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Biomedical subjects

J S Siegel

Publications and source records attributed to J S Siegel.

At least 19 recordsLinked to original sources
PubMed2001

Persistent oxidation dications from twisted fluoranthenes, benzo[k]fluoranthene and dimethyldibenzo[j.l]fluoranthene: charge delocalization mode, tropicity, and formation of novel 8,8'-bifluoranthenyls. An NMR and theoretical study.

First examples of persistent oxidation dications from fluoranthene-PAHs namely 1,3,4,6,7,10-hexamethyl- 2 and 3,4-dichloro-1,6,7,10-tetramethylfluoranthene 3, benzo[k]fluoranthene 6, and 3,6-dimethyldibenzo[j,l]fluoranthene 9 are reported. Charge delocalization mode and tropicity in the resulting nonalternant dications are examined. Quenching of the superacid solutions of the dications resulted in the formation of novel 8,8'-bifluoranthenyls 2a-4a. AM1 was used as an initial guide for dication generation (DeltaDeltaH(f) degrees and ionization potentials) and for probing the structures of the crowded fluoranthene substrates and their bifluoranthenyls. In selected cases, the dications and their neutral precursors were calculated at the B3LYP/6-31G(d,p) level. Charge delocalization mode (difference in NPA charges) and DFT/GIAO-derived NMR chemical shifts were obtained for comparison with experiment; aromaticity was assessed via nucleus independent chemical shift (NICS) calculations.

Fluorenes↗
PubMed2001

Synthesis of oligopyridines and their metal complexes as precursors to topological stereoisomers.

[structure: see text]. Palladium-based carbon-carbon coupling reactions in sequence with halogen-exchange chemistry on a series of heterocycles lead to an efficient synthetic strategy for oligopyridines that bind metal ions such as ruthenium to form coordination racks. The particular structures are designed to form terpyridine subunits for octahedral binding. Reaction of 4,6-diiodopyrimidine produces a "double-bay" terpyridine from which binuclear coordination complexes have been formed.

Journal Article↗
PubMed2001

Quantum mechanical designs toward planar delocalized cyclooctatetraene: a new target for synthesis.

Ab initio and hybrid density functional quantum mechanical computation are applied to the structure and energetics of a series of annelated cyclooctatetraenes. Tetrakis-cyclobuteno, perfluorocyclobuteno or bicyclo[2.1.1]hexeno annelations result in planar structures with distinct exo and endo valence tautomers of the double bonded cycle. The contribution of each basic annelation to the exo/endo relative energy is estimated. An additivity scheme for approximating the energy of a mixed system is developed and compared to the quantum mechanical prediction. Bis bicyclic annelation to the a and d positions creates "valence tautomeric frustration" and strongly perturbs the molecular structure. This phenomenon leads to a general design for a planar cyclooctatetraenes where the "delocalized" diradicaloid state is the minimum energy form. These compounds are seen as excellent targets for chemical synthesis.

Alkenes↗
PubMed2001

Structure/energy correlation of bowl depth and inversion barrier in corannulene derivatives: combined experimental and quantum mechanical analysis.

Synthesis of a series of corannulene derivatives with varying bowl depths has allowed for a study correlating the structure (bowl depth) and the energy of bowl inversion. Substituents placed in the peri positions are repulsive and flatten the bowl, thus causing a decrease in the bowl inversion barrier. Conversely, annelation across the peri positions causes a deepening of the bowl, thus an increase in the bowl inversion barrier. Barriers between 8.7 and 17.3 kcal/mol have been measured, and their structures have been calculated using a variety of ab initio methods. The energy profile of an individual corannulene derivative is assumed to fit a mixed quartic/quadratic function from which an empirical correlation of bowl depth and inversion barrier that follows a quartic function is derived. Structure/energy correlations of this type speak broadly of the nature of enzymatic and catalytic activation of substrates.

Chemical Phenomena↗
PubMed2001

Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain.

Integration of the reverse-transcribed HIV cDNA into the host DNA is a required step in viral replication. The virus-encoded integrase protein catalyzes the initial DNA breaking and joining reactions that mediate cDNA integration. Here, the identification by X-ray crystallography of a small-molecule binding site on the integrase catalytic domain is reported. The small-molecule family studied consists of a core of arsenic or phosphorus surrounded by four aromatic groups. Two arsenic derivatives were visualized bound to integrase. In each case, two molecules bound at symmetry-related sites on the catalytic domain dimer interface. The first compound studied, tetraphenyl arsonium, did not inhibit integrase. However, a synthetic compound substituting a catechol for one of the phenyl rings, dihydroxyphenyltriphenylarsonium, bound to the same site and did inhibit the enzyme. Changes in the vicinity of the catalytic site were seen with the inhibitory compound only, potentially explaining its mechanism of action. Further substituting phosphonium for arsonium yielded a compound with an IC(50) in the low micromolar range. These findings may be useful in designing new inhibitors of integrase, which is at present the only one of the three HIV enzymes for which clinically useful inhibitors are not available.

Amino Acid Substitution↗
PubMed2000

A new class of HIV-1 integrase inhibitors: the 3,3,3', 3'-tetramethyl-1,1'-spirobi(indan)-5,5',6,6'-tetrol family.

Integration is a required step in HIV replication, but as yet no inhibitors of the integration step have been developed for clinical use. Many inhibitors have been identified that are active against purified viral-encoded integrase protein; of these, many contain a catechol moiety. Though this substructure contributes potency in inhibitors, it is associated with toxicity and so the utility of catechol-containing inhibitors has been questioned. We have synthesized and tested a systematic series of derivatives of a catechol-containing inhibitor (1) with the goal of identifying catechol isosteres that support inhibition. We find that different patterns of substitution on the aromatic ring suffice for inhibition when Mn(2+) is used as a cofactor. Importantly, the efficiency is different when Mg(2+), the more likely in vivo cofactor, is used. These data emphasize the importance of assays with Mg(2+) and offer new catechol isosteres for use in integrase inhibitors.

Antiviral Agents↗
PubMed1999

Integration complexes derived from HIV vectors for rapid assays in vitro.

Of three enzymes encoded by HIV-reverse transcriptase, protease, and integrase-only the first two have been exploited clinically as inhibitor targets. Efforts to develop inhibitors of purified integrase protein have yielded many compounds, but none with clinical utility. A different source of integration activity for studies in vitro is provided by replication intermediates isolated from HIV-infected cells. These preintegration complexes (PICs) can direct integration of the endogenously synthesized viral cDNA into an added target DNA in vitro. Despite their authentic activities, assays of PICs have not been widely used due to technical obstacles, particularly the requirement for handling large amounts of infectious HIV. Here, we describe greatly improved methods for producing PICs using HIV-based vectors that are capable of establishing an integrated provirus but not a spreading infection. We also report the development of a PIC integration assay using DNA-coated microtiter plates, which speeds assays of PIC integration in vitro. We used this method to screen a library of chemicals related to known integrase inhibitors and found a new compound, quinalizarin sulfate, that displayed enhanced activity against PICs.

Anti-HIV Agents↗
PubMed1997

Glycolonitrile oligomerization: structure of isolated oxazolines, potential heterocycles on the early earth.

A study of glycolonitrile polymerization has led to the isolation and characterization of two 2,5-dihydro-4-aminooxazoles, 4 and 5. Previous reports have misassigned these structures as s-triazines or pyrimidines. X-ray diffraction analysis of crystals of 4 and an acetylated oxazole derivative of 5 (6) confirm the proposed structures. Ab initio computations are used to assess the relative thermodynamic stability of three trimer isomers (an s-triazine, an aminohydroxypyrimidine, and an aminooxazoline), and the results indicate that 4 is a novel kinetic product. Mechanistic considerations rationalize kinetic oxazole formation over the more customary triazine or pyrimidine trimers.

Acetonitriles↗
PubMed1996

Trends in retirement age in the United States, 1955-1993, by sex and race.

To meet the need for a labor-force-based time series on the average age at retirement differentiated by sex and race, net labor force withdrawal rates (NWR) are calculated on a cohort basis for periods of time. The NWR are used to calculate the medium age of exit from the labor force. From the late 1950s through the late 1980s, declines of about 3-4 years occurred among Black and White women and men. These results are very similar to those obtained from Social Security data. The decline slowed during the 1970s and leveled off during the 1980s and early 1990s. The findings are a valuable addition to the meager knowledge available now about the retirement behavior of women and Blacks. The labor force and the Social Security time series of the average age of retirement are useful, especially in combination, to private and public planners and policymakers.

Black or African American↗
PubMed1993

Retirement quandary: more retirees at younger ages, living longer.

The authors examine trends in age at retirement and life expectancy in the United States. "We used labor-force data from the Current Population Survey...to calculate the percentage change in labor-force participation rates for five-year birth cohorts over a series of five-year intervals.... Using these percentage changes, corrected for mortality during each five-year interval, we calculated the average age at retirement (median age) from the early 1950s to the late 1990s."

Age Factors↗
PubMed1983

Evaluation of N-bromoacetyl-L-thyroxine as an affinity label for the thyroxine (T4)-binding site in human T4-binding globulin.

The T4 analog N-bromoacetyl-L-T4 (BrAcT4) has been investigated as a possible affinity labeling reagent for identification of amino acids located within the T4-binding site in T4-binding globulin (TBG). As shown by fluorescence measurements involving displacement of 8-anilino-1-naphthalene-sulfonic acid from TBG, BrAcT4 is an effective competitor for the T4-binding site in TBG, with an association constant one seventh that of T4. Covalent modification of TBG by BrAcT4 was a slow process; after 48 h at a 10:1 molar ratio of [14C] BrAcT4 to TBG, incorporation of the 14C label reached 0.58 mol/mol protein or 77% of the theoretical value, correcting for 0.25 mol residually bound T4 in the original TBG sample. When [14C] BrAcT4 was reacted with TBG in the presence of T4, a partial inhibition of 25% in the degree of modification was obtained. The low inhibition of incorporation of label in the presence of T4 may be attributed to displacement of T4 from the binding site by BrAcT4 during the 20-h reaction time. To determine the effect of modification of the protein on binding activity, TBG was reacted with [14C]BrAcT4, and the binding capacity of modified TBG was determined by equilibrium dialysis. Three different TBG and three different [14C]BrAcT4 preparations were used. In two experiments, there was no reduction in binding capacity of modified TBG compared to that of control, although 0.6 and 0.48 mol label were incorporated per mol protein. In the third experiment, the decrease in binding capacity of modified TBG was 45% of the expected value. The lack of correspondence between the reduction in binding capacity and the degree of modification indicates that instead of reacting with amino acids within the T4-binding site, BrAcT4 derivatizes amino acids that are near but not actually part of the site. Covalent attachment of BrAcT4 to amino acids outside the T4-binding site places this compound in the category of an exoaffinity labeling reagent with regard to TBG and limits its usefulness for unequivocal identification of amino acids in the protein that participate directly in binding T4.

Affinity Labels↗
PubMed1983

Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock.

Twenty-six consecutive patients in hypovolemic shock were randomized to fluid challenge with 5% albumin (A), 6% hetastarch (H), or 0.9% saline (S) solutions. Fluid challenge consisted of 250 ml of test fluid every 15 min until the pulmonary artery wedge pressure (WP) reached 15 mm Hg. Thereafter, WP was maintained at 15 mm Hg for an additional 24 h with infusions of the same test fluid. Vital signs, hemodynamic and respiratory variables, as well as arterial lactate and colloid osmotic pressure (COP) were monitored according to protocol. Chest x-rays were performed by standardized technique before fluid challenge and at 12 and 24 h of maintenance fluid therapy and were evaluated for evidence of pulmonary edema. Cardiac function and hemodynamic stability were restored by fluid challenge with A, H, and S. Two to 4 times the volume of S as A or H was required to achieve similar hemodynamic endpoints. COP was increased by fluid challenge with A or H but was markedly reduced by fluid challenge with S and throughout the 24-h maintenance period. Fluid challenge resulted in reductions in COP-WP gradient of 62% in the A, 43% in the H, and 125% in the S groups. Resuscitation with S resulted in a significantly higher incidence of pulmonary edema (87.5%) than did resuscitation with A (22%) or H (22%). Urine output was not different among the groups at any time during the study. We conclude that 6% H performs as well as 5% A as a resuscitative fluid and that resuscitation with either of these colloids is associated with a lower incidence of pulmonary edema than is resuscitation with 0.9% S.

Aged↗