Acyclonucleoside Iron Chelators of 1‐(2‐Hydroxyethoxy)methyl‐2‐alkyl‐3‐hydroxy‐4‐pyridinones: Potential Oral Iron Chelation Therapeutics

The method of synthesizing acyclonucleoside iron chelators is both convenient and cost effective compared to that of synthesizing ribonucleoside iron chelators. The X‐ray crystal structural analysis shows that the 2‐hydroxyethoxymethyl group does not affect the geometry of the iron chelating sites. Therefore, the iron binding and removal properties of the acyclonucleoside iron chelators should remain similar to the ribonucleoside iron chelators, which is confirmed by the titration and competition reaction of the acyclonucleoside chelators with iron and ferritin, respectively. The acyclonucleoside iron chelators are more lipophilic with measured n‐octanol and Tris buffer distribution coefficients than ribonucleoside iron chelators.     

An Efficient Route to Novel 4,5‐Di‐ and 2,4,5‐Tri Substituted Imidazoles from Imidazo[1,5‐a]‐1,3,5‐triazine (5,8‐Diaza‐7,9‐dideazapurine) Derivatives

Two new types of imidazole derivatives: N‐(2‐R¹‐5‐R²‐1H‐imidazol‐4‐yl) thioureas 7a–g and N‐(2‐R¹‐5‐R²‐1H‐imidazol‐4‐yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6‐R¹‐8‐R²‐2‐thioxo‐2,3‐dihydroimidazo[1,5‐a]‐1,3,5‐triazin‐4(1H)‐ones 5a–g and 6‐R¹‐8‐R²‐imidazo[1,5‐a]‐1,3,5‐triazin‐4(3H)‐ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined.     

Synthesis and Biological Evaluation of Novel Apio Nucleosides with Thiazole‐4‐carboxamide and 1,2,4‐Triazole‐3‐carboxamide

In view of biological activities of azole nucleosides and apio‐dideoxynucleoside, novel apio nucleoside analogues (1 and 2) with thiazole and triazole base moiety were synthesized using 2,3‐O‐isopropylidene‐apio‐β‐d‐furanose (3), which was prepared from d‐mannose.     

Synthesis of Oligoribonucleotides Containing 4‐Thiouridine Using the Convertible Nucleoside Approach and the 1‐(2‐Fluorophenyl)‐4‐Methoxypiperidin‐4‐yl Group

Oligoribonucleotides containing 4‐thiouridine were prepared using the Fpmp group for protection of the 2′‐OH. Two uridine derivatives with the 1,2,4‐triazolyl and the 2‐nitrophenyl groups at position 4 were used to obtain 4‐thiouridine by postsynthetic substitution with sodium hydrogen sulfide. Both uridine derivatives allow the preparation of the desired oligonucleotides in good yields.     

The season‐of‐birth paradox

Abstract

Vital statistics data show a remarkably consistent seasonality in U.S. birth patterns, with peaks in late summer and winter months, and a valley in the spring. An attitude survey of college students suggests that peaks in the actual birth distribution occur in unpopular months in which to give birth; the valley in the actual birth distribution occurs in popular months. This paradoxical finding is named the Season‐of‐Birth Paradox. Explanations to resolve the paradox include biological and psychological components. A psychological mechanism—named the Misinformed Reproducer Hypothesis—is tested using NSFG data from the 1973–75 and 1979–81 cycles. Results suggest that women stop contracepting with the expectation that they will get pregnant almost immediately. When it takes several months on the average for a successful conception to occur, the actual birth distribution is shifted away from the preferred birth distribution. These results suggest that psychological as well as biological mechanisms underlie the consistent seasonality patterns in U.S. births.     

Design,Efficient Synthesis,and Anti‐HIV Activity of 4′‐C‐Cyano‐ and 4′‐C‐Ethynyl‐2′‐deoxy Purine Nucleosides

Some 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides showed the most potent anti‐HIV activity among the series of 4′‐C‐substituted 2′‐deoxynucleosides whose 4′‐C‐substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show. Thus, 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′‐C‐cyano‐2′‐deoxy purine nucleosides (4′‐CNdNs) and 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides (4′‐EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′‐deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C‐4′ position of the sugar moiety from 2′‐deoxyadenosine and 2,6‐diaminopurine 2′‐deoxyriboside. Unfortunately, 4′‐C‐cyano derivatives showed lower activity against HIV‐1, and two 4′‐C‐ethynyl derivatives suggested high toxicity in vivo.     

Thiosugars. XII. Synthesis of New 3′‐O‐Substituted 2′,5′‐Anhydro‐2′‐thio‐α‐d‐pentofuranosyl Nucleoside Analogues

Methyl 2,5‐anhydro‐3‐O‐(2‐methoxyethyl)‐2‐thio‐β‐d‐arabinofuranoside and methyl 2,5‐anhydro‐3‐O‐(2‐fluorobenzyl)‐2‐thio‐α‐d‐lyxofuranoside were transformed into the corresponding uridine, thymidine, cytidine and adenosine analogues, which exclusively exhibited the α‐configuration irrespective of the anomeric configuration of the donor. The structure, configuration, and conformation of the products was elucidated by X‐ray structure analyses. The nucleoside analogues were tested for antiviral activities.     

Synthesis of D‐Altritol Nucleosides with a 3′‐O‐Tert‐Butyldimethylsilyl Protecting Group

Four D‐altritol nucleosides with a 3′‐O‐tert‐butyldimethylsilyl protecting group are synthesized (base moieties are adenine, guanine, thymine and 5‐methylcytosine). The nucleosides are obtained by ring opening reaction of 1,5:2,3‐dianhydro‐4,6‐O‐benzylidene‐D‐allitol. Optimal reaction circumstances (NaH, LiH, DBU, phase transfer, microwave irridation) for the introduction of the heterocycles are base‐specific. For the introduction of the 3′‐O‐silyl protecting group, long reaction times and several equivalents of tert‐butyldimethylsilyl chloride are needed.     

Design and synthesis of 4,5,6,7‐tetrahydro‐1H‐1,2‐diazepin‐7‐one derivatives as a new series of Phosphodiesterase 4 (PDE4) inhibitors

Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cell-based assays comparable to the Zardaverine control used, suggesting potential avenues for their further development.     

One‐Pot Solvent Free Synthesis and DNA Binding Studies of Thieno[2,3‐b]‐1,8‐Naphthyridines

Abstract

With the aim of evaluating interaction between double‐stranded calf thymus (ds)DNA and sulphur containing fused planar rings, the derivatives of 1,8‐naphthyridine containing thiono groups were synthesized by the condensation of 2‐mercapto‐3‐formyl[1,8]naphthyridines using 1‐chloroacetone, 2‐chloroacetamide, chloroaceticacid, and 2‐chloro‐1‐phenylethanone in the presence of anhydrous potassium carbonate as s catalyst under solvent free microwave irradiation. The structures of the compounds were elucidated on the basis of elemental analysis, IR, ¹H NMR, and mass spectra. The interaction of thieno[2,3‐b]‐1,8‐naphthyridine‐2‐carboxylic acid (TNC) (3a) with ct‐DNA was studied by UV‐Vis spectrophotometry, viscosity, thermal denaturation, as well as cyclic voltammetry experiments. On binding to DNA, the absorption spectrum underwent bathochromic and hypochromic shifts. Binding parameters, determined from spectrophotometric measurements indicated a binding constant of K _b =2.1×10⁶ M^?1. The thieno[2,3‐b]‐1,8‐naphthyridine‐2‐carboxylic acid (3a) increases the viscosity of sonicated rod‐like DNA fragments. The binding of TNC to DNA increased the melting temperature by about 4°C. The decrease in peak current heights and shifts of peak potential values are observed by the addition of calf thymus DNA in cyclic voltammetry studies.     

Second Generation of cycloSal‐Pronucleotides with Esterase‐Cleavable Sites: The ”Lock‐In”‐Concept

A conceptual extension of the cycloSal‐pronucleotide approach is presented. The characteristic feature of the new cycloSal‐derivatives of the anti‐HIV active nucleoside analogue d4T 1 is the incorporation of an enzymatically cleavable carboxylic ester moiety with the intention to trap the triesters inside cells (”lock‐in”‐concept). CycloSal‐triesters bearing different ester groups in the 3‐or 5‐position of the cycloSal‐moiety are described. Surprisingly, only acetyl‐and levulinyl esters are cleaved readily in CEM cell extracts while alkyl esters were found to be stable. Nevertheless, in in‐vitro anti‐HIV assays most of the compounds achieve the thymidine–kinase bypass, thus proving that they act at least as nucleotide delivery systems.     

Morning‐to‐Evening Differences in Oxygen Uptake Kinetics in Short‐Duration Cycling Exercise

This study analyzed diurnal variations in oxygen (O₂) uptake kinetics and efficiency during a moderate cycle ergometer exercise. Fourteen physically active diurnally active male subjects (age 23±5 yrs) not specifically trained at cycling first completed a test to determine their ventilatory threshold (T_vent) and maximal oxygen consumption (VO_2max); one week later, they completed four bouts of testing in the morning and evening in a random order, each separated by at least 24 h. For each period of the day (07:00–08:30 h and 19:00–20:30 h), subjects performed two bouts. Each bout was composed of a 5 min cycling exercise at 45 W, followed after 5 min rest by a 10 min cycling exercise at 80% of the power output associated with T_vent. Gas exchanges were analyzed breath‐by‐breath and fitted using a mono‐exponential function. During moderate exercise, the time constant and amplitude of VO₂ kinetics were significantly higher in the morning compared to the evening. The net efficiency increased from the morning to evening (17.3±4 vs. 20.5±2%; p<0.05), and the variability of cycling cadence was greater during the morning than evening (+34%; p<0.05). These findings suggest that VO₂ responses are affected by the time of day and could be related to variability in muscle activity pattern.     

Crescent‐shaped lime‐spatulas from British New Guinea

This paper situates hill sheep farming within the context of the encompassing British state and the E.E.C. and thus within a cultural world dominated by a technological ontology. Through an analysis of co‐operative work activities, it is shown how the use of modern equipment for increased production inflects the class experience of farmers and shepherds as a hermeneutic relation between whole and part. This provides an understanding of the cultural processes—complementing the historical and economic factors— of class domination by locating it in the experiential linkage of farmers with the encompassing E.E.C. Accordingly, this paper develops an analytic perspective for class relations based on an encompassing‐encompassed model, derived from the work of Dumont.     

Synthesis of Some Novel 6‐Benzyl(or Substituted Benzyl)‐2‐β‐d‐Glucopyranosyl‐1,2,4‐Triazolo[4,3‐b][1,2,4]Triazines as Potential Antimicrobial Chemotherapeutics

Glucosidation of the new 8‐amino‐6‐benzyl(or substituted benzyl)‐2,8‐dihydro‐1,2,4‐triazolo[4,3‐b][1,2,4]triazin‐7(3H)‐ones (3a–d) with 2,3,4,6‐tetra‐O‐acetyl‐α‐d‐glucopyranosyl bromide 4 gave the corresponding N‐glucosides 5a–d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7–12. Antimicrobial activity of compounds 5a–c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described.     

Origin of pre‐islamic architecture in West‐Africa

’Cultural theory’, launched by social anthropologist Mary Douglas, has been highly influential in the inter‐disciplinary field concerned with the study of risk perception and risk communication. The theory derives from the grid‐group analyses that Douglas developed in the 1970s. Cultural theory aims to explain universal ‘cultural bias’ by way of a general typology of group formation and a concomitant cosmology or world view. This article critically examines cultural theory and the study of hazards as culturally construed phenomena.     

Building cross‐cultural coalitions: A case‐study of the Black‐Korean Alliance and the Latino‐Black Roundtable

A case‐study is presented of two Los Angeles‐based cross‐cultural coalitions, the Black‐Korean Alliance [BKA] and the Latino‐Black Roundtable [LBR]. An analysis of the development and eventual dissolution of these two coalitions is presented against the backdrop of the history of relations between the African‐American, Korean‐American and Latino communities of Los Angeles. The central issues leading to the breakup of the two coalitions were: lack of resources, internal power dynamics between coalition partners, nationalistic factions within the broader communities, cross‐cultural dynamics between coalition members, the use of a dialogue model to frame coalition activities, and the analysis of intergroup relations underlying the formation of the coalitions. The applied and theoretical implications of the research are discussed.     

Improved and Reliable Synthesis of 3′‐Azido‐2′,3′‐dideoxyguanosine Derivatives

An improved synthesis of N²‐protected‐3′‐azido‐2′,3′‐dideoxyguanosine 20 and 23 is described. Deoxygenation of 2′‐O‐alkyl (and/or aryl) sulfonyl‐5′‐dimethoxytritylguanosine coupled with [1,2]‐hydride shift rearrangement gave protected 9‐(2‐deoxy‐threo‐pentofuranosyl)guanines ( 10 , 12 and 16 ). This rearrangement was accomplished in high yield with a high degree of stereoselectivity using lithium triisobutylborohydride (l‐Selectride®). Compounds 10 , 12 and 16 were transformed into 3′‐O‐mesylates ( 18 and 21 ), which can be used for 3′‐substitution. The 3′‐azido nucleosides were obtained by treatment of 18 and 21 with lithium azide. This procedure is reproducible with a good overall yield.     

Synthesis and Antiviral Properties of Arabino and Ribonucleosides of 1,3‐Dideazaadenine, 4‐Nitro‐1, 3‐dideazaadenine and Diketopiperazine

Different arabinosides and ribosides, viz. Ara‐DDA or 9(1‐β‐d‐arabinofuranosyl) 1,3‐dideazaadenine (6), Ara‐NDDP or 9(1‐β‐d‐arabinofuranosyl) 4‐nitro‐1,3‐dideazapurine (7), Ara‐DKP or 1(1‐β‐d‐arabinofuranosyl) diketopiperazine (8), Ribo‐DDA or 9(1‐β‐d‐ribofuranosyl) 1,3‐dideazaadenine (9) and Ribo‐NDDP or 9(1‐β‐d‐ribofuranosyl) 4‐nitro‐1,3‐dideazapurine (10) have been synthesized as probable antiviral agents. The arabinosides have been synthesized using the catalyst TDA‐1 that causes stereospecific formation of β‐nucleosides while a one‐pot synthesis procedure was adopted for the synthesis of the ribonucleosides where β‐anomers were obtained in higher yields. All the five nucleoside analogs have been screened for antiviral property against HIV‐1 (III_B), HSV‐1 and 2, parainfluenza‐3, reovirus‐1 and many others. It was observed that arabinosides had greater inhibitory action than ribosides. The compound 7 or Ara‐NDDP has shown maximum inhibition of HIV‐1 replication than the rest of the molecules with an IC₅₀ of 79.4 µg/mL.