Prostaglandins and congeners XXIII (1). Synthesis of 15-deoxy-16-hydroxy-16-methylprostanglandins. The importance of the C13--C14 trans double bond for bronchodilator activity.

The synthesis and bronchodilator activity in the guinea pig of several 15-deoxy-16-hydroxy-16-methylprostaglandin analogs is described. The E2 (VIa) and E1 (VIb) analogs are potent bronchodilators comparable in activity to the natrual prostaglandins, but possessing a longer duration of effect. Replacement of the C13--C14 trans double bond by a cis double bond or an ethylene linkage causes a substantial diminishment of this activity.     

Prostaglandins and congeners IX (1). The synthesis of 15-deoxy-16-, 17-, or 20-hydroxyprostaglandins and 15-deoxy-15-hydroxymethylprostaglandin E2

Prostaglandin congeners wherein the 15-hydroxy group is moved to the C₁₆, C₁₇, or C₂₀ position or is replaced by a hydroxymethyl group were prepared via the 1,4-addition of a lithium trialkyl-trans-alkenyl alanate to an appropriate cyclopentenone. Several of the 16-hydroxy derivatives showed significant activity as constrictors of the isolated gerbil colon and in bronchodilator and anti-secretory assays.     

Prostaglandins and congeners IX (1). The synthesis of 15-deoxy-16-,17-, or 20-hydroxyprostaglandins and 15-deoxy-15-hydroxymethylprostaglandin E2

Prostaglandin congeners wherein the 15-hydroxy group is moved to the C₁₆, C₁₇, or C₂₀ position or is replaced by a hydroxymethyl group were prepared the 1,4-addition of a lithium trialkyl- -alkenyl alanate to an appropriate cyclopentenone. Several of the 16-hydroxy derivatives showed significant activity as constrictors of the isolated gerbil colon and in bronchodilator and anti-secretory assays.     

Prostaglandin E antagonist activity of 11-deoxy-16, 16-trimethyleneprostaglandin E1

11-Deoxy-16,16-trimethyleneprostaglandin E₁ is a potent inhibitor of prostaglandin E-induced contractions of the gerbil colon. The antagonism is directed specifically against the prostaglandin E receptor and is not manifested when contractions are induced by either prostaglandin F_2α or acetylcholine.     

Prostaglandins V (1). Synthesis and pharmacology of (±)-11-deoxy-10-hydroxyprostaglandin E1 methyl ester

(±)-11-Deoxy-10-hydroxy-PGE₁ methyl ester (Va) has been synthesised conjugate addition of the cuprate (III) to the 5-tetrahydropyranyloxycyclopentenone (IId).Va was found to be 0.1 times as active as PGE₁ as a uterine stimulant in the anaesthetized pregnant rat, 0.25 times as active as PGE₁ in causing vasodepression in the anaesthetized cat, and approximately equiactive to PGE₁ in inducing bronchoconstriction.     

Prostaglandins and congeners V. (1) Synthesis of d1-prostaglandin E1, d1-11-deoxyprostaglandin E1, and d1-15-hydroxy-9-oxo-13-cis-prostenoic acid via conjugate addition of 3-trityloxy-1-octenylmagnesium bromides

d1-Prostaglandin E₁ and d1-11-deoxyprostaglandin E₁ are conveniently synthesized via the copper (I) catalyzed conjugate addition of the Grignard reagent prepared from 3-trityloxy-$\text{trans}$-1-octenyl bromide to the appropriate cyclopentenone precursor. The Grignard reagent also afforded the synthesis of a novel structure, d1-15-hydroxy-9-oxo-13-$\text{cis}$-prostenoic acid.     

Heats of reaction of HMo(CO)3(C5R5) (R = H, CH3) with diphenyldisulfide and of formation of the clusters [PhSMo(CO)x(C5H5)]2, X = 1,2. Thermodynamic study of molybdenum-sulfur bond strengths

The enthalpies of reaction of HMo(CO)₃C₅R₅ (R = H, CH₃) with diphenyldisulfide producing PhSMo(CO)₃C₅R₅ and PhSH have been measured in toluene and THF solution (R = H, ΔH= −8.5 ± 0.5 kcal mol⁻¹ (tol), −10.8 ± 0.7 kcal mol⁻¹ (THF); R = CH₃, ΔH = −11.3±0.3 kcal mol⁻¹ (tol), −13.2±0.7 kcal mol⁻¹ (THF)). These data are used to estimate the Mo---SPh bond strength to be on the order of 38–41 kcal mol⁻¹ for these complexes. The increased exothermicity of oxidative addition of disulfide in THF versus toluene is attributed to hydrogen bonding between thiophenol produced in the reaction and THF. This was confirmed by measurement of the heat of solution of thiophenol in toluene and THF. Differential scanning calorimetry as well as high temperature calorimetry have been performed on the dimerization and subsequent decarbonylation reactions of PhSMo(CO)₃Cp yielding [PhSMo(CO)₂Cp]₂ and [PhSMo(CO)Cp]₂. The enthalpies of reaction of PhSMo(CO)₃Cp and [PhSMo(CO)₂Cp]₂ with PPh₃, PPh₂Me and P(OMe)₃ have also been measured. The disproportionation reaction: 2[PhSMo(CO)₂Cp]₂ → 2PhSMo(CO)₃Cp + [PhSMP(CO)Cp]₂ is reported and its enthalpy has also been measured. These data allow determination of the enthalpy of formation of the metal-sulfur clusters [PhSMo(CO)_nC₅H₅]₂, N = 1,2.     

The vasorelaxant effect of (±)-15-deoxy-16-hydroxy-16(α/β)-vinyl-prostaglandin E2 (CL 115,129) and its methyl ester (CL 115,347) on the isolated ductus arteriosus preparation

CL 115,129 and its methyl ester, CL 115,347, were studied for their vasorelaxant effects and compared to that of prostaglandin (PG) E₂ and its methyl ester on isolated ductus arteriosus (DA) from fetal lambs and rabbits. CL 115,129 and CL 115,347 potently relaxed the oxygen-indomethacin constricted ductus in a concentration dependent manner. The threshold concentration was 1×10^?13M and the estimated EC₅₀'s (M) were 6.9×10^?8 and 4.3×10^?8, respectively, for CL 115,129 and CL 115,347. Also confirmed was the vasorelaxant ability of PGE₂. These studies indicate that the CL compounds possess potent vasorelaxant effects on the DA although less potent than PGE₂ or its methyl ester.     

Kinetics and mechanisms of ligand substitution reactions of molybdenum SO2 complexes. Synthesis and X-ray structure of trans-Mo(CO)2 (dmpe) (PPh3) (SO2)

Kinetic results are reported for intramolecular PPh₃ substitution reactions of Mo(CO)₂(η¹-L)(PPh₃)₂(SO₂) to form Mo(CO)₂(η²-L)(PPh₃)(SO₂) (L = DMPE = (Me)₂PC₂H₄P(Me)₂ and dppe=Ph₂PC₂H₄PPh₂) in THF solvent, and for intermolecular SO₂ substitutions in Mo(CO)₃(η²-L)(η²-SO₂) (L = 2,2′-bipyridine, dppe) with phosphorus ligands in CH₂Cl₂ solvent. Activation parameters for intramolecular PPh₃ substitution reactions: ΔH^≠ values are 12.3 kcal/mol for dmpe and 16.7 kcal/mol for dppe; ΔS^≠ values are −30.3 cal/mol K for dmpe and −16.4 cal/mol K for dppe. These results are consistent with an intramolecular associative mechanism. Substitutions of SO₂ in MO(CO)₃(η²-L)(η²-SO₂) complexes proceed by both dissociative and associative mechanisms. The facile associative pathways for the reactions are discussed in terms of the ability of SO₂ to accept a pair of electrons from the metal, with its bonding transformations of η²-SO₂ to η¹-pyramidal SO₂, maintaining a stable 18-e count for the complex in its reaction transition state. The structure of Mo(CO)₂(dmpe)(PPh₃)(SO₂) was determined crystallographically: P2₁/c, A=9.311(1), B = 16.344(2), C = 18.830(2) Å, ß=91.04(1)°, V=2865.1(7) ų, Z=4, R(F)=3.49%.     

Synthesis and anti-ulcer activity of 16-phenoxy analogues of (+)-11-deoxyprostaglandin E1

( )-11-Deoxy-16-phenoxy-17,18,19,20-tetranor-prostaglandin E₁ is a highly potent and selective anti-ulcer agent. Analogues of this compound have been synthesized and structure-activity relationships are reported.     

Organometallic chemistry of diphosphazanes. Rhodium(I) complexes of RN(PX2)2 (R = C6H5; X = OC6H5, OC6H4Br−p, R = CH3; X = OC6H5)

Reactions of [Rh(COD)Cl]₂ with the ligand RN(PX₂)₂ (1: R = C₆H₅; X = OC₆H₅) give mono- or disubstituted complexes of the type [Rh₂(COD)Cl₂{ν²−C₆H₅N(P(OC₆H₅)₂)₂}] or [RhCl{ν²−C₆H₅ N(P(OC₆H₅)₂)₂ }]₂ depending on the reaction conditions. Reaction of 1 with [Rh(CO)₂Cl]₂ gives the symmetric binuclear complex, [Rh(CO)Cl{μ−C₆H₅N(P(OC₆H₅)₂)₂} ₂, whereas the same reaction with 2 (R = CH₃; X = OC₆H₅) leads to the formation of an asymmetric complex of the type [Rh(CO)(μ−CO)Cl{μ−CH₃N(P(OC₆H₅)₂)₂}₂ containing both terminal and bridging CO groups. Interestingly the reaction of 3 (R = C₆H₅, X = OC₆H₄Br−p with either [Rh(COD)Cl]₂ or [Rh(CO)₂Cl]₂ leads only to the formation of the chlorine bridged binuclear complex, [RhCl{ν²−C₆H₅N(P(OC₆H₄Br−p)₂)₂}]₂. The structural elucidation of the complexes was carried out by elemental analyses, IR and ³¹P NMR spectroscopic data.     

Synthesis of 2α-substituted-14-epi-previtamin D3 and its genomic activity

We synthesized and isolated 2α-substituted analogs of 14-epi-previtamin D₃ after thermal isomerization at 80 °C for the first time. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were evaluated, and the 2α-methyl-substituted analog was found to have greater genomic activity than 14-epi-previtamin D₃.     

Water-filled pseudo-nanotubes in Ag11.60H0.40[Cr(C2O4)3]4 · 15H2O: Synthesis, characterization and X-ray structure

The title compound, Ag_11.60H_0.40[Cr(C₂O₄)₃]₄ · 15H₂O (1) precipitates from aqueous solution as a dark violet solid in which silver ions are partially replaced by protons, and it crystallizes in an unusual structure with water-filled one-dimensional pseudo-nanotubes.     

Plasma 13, 14-dihydro-15-keto-PGF2 (PGFM) in pregnant and nonpregnant heifers prior to and during surgery and following intrauterine injection of PGF2

On day 17 postestrus or postmating, heifers were given intrauterine injections of saline (2 pregnant, 2 non-pregnant) or 200 μg PGF₂α (7 pregnant, 6 nonpregnant) through cannulae installed surgically into the uterine horn ipsilateral to the corpus luteum bearing ovary. Jugular blood samples were collected prior to the laparotomy at which the cannulae were installed during surgery, and for 90 min following the intrauterine injection. Plasma was assayed for progesterone and 13,14-dihyro-15-keto-PGF₂α )PGFM). Laparotomies were reopened to confirm proper cannula placement and to determine if blastocysts were present in mated heifers. Concentrations of PGFM were higher in pregnant compared to nonpregnant heifers during the presurgery (68 26 24 26 pg/ml; P < 0.25) and surgery (186 47 65 17 pg/ml; P < .05) periods. Pregnancy status did not alter the mean concentrations of PGFM (pregnant, 554 70 pg/ml; nonpregnant, 422 81 pg/ml) or the half-life of its decline in concentration (18 min) following intrauterine injection of PGF₂α. Pregnancy at 17 days in cattle does not appear to influence PGF₂α transport from the uterine lumen or its metabolism in the uterus or elsewhere in response to an acute intrauterine injection.     

Metal complexes of 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine, (trimethoprim). Part II. Synthesis,magnetic characterization and X-ray structure of [Cu2(O2CCH3)4(trimethoprim)2]·2C6H6·CH3OH

The reaction of [Cu₂(O₂CCH₃)₄·2H₂O] with trimethoprim is reported. In methanol a green solution was obtained, which, on adding benzene, yielded tetrakis(μ-acetato)bis(trimethoprim)dicopper(II) di-benzene methanol solvate. The compound crystallizes with four molecules per cell in the monoclinic space group C2/c, with a = 24.109(5), b = 15.256(3), c = 16.532(3) Å, β = 116.89(2) for λ(Mo-Kα) = 0.71073 Å. The copper atoms are bridged by four acetate groups to form the binuclear molecule [Cu₂-(O₂CCH₃)₄(TMP)₂]·2C₆H₆·CH₃OH. The TMP ligand acts as a donor molecule through one pyrimidinic nitrogen atom.     

Iron-nickel mixed metal nitrido clusters: Synthesis and solid state structure of the anions [HFe5NiN(CO)14] and [HFe4Ni2N(CO)13]

The two clusters [HFe₅NiN(CO)₁₄]²⁻ (1) and [HFe₄Ni₂N(CO)₁₃]²⁻ (2) were obtained by reaction of [Fe₄N(CO)₁₂]⁻ and [Ni₆(CO)₁₂]²⁻ in refluxing MeCN and EtCN, respectively, along with other Fe-Ni mixed metal clusters. Their solid state structures were determined on the [PPh₄]⁺ salts, and both have an octahedral metal cage, containing an interstitial nitrogen atom. The two Ni atoms in 2 are cis, with a Ni-Ni separation of 2.724(1) Å. The two anions have different stereochemistry of the carbonyl ligands: in 1, five CO’s are semi-bridging, and the remaining nine are terminal; in 2 there are three asymmetric bridging and ten terminal ligands (two for each iron and one for each nickel). The hydride ligands were located in the final difference maps, both bridging a Ni-Fe edge of the clusters but, thanks to the better quality of the diffraction data, the metal-hydrogen distances were refined only in 2. In this cluster, the Fe-H and Ni-H bond lengths are 1.77(2) and 1.79(2) Å, respectively.     

Contrasting effects of peroxisome-proliferator-activated receptor (PPAR)γ agonists on membrane-associated prostaglandin E2 synthase-1 in IL-1β-stimulated rat chondrocytes: evidence for PPARγ-independent inhibition by 15-deoxy-Δ12,14prostaglandin J2

Microsomal prostaglandin E synthase (mPGES)-1 is a newly identified inducible enzyme of the arachidonic acid cascade with a key function in prostaglandin (PG)E₂ synthesis. We investigated the kinetics of inducible cyclo-oxygenase (COX)-2 and mPGES-1 expression with respect to the production of 6-keto-PGF_1α and PGE₂ in rat chondrocytes stimulated with 10 ng/ml IL-1β, and compared their modulation by peroxisome-proliferator-activated receptor (PPAR)γ agonists. Real-time PCR analysis showed that IL-1β induced COX-2 expression maximally (37-fold) at 12 hours and mPGES-1 expression maximally (68-fold) at 24 hours. Levels of 6-keto-PGF_1α and PGE₂ peaked 24 hours after stimulation with IL-1β; the induction of PGE₂ was greater (11-fold versus 70-fold, respectively). The cyclopentenone 15-deoxy-Δ^12,14prostaglandin J₂ (15d-PGJ₂) decreased prostaglandin synthesis in a dose-dependent manner (0.1 to 10 μM), with more potency on PGE₂ level than on 6-keto-PGF_1α level (-90% versus -66% at 10 μM). A high dose of 15d-PGJ₂ partly decreased COX-2 expression but decreased mPGES-1 expression almost completely at both the mRNA and protein levels. Rosiglitazone was poorly effective on these parameters even at 10 μM. Inhibitory effects of 10 μM 15d-PGJ₂ were neither reduced by PPARγ blockade with GW-9662 nor enhanced by PPARγ overexpression, supporting a PPARγ-independent mechanism. EMSA and TransAM^? analyses demonstrated that mutated IκBα almost completely suppressed the stimulating effect of IL-1β on mPGES-1 expression and PGE₂ production, whereas 15d-PGJ₂ inhibited NF-κB transactivation. These data demonstrate the following in IL-1-stimulated rat chondrocytes: first, mPGES-1 is rate limiting for PGE₂ synthesis; second, activation of the prostaglandin cascade requires NF-κB activation; third, 15d-PGJ₂ strongly inhibits the synthesis of prostaglandins, in contrast with rosiglitazone; fourth, inhibition by 15d-PGJ₂ occurs independently of PPARγ through inhibition of the NF-κB pathway; fifth, mPGES-1 is the main target of 15d-PGJ₂.