Prostaglandin VIII — Synthesis of some 9-oxoprostynoic acids

The communication describes the synthesis of (±) 13-dehydro-11-deoxy-PGE₁, 9-oxo-13-hydroxyprost-14-ynoic acid, and (14z)-9-oxo-13-hydroxy-prost-14-enoic acid.     

Prostaglandin VIII — Synthesis of some 9-oxoprostynoic acids

The communication describes the synthesis of (±) 13-dehydro-11-deoxy-PGE₁, 9-oxo-13-hydroxyprost-14-ynoic acid, and (14z)-9-oxo-13-hydroxy-prost-14-enoic acid.     

Inter and intra-species-related differences in the regulation of the cardiac autonomic system

The heart rate response to isoproterenol (HR-Iso), density and affinity (k_d) of β-adrenergic (β-AR) and muscarinic (M₂) receptors were compared among three rodents with different generation-life histories of confinement and of high altitude exposure. The European guinea pig (Cavia porcellus) (EGp), a laboratory animal that arrived in Europe after the Spanish Conquest of South America and the Peruvian guinea pig (C. porcellus) (PGp), a semi-wild animal that came from the altiplano to sea level at least 25 generations ago, were used for intra-species comparison. Wistar rats (WR) were used for inter-species comparison as representative of a typical sea level laboratory animal. The HR-Iso was lower in EGp than in the PGp. The PGp showed the highest β-AR density (P<0.0005) and the highest β-AR k_d values (P<0.0005) when compared to both EGp and WR groups (β-AR B_max (fmol mg⁻¹ prot), WR, 19±4; Egp, 34±10; PGp, 74±15. β-AR k_d (pM), WR, 24±10; Egp, 17±7; PGp, 39±14). In contrast, PGp showed lower M₂ receptor density values than the EGp (P<0.0005). The WR had the highest M₂ receptor densities (M₂ B_max (fmol mg⁻¹ prot), WR, 188±15; Egp, 147±9; PGp, 118±6 and M₂ k_d (pM), WR, 65±12; Egp, 67±6; PGp, 92±2). The inter and intra-species differences found may be related to their respective history of confinement rather than to their history of exposure to high altitude.     

TPA Increases Conductance but Decreases Permeability in Neonatal Rat Cardiomyocyte Gap Junction Channels

Short-term (10 min) effects of 100 nM 12-O-tetradecanoylphorbol-13-acetate (TPA), the protein kinase C (PKC) activator, on cardiac macroscopic (g_j) and single channel (γ_j) gap junctional conductances were studied in pairs of neonatal rat cardiomyocytes. Under dual whole-cell (WC) or perforated patch (PP) voltageclamp, g_j increased by 15.5 ± 7.2% (mean ± SD, n = 9) and by 46.3 ± 17.0% (n = 5), respectively. The latter difference is not related to intracellular calcium concentration, because raising the Ca²⁺ concentration in the electrode solution did not change the TPA-induced increase in g_j observed under WC conditions. The inactive phorbol ester, 4α-phorbol 12,13-didecanoate (αPDD), did not affect g_j. Single cardiac gap junction channel events, resolved in the presence of heptanol, indicated two γ_j sizes of 20 and 40-45 pS. Under control conditions, the larger events were most frequently observed. Whereas αPDD did not change this distribution, TPA shifted the γ_j distribution to the lower sizes. Diffusion of Lucifer Yellow (LY) and 6-carboxyfluorescein (6-CF), gap junction permeant tracers, was studied on small clusters of cardiomyocytes. Under control conditions, LY labeled 19.4 ± 7.2 cells (mean ± SD, n = 18) and 6-CF labeled 8.4 ± 2.2 cells (n = 20). Whereas αPDD did not change the extent of dye transfer, TPA restricted the diffusion of LY to 2.8 ± 1.3 cells (n = 11) and of 6-CF to 2.4 ± 1.4 cells (n = 20). This suggests that permeability and single channel conductance of connexin 43 channels are parallely related. Altogether, these results point to the opposite modulation of electrical and metabolic coupling of cardiac cells evoked by TPA.     

Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists

5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119. The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC₅₀ values. 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl)phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13).     

(10E,12Z,15Z)-9-Hydroxy-10,12,15-octadecatrienoic Acid Methyl Ester as an Anti-inflammatory Compound from Ehretia dicksonii

The methanol extract of Ehretia dicksonii provided (10E,12Z,15Z)-9-hydroxy-10,12,15-octadecatrienoic acid methyl ester (1) which was isolated as an anti-inflammatory compound. Compound 1 suppressed 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced inflammation on mouse ears at a dose of 500 μg (the inhibitory effect (IE) was 43%). Linolenic acid methyl ester did not inhibit this inflammation at the same dose. However, the related compounds of 1, (9Z,11E)-13-hydroxy-9,11-octadecadienoic acid (5) and (9Z,11E)- 13-oxo-9,11-octadecadienoic acid (6), showed potent activity (IE_{500 μg} of 63% and 79%, respectively). Compounds 1, 4 ((9Z,12Z,14E)-16-hydroxy-9,12,14-octadecatrienoic acid), 5 and 6 also showed inhibitory activity toward soybean lipoxygenase at a concentration of 10 μg/ml.     

Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

Preparation and characterization of hydroperoxy-eicosatetraenoic acids (HPETEs)

5-, 8-, 9-, 11-, 12- and 15 hydroperoxy-eicosatetraenoic acids (HPETEs) were generated from arachidonic acid by a reaction with H₂O₂ and Cu++ ions. They were purified by high performance liquid chromatography, either on a silica gel (μ Porasil) column or on a reversed phase (μ Bondapak C₁₈) column. The yield of 5-HPETE was considerably greater when the μ Bondapak C₁₈ column was used. The HPETEs were characterized and assayed by their ability to oxidize triphenylphosphine: triphenylphosphine oxide formation was monitored by gas chromatography. When stored in methylene chloride at −20°C, the HPETEs were stable for several months.     

Synthetic, structural and solution speciation studies on binary Al(III)–(carboxy)phosphonate systems. Relevance to the neurotoxic potential of Al(III)

Efforts to delineate the interactions of neurotoxic Al(III) with low molecular mass substrates relevant to neurodegenerative processes, led to the investigation of the pH-specific synthetic chemistry of the binary Al(III)-[N-(phosphonomethyl) iminodiacetic acid] (Al-NTAP), Al(III)-[nitrilo-tris(methylene-phosphonic acid)] (Al-NTA3P), and Al(III)-[1-hydroxy ethylidene-1,1-diphosphonic acid] (Al-HEDP) systems, in correlation with solution speciation studies. Reaction of Al(NO₃)₃·9H₂O with NTAP at pH 7.0 and 4.0 afforded the new species (CH₆N₃)₄[Al₂(C₅H₆NPO₇)₂(OH)₂]·8H₂O (1) and (NH₄)₂[Al₂(C₅H₆NPO₇)₂(H₂O)₂]·4H₂O (2), while reaction of Al(NO₃)₃·9H₂O with NTA3P led to K₈[Al₂(C₃H₆NP₃O₉)₂(OH)₂]·20H₂O (3). Complexes 1–3 were characterized by elemental analysis, FT-IR, ¹³C, ³¹P, ¹H NMR (for 1–2 solid state and solution NMR where feasible), and X-ray crystallography. The structures of 1–3 reveal the presence of uniquely defined dinuclear complexes of octahedral Al(III) bound to fully deprotonated phosphonate ligands, water and hydroxo moieties. The aqueous solution speciation studies on the aforementioned binary systems project a clear picture of the binary Al(III)–(carboxy)phosphonate interactions and species under variable pH-conditions and specific Al(III):ligand stoichiometry. The concurrent solid state and solution work (a) exemplifies essential structural and chemical attributes of soluble aqueous species, reflecting well-defined interactions of Al(III) with phosphosubstrates and (b) strengthens the potential linkage of neurotoxic Al(III) chemical reactivity toward O,N-containing (carboxy)phosphate-rich cellular targets.     

Prostaglandin E2 secretion by day-6 to day-9 equine embryos

Prostaglandin E₂ (PGE₂) secreted by Day-6, Day-7, Day-8 and Day-9 equine embryos (ovulation = Day 0) during in vitro incubation was measured by radioimmunoassay. Embryonic PGE₂ secretion (ng/embryo/24 hr) was detectable on Day 6 (0.27±0.39), tended to increase (P <0.1) on Day 7 (0.57±0.88), and increased significantly (P <0.05) on Day 8 (2.23±0.86) and Day 9 (4.13±0.71). Embryo diameter at the start of the incubation period was linearly correlated (P <0.01) to embryonic PGE₂ secretion.     

9α-homo-9,11-epoxy-5,13-prostadienoic acid analogues: Specific stable agonist (SQ 26,538) and antagonist (SQ 26,536) of the human platelet thromboxane receptor

A newly synthesized 9α-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26,536, (8(R)9(S)11(R)12(S)-9α-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I₅₀ value of 1.7 μ . SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH₂ and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9α-homo-9-, 11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A₅₀ value of 2.5 μ . SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a K_i value of 3 μ . Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH₂-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.     

Bis(undecatungstogermanate) lanthanates of potassium

The K₁₃[Ln(GeW₁₁O₃₉)₂]·nH₂O (Ln = Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Tm, Yb) have been prepared. Some properties of these compounds have been studied. The change of main bands in their IR spectra with reference to α-GeW₁₂O₄₀⁴⁻ is discussed. v_as (W---O_d) is shifted toward low wavenumber and v_as (W---O_b---W), δ(O---Ge---O) each appear as two distinct bands. X-ray powder diffraction shows that the molecular symmetry of K₁₃[Ln(GeW₁₁O₃₉)₂] is lower than that of α-K₈(GeW₁₁O₃₉). XPS determinations reveals that the Ln---O bond has coordination character and that the shifts of W_4f and O_ls are between K₁₃Ln (GeW₁₁O₃₉₂ and α-H₄(GeW₁₂O₄₀). Magnetic measurement confirms that the lanthanide elements are +3 valent in this complexes and the magnetic moments are very close to the values found by Van Vleck.     

Preparation, X-ray structure and solution behavior of [Ag(9-EtGH-N7)2]NO3·H2O (9-EtGH=9-ethylguanine)

The preparation and X-ray structure of [Ag(9-EtGH-N7)₂]NO₃·H₂O(9-EtGH=neutral 9-ethylguanine) is reported. The compound crystallizes in the triclinic system, space group P with a=7.063(6), b=7.153(3), c=11.306(10) Å, α=83.36(6), β=76.66(7), γ=81.44(6)°. The cation is centrosymmetric with Ag(I) coordinated via two N7 positions and Ag---N7 bond lengths of 2.11(1) Å. Applying ¹⁰⁹Ag NMR spectroscopy, complex formation constants for both the 1:1 complex (log β₁=0.6) and the title compound (log β₂=1.6) in Me₂SO have been determined.     

Indole and benzimidazole derivatives as steroid 5α-reductase inhibitors in the rat prostate

A novel series of indole and benzimidazole derivatives were synthesized and evaluated for their inhibitory activity of rat prostatic 5α-reductase. Among these compounds, 4-{2-[1-(4,4′-dipropylbenzhydryl)indole-5-carboxamido]phenoxy}butyric acid (15) and its benzimidazole analogue 25 showed potent inhibitory activities for rat prostatic 5α-reductase (IC₅₀ values of 9.6 ± 1.0 and 13 ± 1.5nM, respectively), with the potency very close to that of finasteride. Compound 30, in which the moiety between the benzene ring and amide bond was replaced by quinolin-4-one ring, showed almost equipotent activity (IC₅₀ = 19 ± 6.2nM) with the correspondent amide derivative 13. This result was consistent with the previous observation that the coplanarity of this moiety might contribute to the potent inhibitory activity.     

Modulation of prostaglandin of the renal vascular action of arginne vasopressin

To determine whether the renal vascular effect of arginine vasopressin (AVP) is modulated by renal prostaglandin E₂ (PGE₂) were determined during the infusion of AVP in dogs during control conditions and after the administration of the inhibitor of prostaglandin synthesis, indomethacin. During control conditions, intrarenal administration for 10 min of a dose of AVP calculated to increase arterial renal plasma AVP concentration by 75 pg/ml produced a slight renal vasodilation (p<0.01) and an increase in renal venous plasma concentration of PGE₂. Renal venous PGE₂ concentration during control and AVP infusion averaged 33 ± 7 and 52 ± 12 pg/ml (p<0.05), respectively. After administration of indomethacin, the same dose of AVP induced renal vasoconstriction (p<0.05) and failed to enhance renal venous PGE₂ concentration (9 ± 1 to 8 ± 1 pg/ml). Intrarenal administration of 20 ng/kg. min of AVP for 10 min induced a marked renal vasoconstriction (p<0.01) and increased renal venous plasma PGE₂. Renal venous PGE₂ during control and AVP infusion averaged 31 ± 10 and 121 ± 31 pg/ml (p<0.01), respectively. Administration of the same dose of AVP following indomethacin produced a significantly greater and longer lasting renal vasoconstriction (p<0.01) and failed to increase renal venous plasma PGE₂ (10 ± 1 to 9 ± 1 pg/ml). These results indicate that a concentration of AVP comparable to that observed in several pathophysiological conditions induces a slight renal vasodilation which is mediated by renal prostaglandins. The results also indicate that higher doses of AVP induce renal vasoconstriction and that prostaglandin synthesis induced by AVP attenautes the renal vasoconstriction produced by this peptide.     

1-Methoxy-, 1-deoxy-11-hydroxy- and 11-Hydroxy-1-methoxy-Δ-tetrahydrocannabinols: new selective ligands for the CB2 receptor

Three series of new cannabinoids were prepared and their affinities for the CB₁ and CB₂ cannabinoid recptors were determined. These are the 1-methoxy-3-(1′,1′-dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(1′,1′-dimethylalkyl)- and 11-hydroxy-1-methoxy-3-(1′,1′-dimethylalkyl)-Δ⁸-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB₂ receptor than for the CB₁ receptor, however only 1-methoxy-3-(1′,1′-dimethylhexyl)-Δ⁸-THC (JWH-229, 6e) has effectively no affinity for the CB₁ receptor (K_i=3134±110 nM) and high affinity for CB₂ (K_i=18±2 nM).     

Molecular conformation of prostaglandin A1 monoclinic cyrstalline polymorph

The molecular conformation of the monoclinic crystalline polymorph of prostaglandin A₁ has been determined by X-ray diffraction techniques. The space group is P2₁ with a = 13.637 (2), b = 7.567 (1), I c = 10.576 (2) Å, β = 107.37 (3)°; D_c = 1.073 g·cm⁻³ for Z = 2. The molecular conformation is characterized by the nearly parallel arrangement of the C₁–C₇ and C₁₃–C₂₀ side chains, with a general flattening of the overall structure when compared with the orthorhombic polymorph. The cyclopentenone moiety assumes a C₈ envelope conformation with C₈ and O₉ displaced +0.29 Å and −0.18 Å from the C₉–C₁₀=C₁₁–C₁₂ plane respectively. Concerted, small variations of the torsion angles, primarily about the C₈–C₁₂, C₁₄–C₁₅ and C₁₆–C₁₇ bonds, bring the monoclinic and orthorhombic conformations into coincidence.     

Luteolysis in the rhesus monkey: Ovarian venous estrogen, progesterone, and prostaglandin F2α-metabolite

The role of prostaglandin F₂α (PGF₂α) in luteolysis in the non-human primate is poorly understood. We have recently reported that chronic PGF₂α infusion to the corpus luteum via Alzet pump, induced premature, functional luteolysis in the rhesus monkey. In the present study we sought to determine the ovarian events leading to spontaneous luteolysis in the monkey. Rhesus monkeys underwent laparotomy during the early luteal (4–5 days after the preovulatory estradiol surge, PES), mid-luteal (7–9 days PES), and late luteal (10–14 days PES) phases or at the first day of menses (M). Concentrations of progesterone, estradiol, estrone, and 13, 14-dihydro-15-keto-PGF₂α (PGFM) were measured in the ovarian venous effluents ipsilateral and contralateral to the ovary bearing the corpus luteum. Steroid levels in the ovarian vein on the corpus luteum side were significantly higher than the non-corpus luteum side throughout the cycle. PGFM levels were similar on both sides until the late luteal phase, when the effluent of the ovary bearing the corpus luteum contained significantly more PGFM (206±3) vs. 123±9 pg/ml, mean±sem); this disparity increased further at the time of menses (241±38 vs. 111±22 pg/ml). These data are the first to show an asymmetric secretion of PGFM in the ovarian venous effluent in the primate and suggest that PGF₂α of ovarian and possibly of corpus luteum origin may be directly involved in luteal demise.     

Increased thromboxane A2 production but normal prostacyclin by the placenta in hypertensive pregnancies

The production of vasodilatory, antiaggregatory prostacyclin (PGI₂) and vasoconstrictory, proaggregatory thromboxane A₂ (TxA₂) by the placenta was studied in the cases of hypertensive pregnancy complications by superfusing pieces from maternal and fetal sides of placentae of 9 pre-eclamptic, 6 hypertensive and 11 healthy women and measuring the release of 6-keto-prostaglandin F_1α (6-keto-PGF_1α) and thromboxane B₂ (TxB₂), the breakdown products of PGI₂ and TxA₂ respectively, from the superfusate. Both sides of the placentae from the controls produced 6-keto-PGF_1α (maternal side 0.5±0.1 ng/g/min dry weight of tissue, mean±SEM; fetal side 0.7±0.2 ng/g/min) and TxB₂ (maternal side 2.5±0.4 ng/g/min; fetal side 2.7±0.5 ng/g/min with no correlation between the two. The 6-keto-PGF_1α production was normal in hypertensive complications whereas the TxB₂ production was increased on the fetal side of the placentae obtained from the pre-eclamptic (3.7±0.3 ng/g/min: p<0.05) and hypertensive women (4.1±0.4 ng/g/min; p<0.025). This may explain the occurrence of microthrombi and infarctions in placentae of hypertensive women.     

Optimum conditions for the activation of the alternative complement pathway of a cyprinid fish (Tinca tinca L.). Seasonal variations in the titres

The present work describes the existence of a haemolytic activity in the serum of tench, Tinca tinca, against rabbit red blood cells (RRBC) which was identified as belonging to the alternative complement pathway from the following findings: haemolytic activity disappeared when the serum was heated to 45°C for 20 min; 10 mM EDTA, which chelates Ca²⁺ and Mg²⁺, induced a complete loss of haemolysis; Mg²⁺, but not Ca²⁺, was required for the activity, and the use of sheep red blood cells (SRBC), which have a high content of sialic acid, resulted in the serum activity falling to a very low degree of haemolysis. The ACH50 value (units ml^-1 serum) was defined as the reciprocal of the serum dilution necessary to lyse 50% of 4 × 10⁷ RRBC in a buffered medium of normal ionic strength (μ=0·15) containing 10 mM EGTA and optimum concentrations of Mg²⁺. The optimum conditions for the ACH50 assay were: pH 7·2-7-7; reaction temperature, 15°C; concentration of Mg²⁺, 5 mM; and reaction time, 90 min. Under these conditions, the values of ACH50 in spring, summer, autumn and winter for male tench were 69±13, 91±22, 90±36 and 137±41, and for female tench 100±11, 108±13, 82±12 and 145±17. The highest serum activity was found in the winter, suggesting the importance of this pathway during cold periods when the specific immune response is depressed in ectothermic vertebrates.