization of bis(pi-conjugated propargyl) sulfones. Monoallene 2b,c and diallene 3b intermediates were also identified by NMR. A kinetic study of the rearrangement of 1a-c revealed that the unusual facile tandem process is highly dependent on the nature of gamma-substitution.
(13)C DNMR studies of codeine and sinomenine (derivatives of N-Me morphinan) indicated that N-inversion-C-N rotation (NIR) is unusually fast for these substituted piperidines when compared with other N-Me piperidines. Since only broadening, but no signal splitting, was reached at low temperatures and the difference of chemical shifts (Delta delta) for individual conformers with the equatorially and axially oriented N-Me substituent was unavailable, the limits of the NIR barrier for these amines were determined by line shape analysis using Delta delta values provided by ab initio calculations. On the basis of the comparison of experimentally determined (13)C NMR chemical shifts for tropane conformers with the ones calculated at different theory levels for this N-Me piperidine, the B3LYP/6-31G(p)/GIAO level was chosen as a sufficiently accurate method for calculations of Delta delta. By this new "semiempirical" procedure of line shape analysis the NIR barrier for the studied morphinans lies within a 25-27 kJ mol(-1) (6.0-6.5 kcal mol(-1)) range. A low NIR barrier for morphine alkaloids is supposed to be an important factor in the activation of morphine receptor.
Sundry dipropargyloxy disulfides have been successfully prepared, and their rearrangement paths and products have been found to be dependent upon their substitution pattern. Inter alia compounds of two heretofore unknown structure types-10 and 11 on one hand and 14 and 15 on the other-have been obtained and characterized.
A detailed high-field NMR analysis of several acylated tetrahydrobenzazepines, supported by molecular mechanics calculations, indicates that the heterocyclic ring in these compounds exists in a chair conformation, with the carbonyl oriented anti to the aryl moiety in the dominant rotamer. Surprisingly, ring methylenes are typically diastereotopic at room temperature, as the barriers for the process of enantiomerization of the seven-membered ring are much higher than expected. It is shown that ring inversion is correlated (but not concerted) with rotation of the amide moiety, as the carbonyl is forced out of conjugation with the nitrogen in the transition state.
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Octakis(bromomethyl)naphthalene (4) adopts in the crystal a chiral conformation with a helical central naphthalene core and the bromomethyl groups disposed in an alternate up-down "in" arrangement. According to MM3 calculations, this conformation is less stable than the corresponding all alternated "out" form, while B3LYP/LANL2DZ calculations suggest the opposite stability order. The topomerization barrier (16.0 kcal mol(-1)) is ascribed to an enantiomerization process requiring 180 degrees rotation of all the bromomethyl groups and reversal of the helical sense of the naphthalene core.
The hitherto unsolved problem of the origin of the unusually high nitrogen inversion-rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic effect) was examined using the natural bond orbital (NBO) approach. Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers increase smoothly on going from nitrogen-bridged bicyclic systems of a larger ring size to the smaller ring homologous systems. The experimental NIR barriers are reproduced with good accuracy using the MP2/6-31G level of theory. The NBO analysis for these and other azabicycles led to the conclusion that the height of these barriers is mostly determined by the energy of the sigma-orbitals of the C(alpha)(-)C(beta) bonds as well as the nitrogen lone pair. Thus, the bicyclic effect is actually an extreme case of a common C(alpha-)N-C(alpha) tripyramid geometry-NIR barrier dependence for N-bridged bicyclic amines. By establishing the rate-determining role of the C(alpha-)N-C(alpha) tripyramid fragment for NIR, we have derived the first sufficiently accurate quantitative correlations amine geometry-NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines (i.e., for an amine set which also includes the bicyclic effect systems).
The octaethyl triptycenes 7 and 8 were synthesized by Diels-Alder reaction of the octaethylanthracene 4with the corresponding benzynes. Low-temperature NMR spectra of 7 and 8 are consistent with the presence of the fully alternated conformation "a" of C(2) symmetry. However, in the determined crystal structures, the compounds adopt a higher energy conformation with a pair of vicinal ethyls oriented in the same direction.
2,2,6,6-Tetramethyl substituted piperidines with a beta-branched N-alkyl substituent were synthesized by the photoreaction of N-Me precursors with ketones. The main conformation features of these sterically-hindered amines (established by NMR and IR spectroscopy) are a ring in the chair form, an eclipsed conformation for the N-substituent and an intramolecular OH...N bond. High barriers for the geminal substituent topomerization were measured for these piperidines at different temperatures by means of line-shape analysis of the temperature-dependent 13C and 1H NMR spectra. An MM3-derived conformation scheme indicated that, for one of the studied analogues, the rotation of the N-substituent determines a slow topomerization rate. A new mechanism of nitrogen inversion--a concerted hydrogen-bond dissociation/nitrogen inversion process--is considered for hydrogen-bonded amines.
In a recent paper, we reported on the base-catalyzed rearrangement of bis-propargylic sulfoxides that eventually leads to polycyclic products featuring an unsaturated, cyclic substituent such as cyclohexenyl or phenyl. Due to steric constraints, the latter is positioned roughly perpendicularly to the tricyclic core, and in most cases, two rotamers can be observed in the ground state. In the present work, we report on the synthesis and the products of both symmetrical and asymmetrical starting materials. We also measure, by NMR techniques, the rotation rate of the side chain for several such polycyclic sulfoxides. The barriers for this process, which is similar to a biphenyl rotation, are very strongly dependent on the nature of the substrate, ranging between <7 and 21.0 kcal.mol(-1) for sulfoxides with two five-membered rings and two seven-membered rings, respectively. These barriers can be successfully simulated by molecular-mechanics calculations, and the geometries of the transition states are discussed.
Coumarin ester derivatives 1, substituted at C-4 and/or C-12 with alkyl chains, were synthesized and intercalated within DMPC liposomal bilayers. By correlating the 13C chemical shift with medium polarity [E(T)(30)], the relative location of these substrates within the liposomal bilayer was determined. The length of the alkyl chain substituents clearly influences the lipophilicity of the substrates and their location and orientation within the liposome: Superoxide readily saponifies the C-12 esteric linkage of 1, when this reaction site lies in a polar region of the liposome (E(T)(30) > 45 kcal/mol), to give the corresponding 7-hydroxy coumarin derivatives 2. However, when C-12 lies deeper and is hence less available to O(2)(*-), the lactonic carbon C-2, which lies in a shallower region (E(T)(30) = 43-49), is the preferred site for superoxide-mediated cleavage. When coumarin 1 is disubstituted with long chains at both C-12 and C-4, these derivatives lie deep within the bilayer and react only slowly with O(2)(*-). These results indicate there is indeed a correlation between location within the bilayer and substrate reactivity. Contrary to the suggestion of Dix and Aikens (Chem. Res. Toxicol.6:2-18; 1993) superoxide can penetrate deep within the liposomal bilayer. Nevertheless, its concentration drops precipitously (to approximately 16% of what it is near the interface) below E(T) values of 38, thereby precluding substantial reaction with many highly lipophilic substrates. This work also confirms the findings of others that reactions of small oxy-radicals occur within cellular membranes and appear to be of significant biological importance.