Biological evaluation of 3'-O-alkylated analogs of salacinol, the role of hydrophobic alkyl group at 3' position in the side chain on the α-glucosidase inhibitory activity

Four analogs with 3′-O-alkyl groups (9a: CH₃, 9b: C₂H₅, 9c: C₁₃H₂₇ or 9d: CH₂Ph) instead of the 3′-O-sulfate anion in salacinol (1), a naturally occurring potent α-glucosidase inhibitor, were synthesized by the coupling reaction of 1,4-dideoxy-1,4-epithio-d-arabinitols (18a and 18b) with appropriate epoxides (10a-10d). These analogs showed equal or considerably higher inhibitory activity against rat small intestinal α-glucosidases than the original sulfate (1), and one of them (9d) was found more potent than currently used α-glucosidase inhibitors as antidiabetics. Thus, introduction of a hydrophobic moiety at the C3′ position of this new class of inhibitor was found beneficial for onset of stronger inhibition against these enzymes.     

Time–activity budget of greater rheas (Rhea americana, Aves) on a human-disturbed area: the role of habitat, time of the day, season and group size

The aim of this study was to evaluate activity–time budget, habitat use and how seasonality and group size influence the expression of greater rhea behaviours. Greater rheas are threatened South American birds; habitat loss, predation and hunting are the main factors responsible for population declines. The study was conducted in farmlands within a matrix of commercial Eucalyptus plantation and remnants of natural habitats of cerrado vegetation (savannah-like) in southeastern Brazil. Rhea groups were located visually in different habitats visited monthly from January 2004 to December 2005. Time spent searching greater rheas in each habitat was equally distributed. Data were collected using scan sampling with instantaneous recording of behaviours every minute. The time–activity budget of greater rheas was influenced by habitat structure, time of the day, season and group size. Rheas spent more time in open areas than in forested areas (p < 0.001). Vigilance behaviours were more displayed in forested areas, in the dry season and by solitary and small groups of birds. Resting behaviours occurred more often in open lands and within groups with more than three rheas. Food availability, good visibility and low human presence are the possible factors for the preference of greater rheas for pasturelands. The results support the resource availability hypothesis, where it is expected that habitats with a higher food availability will be more used by the animals, group size hypothesis, where the scarcity of resources will lead to smaller groups of animals and that forestry modifies greater rheas habitat use and behaviours.     

Mechanistic study of the structure–activity relationship for the free radical scavenging activity of baicalein

Density functional theory calculations were performed to evaluate the antioxidant activity of baicalein. The conformational behaviors of both the isolated and the aqueous-solvated species (simulated with the conductor-like polarizable continuum solvation model) were analyzed at the M052X/6-311 + G(d,p) level. The most stable tautomers of various forms of baicalein displayed three IHBs between O4 and OH5, O5 and OH6, and O6 and OH7. The most stable tautomer of the baicalein radical was obtained by dehydrogenating the hydroxyl at C6, while the most stable anion tautomer was obtained by deprotonating the C7 hydroxyl in gaseous and aqueous phases. The expected antioxidant activity of baicalein was explained by its ionization potentials (IPs) and homolytic O–H bond dissociation enthalpies (BDEs), which were obtained via the UM052X optimization level of the corresponding radical species. Heterolytic O–H bond cleavages (proton dissociation enthalpies, PDEs) were also computed. The calculated IP, BDE, and PDE values suggested that one-step H-atom transfer, rather than sequential proton loss–electron transfer or electron transfer–proton transfer, would be the most favorable mechanism for explaining the antioxidant activity of baicalein in the gas phase and in nonpolar solvents. In aqueous solution, the SPLET mechanism was more important.     

Structure–activity relationships in aminosterol antibiotics: The effect of stereochemistry at the 7-OH group

Squalamine and three aminosterol analogs have been shown to inhibit bacterial cell growth and induce lysis of large unilamellar phospholipid vesicles. The analogs differ in the identity of the polyamine attached at C3 of the sterol, and the stereochemistry of a hydroxyl substituent at C7. Analogs with a tetraammonium spermine polyamine are somewhat more active than analogs with a shorter trisammonium spermidine polyamine, and analogs with an axial (α) hydroxyl substituent at C7 are more active than analogs with the corresponding equatorial (β) hydroxyl group. There is some variability noted; the 7β-OH spermine analog is the most active compound against Escherichia coli, but the least effective against Pseudomonas aeruginosa. Lytic activity correlates well with antimicrobial activity of the compounds, but the lytic activity varies with the phospholipid composition of the vesicles.     

Genetic structure of an isolated group of the indigenous population of northern Siberia, the Nganasans (Tavginians) of Ta?mir

Demographic data of genetic interest were studied in presently living population in comparison with preseding generations of Nganasans. Decrease of sex ratio in the whole population has been revealed along with the reduction of reproductive and, possibly, effective size. The number and variance of livebirths per female were 7.29 and 9.86 respectively. Crow' index of the opportunity for selection (I) and its components (Im and If) were estimated. I was found to be 1.17, whereas Im and If--1.56 and 0.18 respectively. Linear pattern of settling in the past as well as the type of migration between adjoining subpopulations depended on culture and economy of arctic reindeer hunters as well as landscape character.     

Substrate sequence influences γ-secretase modulator activity, role of the transmembrane domain of the amyloid precursor protein

A subset of non-steroidal anti-inflammatory drugs modulates the γ cleavage site in the amyloid precursor protein (APP) to selectively reduce production of Aβ42. It is unclear precisely how these γ-secretase modulators (GSMs) act to preferentially spare Aβ40 production as well as Notch processing and signaling. In an effort to determine the substrate requirements in NSAID/GSM activity, we determined the effects of sulindac sulfide and flurbiprofen on γ-cleavage of artificial constructs containing several γ-secretase substrates. Using FLAG-tagged constructs that expressed extracellularly truncated APP, Notch-1, or CD44, we found that these substrates have different sensitivities to sulindac sulfide. γ-Secretase cleavage of APP was altered by sulindac sulfide, but CD44 and Notch-1 were either insensitive or only minimally altered by this compound. Using chimeric APP constructs, we observed that the transmembrane domain (TMD) of APP played a pivotal role in determining drug sensitivity. Substituting the APP TMD with that of APLP2 retained the sensitivity to γ-cleavage modulation, but replacing TMDs from Notch-1 or ErbB4 rendered the resultant molecules insensitive to drug treatment. Specifically, the GXXXG motif within APP appeared to be critical to GSM activity. Consequently, the modulatory effects on γ-cleavage appears to be substrate-dependent. We hypothesize that the substrate present in the γ-secretase complex influences the conformation of the complex so that the binding site of GSMs is either stabilized or less favorable to influence the cleavage of the respective substrates.     

Chirality of the acyl group of β-hydroxy-β-methylglutarylhydroxyabscisic acid

The β-carbon of the acyl group of β-hydroxy-β-methylglutarylhydroxyabscisic acid was shown to possess R-configuration by HPLC analysis of the reduced product.     

The effects of hydroxy fatty acids on the hyphal branching of germinated spores of AM fungi

Two hydroxy fatty acids, tentatively identified previously in carrot root exudates, were tested for their effects on hyphal growth of the arbuscular mycorrhizal (AM) fungus, Gigaspora gigantea (Nicol. and Gerd.) Gerdemann and Trappe. Best results were achieved with a long-term bioassay (7–8 d) with nanomolar concentrations throughout the Petri dish in contrast to the rapid microinjection bioassay (16–24 h) in which nanogram quantities were injected near growing hyphal tips. When 5 nM 2-hydroxy fatty acids of various chain length were tested, the length of the hydroxyl fatty acid was significant since only 2-hydroxytetradecanoic acid (2OH-TDA) and to a slightly lesser degree, 2-hydroxydodecanoic acid (2OH-DDA) induced a hyphal growth response while 2-hydroxydecanoic acid (2OH-DA) and 2-hydroxyhexadecanoic (2OH-HDA) acid did not. The position of the hydroxyl group was critical since 5 nM 3-hydroxytetradecanoic acid (3OH-TDA) had no effect on hyphal growth. The length of the non-hydroxy containing straight chain fatty acid, per se, did not appear significant since none of these fatty acids had an effect on hyphal growth. The morphological growth response promoted by 2OH-TDA consisted of multiple lateral branches, spaced fairly regularly apart, along the primary germ tubes as well as some lateral branch formation off the major secondary hyphae. This growth response was identical to that observed when germinated spores were allowed to grow towards cultured carrot roots in vitro. This response to 2OH-TDA also was observed with an unidentified Gigaspora species but no morphological response was observed with Glomus intraradices Schenck and Smith. The results indicate that 2-hydroxy fatty acids are another putative category of root exudate signals perceived by Gigaspora species, stimulating an increase in elongated lateral branches.     

The group of 77 and the establishment of the international sea‐bed authority

Abstract

The Group of 77 favors the establishment of a strong International Sea‐Bed Authority with powers to regulate and control all the activities of exploration and exploitation of the “common heritage of mankind,”; referred to in the draft articles as “the Area.”; The Authority itself is to be composed of an Assembly as the supreme policy‐making organ in which the Contracting Parties are to be represented on the basis of sovereign equality; a Council as the executive organ implementing the policies emanating from the Assembly, to be composed of at least 36 states elected to ensure representation of clearly defined special interests and the principle of equitable geographical distribution, and to eschew any form of veto mechanism in its decision‐making process; the Enterprise as the operational organ through which the Authority is to undertake direct exploitation of the Area along with the other entities given access to the Area; and a Secretariat as well as certain subsidiary bodies of the Council.

The Group of 77 takes the position that the Convention itself and the Basic Conditions governing the entire process of exploration and exploitation of the Area must leave the Authority an appreciable margin of discretion in managing the Area for the benefit of mankind as a whole. Thus, a limited category of judicially reviewable decisions of the Authority is envisaged so long as such review does not challenge the legislative powers and resource policy decisions of the Authority. A Sea‐Bed Tribunal is no longer necessary as an organ of the Authority, since the work of such a Tribunal could be done by the special Sea‐Bed Disputes Chamber of the Proposed Law of the Sea Tribunal dealing with disputes arising under the Convention as a whole.     

Spontaneous activity of foregut and hindgut visceral muscle of the locust,locusta migratoria—I. Normal activity and the effect of KCl depolarization and glutamate

1. Locust foregut and hindgut differed in their spontaneous contractility. The foregut was constantly active with regular contractions or with a fast rhythm incorporating larger irregular contractions.2. The hindgut showed bursts of large regular contractions interrupted by periods of quiescence.3. Foregut fluid, of unknown content, inhibited rhythmic contractions but induced large foregut tonic contractures.4. High KCl salines induced contractures in both gut sections, but the tension/[K]₀ curve showed no clear mechanical threshold.5. Glutamate (10⁻⁵ M) increased contraction frequency in the hindgut and stimulated quiescent preparations. At 10⁻⁴M, glutamate usually increased foregut contraction amplitude and frequency, this action being inhibited by 10⁻⁵ M tvramine.6. Considerable differences exist in natural rhythm, contractile properties and drug responses between these two divisions of locust gut.     

Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase

The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17β-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Δ⁴-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17β-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17β-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.     

In vitro acylation of the ϵ-amino group of l-lysine in calf thymus histones by the carcinogen, β-propiolactone

We had previously reported that the carcinogen, β-propiolactone (BPL) reacted in vitro with histones in whole mouse skin chromatin and that among the histone classes BPL was preferentially bound to the lysine-rich histones H1 and H1°. In order to determine if in vitro reaction of BPL with calf thymus histones resulted in binding of BPL to l-lysine, we synthesized the model compounds ?-N-(3-hydroxypropionyl)lysine (HPL) and ?-N-(2-carboxyethyl)lysine (CEL) from BPL and l-lysine. The α-amino group of l-lysine was protected from reaction with BPL by the formation of a copper chelate.Structures were assigned on the basis of infrared spectra, pKa values and chemical analyses. BPL was reacted in vitro with calf thymus histones and the BPL-reacted calf thymus histones and control calf thymus histones were digested with trypsin followed by pronase. The respective digests were each chromatographed on a column of AA-15 cation-exchange resin. The elution profiles of the two digests were very similar except for the appearance of a new ninhydrin-positive peak (NNPP) in the eluate of the trypsin-pronase digest of BPL-reacted calf thymus histones. When compounds HPL and CEL were added to the trypsin-pronase digest of control calf thymus histones and the mixture chromatographed on AA-15, both compounds were resolved from the other peptide (or amino acid) peaks. HPL was eluted in the same fractions as NNPP, HPL and NNPP exhibited identical R_F values on silica gel TLC with acidic, alkaline and neutral solvents. CEL was not identified as a product of the reaction between BPL and calf thymus histones.     

Improved histochemical method for the demonstration of the activity of α-glucan phosphorylase

Summary The activity and localization of -glucan phosphorylase in experimental canine glycogen-depleted heart tissue has been investigated with biochemical and histochemical methods using dextran as enzyme acceptor. Only linear, essentially unbranched, dextrans exhibit acceptor properties; highly branched dextrans are not suitable acceptors for the enzyme. Results of Michaelis-Menten constant measurements for the linear essentially unbranched dextran fractions used, indicate that the affinity of the enzyme for the non-reducing end group of the dextran molecule increases with increasing molecular weight of the acceptor.In the glycogen-depleted tissue of anoxic and ischaemic cardiac musculature there is a gradual inactivation of the enzyme during the ischaemic period. Shortly before total inactivation the affinity of the enzyme, especially for the lower molecular dextran fractions, is greatly reduced. Therefore, for the histochemical demonstration of phosphorylase activity in infarcted areas of the heart it is essential to use as acceptor an unbranched dextran fraction with a high average molecular weight.This investigation was partially supported by a grant from the Netherlands Organization for the Advancement of Pure Research (Z.W.O.).