Strategic approaches to drug design. II. Modelling studies on phosphodiesterase substrates and inhibitors

Summary Modelling studies have been carried out on the phosphodiesterase (PDE) substrates, adenosine- and guanosine-35-cyclic monophosphates, and on a number of non-specific and type III-specific phosphodiesterase inhibitors. These studies have assisted the understanding of PDE substrate differentiation and the design of potent, selective PDE type III inhibitors.     

Synthesis and structure-activity relationship of N-arylrolipram derivatives as inhibitors of PDE4 isozymes

Structure activity studies of N-phenylrolipram derivatives have led to the identification of highly potent PDE4 inhibitors. The potential of these inhibitors for cellular activity was routinely assessed in an assay of fMLP induced oxidative burst in human eosinophils. Since first generation PDE4 inhibitors have been plagued with a number of unwanted side effects, parallel structure activity studies for competition with the [3H]-rolipram binding site in rat brain were performed. In this fashion 5-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-3-(3-methoxybenzyloxy)benzoic acid N',N'-dimethylhydrazide (22) was identified as a potent inhibitor of PDE4 which exhibits >1000 fold selectivity versus PDE3, and is a nanomolar inhibitor in all the cellular assays tested. Studies on the stereoselectivity of PDE4 inhibition of this class of rolipram based compounds revealed, that for example (S)-11 is a more potent inhibitor than (R)-11. This effect can also be observed in primary human cells where the (S)-enantiomer is about 10 fold more potent than the corresponding (R)-enantiomer.     

Kinetics and mechanism of Ru(III)-catalysed oxidation of organic sulphides and triphenylphosphine by N-methylmorpholine N-oxide

The selective oxidation of thioethers to sulphoxides and of PPh₃ to PPh₃O can be effected by NMO in DMF as solvent in the presence of Ru(III) chloride as catalyst. Kinetic investigations indicate that the orders with respect to the catalyst and oxidant are one each. The order with respect to the substrate is variable being fractional order at low concentrations and zero at high concentrations. Spectrophotometric studies reveal the formation of a 1:1 complex between the substrate and the catalyst. A mechanism consistent with the above observations has been proposed and verified.     

咪唑并吡啶类化合物结构及PDE抑制活性的三维构效关系研究

对咪唑并吡啶类化合物作为环核苷酸磷酸二酯酶(PDE)的抑制剂的抑制活性进行了比较分子力场分析.结果表明,立体效应和静电作用场是描述对PDE抑制活性和进行结构性能关系研究的最重要的结构参数,提出了对该类化合物进行结构修饰的方法,并由新建立的三维定量构效关系模型对该类化合物的PDE抑制活性进行了预报.     

Synthesis,structure, DNA binding studies and nuclease activities of two luminescent neodymium complexes

Two neodymium(III) complexes, [Nd(Phen)(NO₃)₃(DMF)₂] (1) and [Nd(Phen)₂(NO₃)₃] (2) (phen = 1,10-phenanthroline; DMF = dimethylformamide), have been synthesized with a view to design artificial luminescent nucleases and nuclease mimics. The complexes were characterized by spectroscopic, powder, and single crystal XRD studies. The complexes, as expected, have luminescent properties. The DNA binding studies of both complexes have been carried out by spectroscopic studies e.g. electronic absorption (UV–Vis), fluorescence emission as well as viscosity measurements. The nuclease activity of the complexes has been established by gel electrophoresis using pUC19 circular plasmid DNA. The results of DNA binding as well as DNA cleavage activity and the model studies of interaction with pNPP indicate that both neodymium complexes demonstrate nuclease activity through phosphoester bond cleavage.     

Studies on cardiotonic agents. VI. Synthesis of novel 4,5-dihydro-3(2H)-pyridazinone derivatives carrying some benzoheterocycles at the 6-position

Several benzothiazolyl, imidazobenzothiazolyl, benzothienyl, benzothienopyrimidinyl and quinazolinyl 4,5-dihydro-3(2H)-pyridazinones were synthesized and examined for cardiotonic activity in anesthetized dogs after i.v. administration. Among them, 4-methylamino-7-(2,3,4,5-tetrahydro-5-methyl-3-oxo-6- pyridazinyl)quinazoline (36) showed potent and long-lasting inotropic activity (relative potency = 2.11, milrinone = 1). The activity of 36 was more potent than indolidan (2) (relative potency = 1.53) which is one of the most potent inotropic agents to date.     

The miR-98-3p/JAG1/Notch1 axis mediates the multigenerational inheritance of osteopenia caused by maternal dexamethasone exposure in female rat offspring

As a synthetic glucocorticoid, dexamethasone is widely used to treat potential premature delivery and related diseases. Our previous studies have shown that prenatal dexamethasone exposure (PDE) can cause bone dysplasia and susceptibility to osteoporosis in female rat offspring. However, whether the effect of PDE on bone development can be extended to the third generation (F3 generation) and its multigenerational mechanism of inheritance have not been reported. In this study, we found that PDE delayed fetal bone development and reduced adult bone mass in female rat offspring of the F1 generation, and this effect of low bone mass caused by PDE even continued to the F2 and F3 generations. Furthermore, we found that PDE increases the expression of miR-98-3p but decreases JAG1/Notch1 signaling in the bone tissue of female fetal rats. Moreover, the expression changes of miR-98-3p/JAG1/Notch1 caused by PDE continued from the F1 to F3 adult offspring. Furthermore, the expression levels of miR-98-3p in oocytes of the F1 and F2 generations were increased. We also confirmed that dexamethasone upregulates the expression of miR-98-3p in vitro and shows targeted inhibition of JAG1/Notch1 signaling, leading to poor osteogenic differentiation of bone marrow mesenchymal stem cells. In conclusion, maternal dexamethasone exposure caused low bone mass in female rat offspring with a multigenerational inheritance effect, the mechanism of which is related to the inhibition of JAG1/Notch1 signaling caused by the continuous upregulation of miR-98-3p expression in bone tissues transmitted by F2 and F3 oocytes.Subject terms: Bone development, Reproductive disorders     

Combined 2D and 3D-QSAR,molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure–activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good ‘leave-one-out’ cross validated correlation coefficient (q²) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r²) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r²_pred) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called ‘glutamine-switch’, and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure–activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.     

A PDE6δ‐KRas Inhibitor Chemotype with up to Seven H‐Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2

Small‐molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (K _D<10 nm ), interference with Ras signaling and growth inhibition require 5–20 μm compound concentrations. We demonstrate that these findings can be explained by fast release of high‐affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and ‐dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas‐PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas.     

Studies in negative ion mass spectrometry. X—Electron capture by a series of tris(hexafluoroacetylacetonato) metal chelates

Results of electron capture and negative ion mass spectrometric studies are reported for a series of tris-chelates of the type Metal. L₃, where L refers to the ligand or enolate ion of the β-diketone 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (hexafluoracetylacetone), and the metals are: Sc(III), Ti(III), V(III), Cr(III), Mn(III), Fe(III), Co(III), A1(III), Ga(III), In(III). The negative ion mass spectra were all relatively simple; the most abundant ions being the molecular and ligand ions for all the metals studied. Reaction schemes have been established to account for the appearance of all significant fragment ions, many of which have been formed as a result of fluorine atom transfer processes. For the transition metal complexes, evidence for elimination of neutral divalent metal fluorides comes from the ion decomposition reactions [Metal.L.F₂]^?→[L]^?, and for the Group III metal complexes, [Metal.L₃]^?→[Metal.L₂]^? as well as [Metal.L₂]^?→[L]^? processes indicate that the metals have been reduced as a consequence of the initial electron capture and subsequent fragmentations of metal-containing ions. The influence of the metal atom and its 3d-electron configuration has been shown not to affect significantly the electron capture processes. However, the relative instabilities of molecular anions of the transition metal tris-complexes show an approximately linear dependence on the increasing 3d-electron populations of the metal ions from Ti(III) to Co(III).     

Ethylene–propylene terpolymers based on methylcyclopentadienyl-5-norborn-2-enylmethane derivatives

The terpolymerization of ethylene, propylene, and methylcyclopentadienyl-5-endonorborn-2-enylmethane (III) by means of different vanadium-based coordination catalysts was investigated. The structure of III and its isomeric composition was studied by using vapor-phase chromatography, mass spectrometry, and NMR, infrared, and ultraviolet spectroscopy. The catalyst system V Acac₃–Et₂AlCl was used under different conditions, and the influence of several variables regulating the terpolymerization process were related to the properties of the resulting terpolymers (EPTM). The insertion of III into EPTM chains takes place randomly and does not influence the random distribution of comonomers. The selective opening of the norbornene double bond of III has been demonstrated by use of 2,3-dihydro-III as model compound. Tritiated III gave a radiochemical titer of unsaturation in excellent agreement with the value deduced from ultraviolet measurements. The influence of Lewis bases added to VAcac₃–Et₂AlCl catalyst is discussed.     

Synthesis and characterization of Ru(III), Rh(III), Pt(IV) and Ir(III) thiosemicarbazone complexes

Ru(III), Rh(III), Pt(IV) and Ir(III) complexes of 2-furfural thiosemicarbazone as ligand have been synthesised. These complexes have the composition [M(ligand)₂X₂]X (M = Ru(III) Rh(III) and Ir(III) X = Cl and Br) and [Pt(ligand)₂ X₂] X₂ (X = Cl, Br and 1/2SO₄). The deprotonated ligand forms the complexes of the formulae M(ligand-H)₃ and Pt(ligand-H)₃Cl. All these complexes have been characterized by elemental analysis, magnetic measurements, electronic and infrared spectral studies. All the complexes are six-coordinate octahedral.     

Light‐Absorption Ratio Variation Approach to Sensitive and Selective Determination of Iron with Trimethoxyphenylflurone,Cetylpyridinium, and Thioglycollic Acid

The complexation between trimethoxyphenylflurone (TMPF) and Fe is highly sensitive at pH 11.80 in the presences of cetylpyridinium chloride (CPC) and thioglycolic acid (TGA), where TGA reduced TMPF into a reduced ligand (RTMPF) and Fe(III) into Fe(II). The complexations of RTMPF with CPC and Fe have been characterized by the break point approach and the spectral correction technique. The binuclear complex, Fe₂ (RTMPF)₁₀(CPC)₂₀ was formed via coordination bond and ion‐pair attraction. The Fe‐TMPF‐CPC complexation is selective in the presence of ethylenediamine tetraacetic acid (EDTA) and Al(III) so it was applied to the spectrophotometric determination of total Fe(II+III) by the light‐absorption ratio variation approach (LARVA). Results indicated that ΔA_r of the Fe‐RTMPF solution is linear at 568 and 641.5 nm at the range between 0 and 100 ng/mL Fe. The limit of detection (3σ) of Fe is only 2 ng/mL. This method was applied to analysis of several samples such as natural waters, cigarette ash, and urine with satisfactory results.     

Separation of rhenium by thin-layer chromatography with polyethyleneimine cellulose in hydrochloric acid media

Summary The thin-layer chromatographic behavior of 49 inorganic ions on polyethyleneimine (PEI) cellulose has been investigated in hydrochloric acid media (0.01–1.0 mol dm⁻³). The sorption on the cellulose decreases with increasing acid concentration for most of the ions, but As(III), Ti(IV) and Te(VI) do not exhibit any R_f variation with the acid concentration. The R_f spectra of TI(I), Cd(II), Pb(II) and Zn(II) have a maximum. Ag(I), Bi(III), Nb(V), Ta(V), Mo(VI) and W(VI) are retained tightly on the layer, due to either insoluble salt formation or extensive hydrolysis. The extremely low R_f values of Hg(II), Pd(II), Au(III), Ru(III) and Pt(IV) are accounted for by stability of their chlorocomplexes. Re(VII) distributes chromatographically, having moderate R_f values between 0.3 and 0.6, so that the selective separation of Re(VII) from the other ions is feasible.     

Tris-Nethyl, m-tolyl)dithiocarbamato complexes of arsenic(III), antimony(III) and bismuth(III)

Tris-N(ethyl, m-tolyl) dithiocarbamato complexes of arsenic(III), antimony(III) and bismuth(III) abbreviated as As(S₂CNRR′)₃ Sb(S₂CNRR′)₃ and Bi(S₂CNRR′)₃, respectively, where R  C₂H₅ and R′  m-C₆H₄CH₃, have been synthesized. These complexes have been characterized on the basis of elemental analyses, molecular weight determinations, conductance measurements and infrared spectral studies. Thermal studies of these complexes have been carried out in nitrogen and air to determine their modes of decomposition. Kinetic parameters, such as apparent activation energy and order of reaction, have been determined by the graphical method of Coats and Redfern [1].     

Separation of yttrium(III) from iron(III) through liquid membrane impregnated with di(2-ethylhexyl)phosphoric acid

The selective transport of yttrium(III) in the presence of iron(III) through a supported liquid membrane (SLM) has been investigated by using di(2-ethylhexyl)phosphoric acid (DEHPA) as a mobile carrier. Yttrium(III) with fast kinetics was preferentially transported from the feed solution of dilute acid into the product solution of 1M H₂SO₄, while most of iron(III) with slow kinetics remained in the feed solution. The effective separation of yttrium(III) from a large amount of iron(III) was accomplished by the selective transport of yttrium(III) through the SLM.     

Synthesis,spectral characterization,crystal structures of lanthanide(III) pyrrolidine dithiocarbamate complexes and their catalytic activity

A series of lanthanide(III) pyrrolidine dithiocarbamate complexes [Ln(Pyrrol-Dtc)₃(Phen)] {Pyrrol-Dtc = pyrrolidine dithiocarbamate; Phen = 1,10-phenanthroline; Ln = La(III), Ce(III), Pr(III), Nd(III), Sm(III), Gd(III), Tb(III), Dy(III), Er(III)} have been synthesized and structurally characterized. The molecular structures of [La(Pyrrol-Dtc)₃(Phen)], [Pr(Pyrrol-Dtc)₃(Phen)], [Sm(Pyrrol-Dtc)₃(Phen)], and [Dy(Pyrrol-Dtc)₃(Phen)] have been confirmed using single crystal XRD studies. The results reveal that in these complexes, the central Ln(III) ion is coordinated to three Pyrrol-Dtc and one Phen and possesses a distorted dodecahedron geometry. Catalytic activity of these complexes in trimethylsilylcyanation reaction has been studied.     

The mechanism of cyclic nucleotide hydrolysis in the phosphodiesterase catalytic site

The cyclic nucleotide phosphodiesterase superfamily of enzymes (PDEs) catalyzes the stereospecific hydrolysis of the second messengers adenosine and guanosine 3',5'- cyclic monophosphate (cAMP, cGMP) to produce 5'-AMP and 5'-GMP, respectively. The PDEs are targets of high-throughput screening to determine selective inhibitors for a variety of therapeutic purposes. The catalytic pocket where the hydrolysis takes place is a highly conserved region and has several residues which are absolutely conserved across the PDE families. In this study, we consider a model cyclic substrate in which the adenine/guanine base has been replaced with a hydrogen atom, and we present results of a quantum computational investigation of the hydrolysis reaction as it occurs within the PDE catalytic site using the ONIOM hybrid (B3LYP/6-31g(d):PM3) method. We characterize the bound substrate, the bound hydrolyzed product, and the transition state which connects them for our model cyclic substrate placed in a truncated model of the PDE4D2 catalytic site. We address the role that the conserved histidine proximal to the bimetal system of the catalytic site, along with its conserved glutamine partner, plays in the generation of the hydroxide nucleophile. Our study provides computational evidence for several key features of the cAMP/cGMP hydrolysis mechanism as it occurs within the protein environment across the PDE superfamily.     

Activation of Iron (III) and Bismuth (III) Nitrates by Tungstophosphoric Acid: Solvent‐Free Oxidative Deprotection of Oximes to Carbonyl Compounds

Abstract

Tungstophosphoric acid (H₃PW₁₂O₄₀ · 6H₂O) has been used as a catalyst for a simple, rapid, selective, and solvent‐free cleavage of oximes to carbonyl compounds using iron (III) and bismuth (III) nitrates as oxidants.     

Pd/C-Mediated Arylation Followed by I2-Catalyzed Hydration Strategy: Preparation of Functionalized Novel Indanone Derivatives

A simple and inexpensive synthesis of novel 2-(3-oxo-3-arylpropyl)-2,3-dihydro-1H-inden-1-one derivatives has been achieved via Pd/C-mediated arylation followed by I₂-mediated regioselective hydration of 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-ones. A wide variety of 3-aryl substituted 2-propynyl indanone derivatives were conveniently prepared by using 10% Pd/C-PPh₃-CuI as a catalyst system, some of which were used to prepare the corresponding ketones via alkyne hydration in the presence of catalytic I₂. In an in vitro study a representative compound showed inhibition of PDE4B (phosphodiesterase type 4B) and binding with this protein in silico