Effect of acyclic nucleoside phosphonates on the HIV-1 integrase in vitro.

Integrase (IN) is an essential enzyme in the human immunodeficiency virus type-1 (HIV-1) replication cycle and, thus, a potential target for chemotherapeutic agents. Because various nucleotide analogues have been reported to inhibit IN in vitro, we investigated the effect of acyclic nucleoside phosphonates. Both unphosphorylated and diphosphorylated derivatives were inhibitory to IN at concentrations ranging between 60 and 800 microM, with diphosphorylated derivatives being 5- to 8-fold more potent than unphosphorylated counterparts.     

Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: synthesis,structure-activity relationship analysis,and biological activity

Four series of forty-five nitrogen-containing polyhydroxylated aromatics based on caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase (IN) inhibitors. Most of these compounds inhibited IN catalytic activities in low micromolar range. Among these new analogues, compounds 9e and 9f were the most potent IN inhibitors with IC₅₀ value of 0.7 μM against strand transfer reaction. Their key structure-activity relationships were also discussed.     

Cultural diversity and schooling

Ashley H. Robins, BIOLOGICAL PERSPECTIVES ON HUMAN PIGMENTATION, (Cambridge Studies in Biological Anthropology, 7), Cambridge: Cambridge University Press, 1991, xiii + 253 pp., £37.50.

Ulfried Geuter, THE PROFESSIONALIZATION OF PSYCHOLOGY IN NAZI GERMANY. Cambridge Studies in the History of Psychology, Cambridge: Cambridge University Press, 1992, v‐xxi + 335 pp., npl.

Clare Midgley, WOMEN AGAINST SLAVERY. THE BRITISH CAMPAIGNS, 1780–1870, London: Routledge, 1992, xii + 281 pp., £37.50.

Maryinez Lyons, THE COLONIAL DISEASE: A SOCIAL HISTORY OF SLEEPING SICKNESS IN NORTHERN ZAIRE, 1900–1940, Cambridge: Cambridge University Press, 1992, xvi + 335 pp., £50.00.

Wim van Binsbergen, TEARS OF RAIN: ETHNICITY AND HISTORY IN CENTRAL WESTERN ZAMBIA, London and New York: Kegan Paul International, 1992, 495 pp., £45.00.

Albert B. Robillard (ed.) SOCIAL CHANGE IN THE PACIFIC ISLANDS, London: Kegan Paul International, 1992, xvi + 507 pp., £45.

Sarah Radcliffe and Sallie Westwood (eds) ‘VIVA’: WOMEN AND POPULAR PROTEST IN LATIN AMERICA, London: Routledge, 1993, 270 pp., £12.99 pb; £40.00 hb.

Cindi Katz and Janice Monk (eds) FULL CIRCLES: GEOGRAPHIES OF WOMEN OVER THE LIFECOURSE, London: Routledge, 1993, 317 pp., £12.99 pb; £40 hb.

Hans van Amersfoort and Hans Knippenberg (eds), STATES AND NATIONS. THE REBIRTH OF THE ‘NATIONALITIES QUESTION’ IN EUROPE, Netherlands Geographical Studies 137, Amsterdam: Koninklijk Nederlands Aardrijkskundig Genootschap, 1991, 189 pp., Dfl. 29.50.

Elizabeth D. Huttman, Wim Blauw and Juliet Saltman (eds), URBAN HOUSING SEGREGATION OF MINORITIES IN WESTERN EUROPE AND THE UNITED STATES, Durham, NC: Duke University Press, 1991, xiii + 431 pp., npl.

Roger Daniels, Sandra C. Taylor, and Harry H. L. Kitano (eds) JAPANESE AMERICANS: FROM RELOCATION TO REDRESS, Seattle, WA: University of Washington Press, 1992, 264 pp., $17.95 US (paper only).

David J. O'Brien and Stephen S. Fugita, THE JAPANESE AMERICAN EXPERIENCE, Bloomington and Indianapolis: Indiana University Press, 1991, 178 pp., £8.99 (paper).

Paul James Rutledge, THE VIETNAMESE EXPERIENCE IN AMERICA, Bloomington and Indianapolis: Indiana University Press, 1992, 173 pp., npl.     

Book reviews

Stephen Cornell, THE RETURN OF THE NATIVE: AMERICAN INDIAN POLITICAL RESURGENCE, New York and Oxford: Oxford University Press, 1988, 278 pp., $29.95.

Jack D. Forbes, BLACK AFRICANS AND NATIVE AMERICANS: COLOR, RACE AND CASTE IN THE EVOLUTION OF RED‐BLACK PEOPLES, Oxford and New York: Basil Blackwell, 1988, 334 pp., £35.00.

Maryon McDonald, ’WE ARE NOT FRENCH!’: LANGUAGE, CULTURE AND IDENTITY IN BRITTANY, London: Routledge, 1989, 384 pp., £40.00.

Ronald Grigor Suny, THE MAKING OF THE GEORGIAN NATION, London: I. B. Taurus and Co. Ltd., 1989, ix‐395 pp., £29.50.

Shlomo Deshen, THE MELLAH SOCIETY: JEWISH COMMUNITY LIFE IN SHERIFIAN MOROCCO, translated and revised from the Hebrew by the author. Chicago: The University of Chicago Press, 1989, xii + 152 pp., £23.95 and £9.50 (paper).

Roger Waldinger, Howard Aldrich, Robin Ward and Associates, ETHNIC ENTREPRENEURS: IMMIGRANT BUSINESS IN INDUSTRIAL SOCIETIES, Sage Series on Race and Ethnic Relations, vol. 1., Newbury Park, CA: Sage Publications, 1990, 226 pp., £29.25 and £13.95 (paper).

Saul Dubow, RACIAL SEGREGATION AND THE ORIGINS OF APARTHEID IN SOUTH AFRICA, 1919–36, St Antony's and Macmillan, London, 1989, xi and 250 pp., £35.00.

Mark Duffield, BLACK RADICALISM AND THE POLITICS OF DE‐INDUSTRIALISATION: THE HIDDEN HISTORY OF INDIAN FOUNDRY WORKERS, Avebury, 1988, 226 pp., £24.50.

John Eade, THE POLITICS OF COMMUNITY: THE BANGLADESHI COMMUNITY IN EAST LONDON, Avebury, 1989, 213 pp., £24.00.

Nicole Hahn Rafter (ed.), WHITE TRASH: THE EUGENICS FAMILY STUDIES 1877–1919, Boston: Northeastern University Press, 1988, 382 pp., £36.00.

Neil R. McMillen, DARK JOURNEY ‐ BLACK MISSISSIPPIANS IN THE AGE OF JIM CROW, Urbana, Ill: University of Illinois Press, 1989, N.P.L.     

Book reviews

John B. Boles (ed.), MASTERS AND SLAVES IN THE HOUSE OF THE LORD: RACE AND RELIGION IN THE AMERICAN SOUTH, 1740–1870, Lexington, KY: The University of Kentucky Press, 1988, 257 pp.

David E. Swift, BLACK PROPHETS OF JUSTICE: ACTIVIST CLERGY BEFORE THE CIVIL WAR, Baton Rouge, Louisiana, LA: Louisiana State University Press, 1989, xv + 384 pp., £31.50.

Alexander B. Murphy, THE REGIONAL DYNAMICS OF LANGUAGE DIFFERENTIATION IN BELGIUM: A STUDY IN CULTURAL‐POLITICAL GEOGRAPHY, Chicago, IL: University of Chicago, Geography Research Paper No. 227, 1988, xiii + 249 pp., $12.00.

Pierre L. van den Berghe, STRANGER IN THEIR MIDST, Denver, CO: University Press of Colorado, 1989, xvii + 300 pp., $24.95.     

The contribution of peroxynitrite generation in HIV replication in human primary macrophages

Background

The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA) derivatives active on the HIV-1 IN strand transfer (ST) step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR) reversing ability.

Results

The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells.

Conclusion

To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.     

Review essay: Nationalism,the past and the present: The case of Sri Lanka

Jonathan Spencer, A SINHALA VILLAGE IN A TIME OF TROUBLE. POLITICS AND CHANGE IN RURAL SRI LANKA, Delhi: Oxford University Press, 1990, 285pp., NPL.

Jonathan Spencer (ed.), SRI LANKA. HISTORY AND THE ROOTS OF CONFLICT, London: Routledge, 1990, 253pp., £35.00.

Manning Nash, THE CAULDRON OF ETHNICITY IN THE MODERN WORLD, Chicago: The University of Chicago Press, 1989, 142pp., $8.95.     

Caecal parameters of rats fed diets supplemented with inulin in exchange for sucrose

Abstract

The effects of different modes of inulin supplementation on caecal fermentation were evaluated in rats. Groups S and IN were fed diets containing 5% of sucrose or inulin, respectively, for the whole experimental period of 40 days. Group IN/S was fed IN and S diets, whereas group S/IN was fed S and IN diets, in the first and the second 20-day period, respectively. Groups IN_up and IN_down were fed diets in which the content of inulin increased from 1 – 5% and decreased from 5 – 1%, every 8 days, respectively. The common effects of inulin on caecal fermentation, i.e. enlargement of tissue, acidification of digesta, a decrease in activities of potentially harmful bacterial enzymes (β-glucuronidase and β-glucosidase), and an increase in the total volatile fatty acids concentration and pool, were especially observed in the IN, S/IN and IN_up groups. The results suggested that the intensity of caecal fermentation is increased when inulin is present at a relatively high dietary level and that these changes are easily reversible after inulin withdrawal from feed.     

Effects of cyclic AMP and fluoride on phosphorylation of ribosomal protein S6 and on protein synthesis in rabbit reticulocytes

The effects of N6,O2-dibutyryl-adenosine 3',5'-monophosphate (Bt2cAMP) and sodium fluoride on the phosphorylation of ribosomal proteins S6 and on protein synthesis were examined. Rabbit reticulocytes were incubated in a nutritional medium containing 32Pi in the presence and absence of Bt2cAMP (1mM) and 3-isobutyl-1-methyl-xanthine (1mM). In the control cells, four phosphorylated derivatives of S6 were observed, with most of the radioactivity in the monophosphorylated form. Upon addition of cyclic nucleotide, a twofold increase in the phosphorylation of ribosomal protein S6 was observed. This was accompanied by an increase of radioactive phosphate in the diphosphorylated derivative. No alteration in protein synthesis was observed upon addition of cAMP and analogues of cAMP in conjunction with 3-isobutyl-1-methyl-xanthine or theophylline. The effects of sodium fluoride on phosphorylation of S6 and on protein synthesis were examined also. At 5 mM sodium fluoride, protein synthesis was inhibited by 85%. A 2.5-fold increase in the phosphorylation of ribosomal protein S6 was observed with an accumulation of 32Pi in the diphosphorylated, triphosphorylated and tetraphosphorylated derivatives. Inhibition of protein synthesis coincided with an increase in the more highly phosphorylated derivatives, whereas an increase of radioactive phosphate in the diphosphorylated derivative could not be correlated with an alteration in globin synthesis.     

Peptide inhibitors of HIV-1 integrase: From mechanistic studies to improved lead compounds

The HIV-1 integrase enzyme (IN) catalyzes integration of viral DNA into the host genome. We previously developed peptides that inhibit IN in vitro and HIV-1 replication in cells. Here we present the design, synthesis and evaluation of several derivatives of one of these inhibitory peptides, the 20-mer IN1. The peptide corresponding to the N-terminal half of IN1 (IN1 1–10) was easier to synthesize and much more soluble than the 20-mer IN1. IN1 1–10 bound IN with improved affinity and inhibited IN activity as well as HIV replication and integration in infected cells. While IN1 bound the IN tetramer, its shorter derivatives bound dimeric IN. Mapping the peptide binding sites in IN provided a model that explains this difference. We conclude that IN1 1–10 is an improved lead compound for further development of IN inhibitors.     

In vitro inhibition effect of some coumarin compounds on purified human serum paraoxonase 1 (PON1)

Human serum paraoxonase 1 (PON1; EC 3.1.8.1) is a high-density lipoprotein associated, calcium-dependent enzyme that hydrolyses aromatic esters, organophosphates and lactones and can protect the low-density lipoprotein against oxidation. In this study, in vitro effect of some hydroxy and dihydroxy ionic coumarin derivatives (1–20) on purified PON1 activity was investigated. Among these compounds, derivatives 11–20 are water soluble. In investigated compounds, compounds 6 and 13 were found the most active (IC₅₀?=?35 and 34?µM) for PON1, respectively. The present study has demonstrated that PON1 activity is very highly sensitive to studied coumarin derivatives.     

Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75

HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their β-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3′/4′-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC₅₀ = 0.826 μg/mL) and high therapeutic index (TI > 242). More significantly, these hydroxyflavones block the IN–LEDGF/p75 interaction with low- to sub-micromolar IC₅₀ values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein–protein interaction domains.     

Nucleosides. Part 3.1 Synthesis of 2-N-Substituted 1-β-D-Arabinofuranosylisocytosine Derivatives by The Reaction of 2′,5′-Dichloro-2′,5′-Dideoxyuridine with Amines

Abstract

Reaction of 2′,5′-dichloro-2′,5′-dideoxyuridine (1) with ammonia and benzylamine afforded the corresponding 2-N-substituted 1-(5-chloro-5-deoxy-β-D-arabinofuranosyl)-isocytosine derivatives (2 and 10). Reaction of 1 with ammonia, methylamine, cyclohexylamine, and benzylamine followed by treatment with methanolic sodium methoxide gave the corresponding 2-N-substituted 1-(2,5-anhydro-β-D-arabino-furanosyl)isocytosine derivatives (6, 11, and 12).     

Dose-dependent effects of two inulin types differing in chain length on the small intestinal morphology,contractility and proinflammatory cytokine gene expression in piglets

ABSTRACT

Inulin is a linear fructose polymer which may affect small intestinal physiology. The effects of dietary level of two inulin types on morphology, contractility and proinflammatory cytokine gene expression in the small intestine of piglets were investigated. Fifty six piglets were divided into seven groups fed diets without inulin addition or with 1%, 2% or 3% of inulin with an average degree of polymerisation of 10 (IN10) or 23 (IN23). All diets were offered from day 10 of life for 40 d. Feeding IN10 diets did not affect villous height to crypt depth ratio in the duodenum, while in the jejunum the 2% IN10 diet increased it as compared to other groups. Jejunal muscle contractions induced by electrical field stimulation were impaired by the 2% and 3% IN10 diets. The ileal expression of interleukin-12p40 was decreased by the 2% IN10 diet. There was no effect of IN23 level on villous height to crypt depth ratio in any segment of the small intestine as well as on jejunal motility. The 2% and 3% IN23 diets decreased the jejunal expression of tumour necrosis factor-α. In conclusion, IN10 is more active in the small intestine than IN23. At the 2% dietary level, it increases absorptive area in the jejunum, but may slightly impair smooth muscle contractions.     

America's paradox

Michael C. Dawson, BEHIND THE MULE: RACE AND CLASS IN AFRICAN‐AMERICAN POLITICS, Princeton, NJ: Princeton University Press, 1994, xii + 234pp., (paper) npl.

Paula D. McClain and Joseph Stewart Jr., ’CAN WE ALL GET ALONG?’: RACIAL AND ETHNIC MINORITIES IN AMERICAN POLITICS, Boulder, CO: Westview, 1995, xv + 208pp., £33.50 and £9.50 (paper).

Joe E. Feagin and Hernán Vera, WHITE RACISM: THE BASICS, New York: Routledge, 1995, xiv + 230pp., £12.99 (paper).     

Synthesis and anti-cancer activity evaluation of new aurone derivatives

Abstract

In this study, we have synthesized 2-[3- or 4-(2-aryl-2-oxoethoxy)arylidene]benzofuran-3-one derivatives (D1–D38) and evaluated their anti-cancer activities. The final compounds were obtained in multistep synthesis reactions using benzofuranon-3-one derivatives (A1–A4, B) as starting materials which were gained in various synthetic ways. Aurone derivatives (C1–C10) were acquired with the condensation reaction of these starting materials and 3-/4-hydroxybenzaldehyde which were then reacted with α-bromoacetophenones to get final compounds. The anti-cancer activity of the selected compounds was performed by National Cancer Institute (NCI), USA against 60 human tumor cell lines derived from nine neoplastic diseases. Compounds exhibited anti-cancer activity in varying ratios.     

A theoretical study of substituent effects on tautomerism of 2-hydroxybenzimidazoles

The geometries, relative stabilities of some 4(7) and 5(6) substituted 2-hydroxybenzimidazole derivatives were calculated with full geometry optimization using AM1 and PM3 in aqueous phase. With the exception of molecules 4, 6 and 7 for all the 4(7) and 5(6) substituted 2-hydroxybenzimidazole derivatives the 3H and keto forms were found to be favored.     

Facile Synthesis of N-(1-Alkenyl) Derivatives of 2,4-Pyrimidinediones

Abstract

N-(1-alkenyl) derivatives of 2,4-pyrimidinediones (6–9) were prepared in a one pot synthesis from aldehydes and the nucleobases using trimethylsilyl trifluoromethanesulfonate (TfOTMS) as coupling reagent. Presilylation of the above nucleobases, and N ⁶-benzoyladenine, with excess N,O-bis(trimethylsilyl)acetamide (BSA) followed by addition of one mol eq. TfOTMS yielded the N-(1-trimethylsilyloxyalkyl) derivatives 1–5.