Isopropyl Analogue Research Articles

Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB)

A series of trimethylangelicin (TMA) derivatives were designed and synthesized to overcome the unwanted effects of TMA, promising agent for treatment of inflammation-related diseases and other pathologies, such as cystic fibrosis. The new generation TMA analogues bore hindered substituents at the 4 position in order to minimize or avoid the photoreactions with DNA. Among them, the 4-isopropyl-6-ethyl derivative 23 exhibited TMA-like inhibitory activity on NF-κB/DNA interactions but it proved unable to photoreact with pyrimidine bases of DNA, nor to induce any other DNA damage. The isopropyl analogue 23 was proven to lack mutagenicity when assayed through Ames test and exhibited no anti-proliferative activity on cystic fibrosis IB3-1 cells, displaying at the same time inhibition of the TNF-α induced release of the NF-κB regulated PDGF-B chain, IL-10, IL-15, IL-17 and IFN-γ. Therefore compound 23 deserves further assay to determine its anti-inflammatory properties, since it lacks photoreaction properties and mutagenicity-related side effects.

Synthesis and structure of open and closed type iron telluride – stibine cluster compounds

Open and closed type triiron chalcogenide stibine cluster molecules have been synthesized and characterized by single crystal X-ray structural studies. A comparison between the phenyl and isopropyl analogues of the open cluster compound shows some unique decarbonylation tendency for the phenyl analogue which easily converts an open cluster to a closed cluster molecule by a “butterfly wing-tip” opening mechanism. DFT study also revealed a critical behavior of such molecules in which the opening of a butterfly wing tip is governed by a decarbonylation step to give a closed cluster geometry. Antibacterial property was also studied with one of the closed cluster compound to understand their inhibition activity.

Propantheline

Propantheline

Benzothiazepine CGP37157 and its 2′-isopropyl analogue modulate Ca2+ entry through CALHM1

CALHM1 is a Ca2+ channel discovered in 2008, which plays a key role in the neuronal electrical activity, among other functions. However, there are no known efficient blockers able to modulate its Ca2+ handling ability. We herein describe that benzothiazepine CGP37157 and its newly synthesized analogue ITH12575 reduced Ca2+ influx through CALHM1 at low micromolar concentrations. These results could serve as a starting point for the development of more selective CALHM1 ligands using CGP37157 as a hit compound, which would help to study the physiological role of CALHM1 in the control of [Ca2+]cyt in excitable cells, as well as its implication in CNS diseases.

새로운 베스타틴 유사체의 입체선택적 합성

두 종류의 새로운 베스타틴(bestatin) 유사체를 <TEX>$\small{D}$</TEX>-leucine과 <TEX>$\small{D}$</TEX>-valine으로부터 효율적이면서 입체선택적으로 합성하였다. 아미노펩티데이즈 억제제인 베스타틴은 면역조절 효과를 보이며 급성백혈병 치료제로 상품화되어 있다. 주요 중간체인 trans-옥사졸리딘 메틸에스터 2a와 2b는 페닐설포닐나이트로메테인(<TEX>$PhSO_2CH_2NO_2$</TEX>)과 N-하이드록시 메틸기가 보호기로 도입된 <TEX>${\alpha}$</TEX>-아미노 알데하이드(4a와 4b) 간의 일련의 세 단계 연속반응과 연이은 가오존분해 반응으로부터 20 : 1 이상의 입체선택성으로 합성되었다. 2a와 2b의 가수분해 반응 후에 <TEX>$\small{L}$</TEX>-Leu-OMe와의 펩타이드 결합을 통하여 베스타틴의 새로운 유사체인 3a와 3b를 보호기가 도입된 형태로 얻었다. 이소부틸기와 이소프로필기를 갖는 두 종류의 새로운 베스타틴 유사체(1a와 1b)는 해당 <TEX>${\alpha}$</TEX>-아미노알데하이드 4로부터 높은 입체선택성으로 6단계에 걸쳐 각각 51%와 38%의 수율로 합성되었다. Two new analogs of bestatin were prepared from <TEX>$\small{D}$</TEX>-leucine and <TEX>$\small{D}$</TEX>-valine in a stereoselective and efficient way. An aminopeptidase inhibitor bestatin shows significant biological effects on immunomodulation and is marketed for the treatment of acute myelocytic leukemia. The key intermediates, trans-oxazolidine methyl esters 2a and 2b, were obtained with more than 20 to 1 stereoselectivity in a one-pot procedure by the three cascade reactions between N-hydroxymethyl protected <TEX>${\alpha}$</TEX>-amino aldehydes (4a and 4b) and phenylsulfonylnitromethane (<TEX>$PhSO_2CH_2NO_2$</TEX>) and the following in-situ ozonolysis. Basic hydrolysis of 2a and 2b, and then the peptide coupling with <TEX>$\small{L}$</TEX>-Leu-OMe produced the protected derivatives of two new bestatin analogs, 3a and 3b, respectively. The new isobutyl and isopropyl analogs of bestatin (1a and 1b) were produced in overall 51% and 38% yields, respectively, with high stereoselectivity from the corresponding protected <TEX>${\alpha}$</TEX>-amino aldehydes 4 in a six-step process.

Development of Phosphonate Monoesters Building Units in Metal-Organic Frameworks

The use of predictable coordination geometries and the development of new ligands has allowed supramolecular chemists to design a plethora of new materials. Among these are metal-organic frameworks (MOFs), which are composed of ligands coordinating to metal atoms or clusters to generate a framework with potential porosity. MOFs exemplify supramolecular design strategy as their extended structure and tunable properties allow them to be applied for various applications.1 To date, many MOFs utilize carboxylates as the coordinating group since they have well studied coordination geometries and thus predictable framework topologies. Though there are examples of carboxylate-based MOFs possessing water stability, most do not possess this key feature, hindering their application in industrial settings. Phosphonate monoesters (PMEs) have been investigated as a means to impart water stability to a MOF by kinetically shielding the linker-metal bond with the ester moiety.2 Unfortunately, phosphonate monoesters have relatively unexplored coordination geometries, with most studies focusing on chlodronic acid and its derivatives, which do not typically form porous materials. In an attempt to establish building units based on PMEs, 1,4-benzenediphosphonate monoester ligands have been synthesized, coordinated to Cu(II), and characterized. It was found that while the methyl and ethyl analogues form similar 3-D structures with poor water stability,3 the isopropyl analogue forms a layered material possessing water stability. The isopropyl analogue contains chains of Cu-PME, with the isopropyl esters lying directly above and below the Cu atoms, kinetically shielding this bond from water. This water stable building unit was predicted to generate a porous framework with non-linear ligands. To test this hypothesis, 1,3,5-benzenetriphosphonate monoisopropyl ester was synthesized and coordinated to Cu(II). Unfortunately, no single crystal of sufficient quality has been produced, though a predicted and refined structure matches well to various characterization techniques. As predicted, this material is porous and does not degrade in harsh humid conditions (353K and 90% relative humidity).

Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1–7nM potency towards both the wild-type virus and a Tyr181C variant.

Cyclopropyl and Isopropyl Derivatives of 11-cis and 9-cis Retinals at C-9 and C-13: Subtle Steric Differences with Major Effects on Ligand Efficacy in Rhodopsin

Retinal is the natural ligand (chromophore) of the vertebrate rod visual pigment. It occurs in either the 11-cis (rhodopsin) or the 9-cis (isorhodopsin) configuration. In its evolution to a G protein coupled photoreceptor, rhodopsin has acquired exceptional photochemical properties. Illumination isomerizes the chromophore to the all-trans isomer, which acts as a full agonist. This process is extremely efficient, and there is abundant evidence that the C-9 and C-13 methyl groups of retinal play a pivotal role in this process. To examine the steric limits of the C-9 and C-13 methyl binding pocket of the binding site, we have prepared C-9 and C-13 cyclopropyl and isopropyl derivatives of its native ligands and of α-retinal at C-9. Most isopropyl analogues show very poor binding, except for 9-cis-13-isopropylretinal. Most cyclopropyl derivatives exhibit intermediate binding activity, except for 9-cis-13-cyclopropylretinal, which presents good binding activity. In general, the binding site shows preference for the 9-cis analogues over the 11-cis analogues. In fact, 13-isopropyl-9-cis-retinal acts as a superagonist after illumination. Another surprising finding was that 9-cyclopropylisorhodopsin is more like native rhodopsin with respect to spectral and photochemical properties, whereas 9-cyclopropylrhodopsin behaves more like native isorhodopsin in these aspects.

Preferential selection of isomer binding from chiral mixtures: alternate binding modes observed for the E and Z isomers of a series of 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines as ternary complexes with NADPH and human dihydrofolate reductase.

The crystal structures of six human dihydrofolate reductase (hDHFR) ternary complexes with NADPH and a series of mixed E/Z isomers of 5-substituted 5-[2-(2-methoxyphenyl)-prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines substituted at the C9 position with propyl, isopropyl, cyclopropyl, butyl, isobutyl and sec-butyl (E2-E7, Z3) were determined and the results were compared with the resolved E and Z isomers of the C9-methyl parent compound. The configuration of all of the inhibitors, save one, was observed as the E isomer, in which the binding of the furopyrimidine ring is flipped such that the 4-amino group binds in the 4-oxo site of folate. The Z3isomer of the C9-isopropyl analog has the normal 2,4-diaminopyrimidine ring binding geometry, with the furo oxygen near Glu30 and the 4-amino group interacting near the cofactor nicotinamide ring. Electron-density maps for these structures revealed the binding of only one isomer to hDHFR, despite the fact that chiral mixtures (E:Z ratios of 2:1, 3:1 and 3:2) of the inhibitors were incubated with hDHFR prior to crystallization. Superposition of the hDHFR complexes with E2 and Z3 shows that the 2'-methoxyphenyl ring of E2 is perpendicular to that of Z3. The most potent inhibitor in this series is the isopropyl analog Z3 and the least potent is the isobutyl analog E6, consistent with data that show that the Z isomer makes the most favorable interactions with the active-site residues. The isobutyl moiety of E6 is observed in two orientations and the resultant steric crowding of the E6 analog is consistent with its weaker activity. The alternative binding modes observed for the furopyrimidine ring in these E/Z isomers suggest that new templates can be designed to probe these binding regions of the DHFR active site.

ChemInform Abstract: An Efficient Low‐Temperature Stille—Migita Cross‐Coupling Reaction for Heteroaromatic Compounds by Pd—PEPPSI—IPent.

AbstractThe isopentyl‐substituted Pd‐PEPPSI precatalyst is shown to show higher efficiency in the Stille—Migita cross‐coupling reaction than its known isopropyl analogue.

The Preparation, Characterization, X-ray Structural Analysis, and Thermogravimetric Analysis of Tetrakis[1,3-Dimethyl-2(3H)-Imidazolethione]Zinc(II) Nitrate and Tetrafluoroborate

Two new compounds, [Zn(dmit)4][BF4]2 and [Zn(dmit)4][NO3]2, have been synthesized and characterized via standard solid and solution state methods including single crystal X-ray crystallography (dmit = 1,3-dimethyl-2(3H)-imidazolethione). [Zn(dmit)4][BF4]2 crystallizes in space group Pbcn with a = 11.954(2) A, b = 21.260(4) A, c = 12.749(3) A, Z = 4. [Zn(dmit)4][NO3]2 crystallizes in space group I 4 1 /a with a = b = 11.091(4) A, c = 22.713(5) A, Z = 4. Both structures display a compressed tetrahedral geometry in the zinc coordination sphere similar to previously reported isopropyl and n-butyl analogs. The degree of distortion is closer to that noted for the recently reported methyl isopropyl analog than to the methyl n-butyl complex. There are no significant differences between the nitrate and tetrafluoroborate coordination spheres, and the source of distortion appears to be close intramolecular contacts. Thermogravimetric analysis results suggest that both complexes decompose to yield ZnS2 instead of ZnS. A two new ionic complexes of 1,3-dmethyl-2(3H)-imidazolethione (dmit) containing tetra-S-coordinated Zn(II) have been synthesized and structurally characterized. Both nitrate and tetrafluoroborate analogs have distorted tetrahedral coordination geometry around the zinc ions similar to that noted for complexes with bulkier alkyl imidazolethiones. There are no significant differences between the nitrate and tetrafluoroborate coordination spheres, and the source of distortion appears to be close intramolecular contacts.

Bioisosteric replacement of the hydrazide pharmacophore of the cannabinoid-1 receptor antagonist SR141716A. Part I: Potent, orally-active 1,4-disubstituted imidazoles

A new series of CB 1 receptor antagonists incorporating an imidazole-based isosteric replacement for the hydrazide moiety of rimonabant (SR141716) is disclosed. Members of this imidazole series possess potent/selective binding to the rCB 1 receptor and exhibit potent hCB 1 functional activity. Isopropyl analog 9a demonstrated activity in the tetrad assay and was orally-active in a food intake model.

Alkylated Trimethylene-Bridged Bis(p-Phenylenediamines)

One and two electron oxidation of N,N',N'',N'''-tetramethyl-1,5,12,16-tetraaza[5,5]paracyclophane (Me3C), a bis-trimethylene bridged bis-p-phenylene diamine (PD), and its ethyl and isopropyl analogues are discussed. The monocation and dication are both stable, as demonstrated by optical studies that show they are in equilibrium in solution, with an especially small difference in first and second oxidation potentials for Me3C in MeCN (+23 to -20 mV, measured by simulation of the optical spectrum and of the cyclic voltammogram, respectively). The monocations have charge localized in one PD unit and show a Hush-type mixed valence transition between their PD0 and PD.+ groups. The dications Me3C2+ and Et3C2+ have optical spectra that appear to show large splittings between their PD.+ groups and have a weak ESR spectrum, and 1H NMR data show that the former is a ground-state singlet. iPr3C2+ has a very different optical spectrum and exhibits a triplet ESR spectrum at 120 K. X-ray crystal structures show that for Me3C0 the N(CH2)3N units on each side are in doubly anti (aa) conformations that put the aryl rings as far apart as possible, but Me3C2+ has doubly gg N(CH2)3N trimethylene bridges and both N,N and C,C distances between the PD.+ groups that are significantly below van der Walls contact. In contrast, iPr3C0 is in a doubly ag conformation, and its diradical dication is suggested to be a triplet because it does not attain the doubly gg conformation.

Unusual effect of bulky isopropyl group on robustness of the U-motif in pyrazolo[3,4- d]pyrimidine core based ‘Leonard linker’ compounds in comparison to methyl/ethyl group: A 1H NMR and X-ray crystallographic study

X-ray crystallographic analysis of new symmetrical ‘Leonard/trimethylene linker’ isopropyl analog 1,3-bis(4-isopropoxy-6-methylsulfonyl-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)propane ( 1h) does not show chain motif formed due to intermolecular C H…O interactions between O atoms of sulfonyl groups and central methylene H atoms of linker along with C H…N interactions or plus (+) motif shown earlier by corresponding methyl- ( 1f) and ethyl- ( 1g) analogs. More importantly, the more or less superimposed U-motif conformation of 1h is very different from earlier related 10 symmetrical compounds ( 1a– 1g & 2). In 1h intramolecular folding is in such a way that whole pyrazolo[3,4- d]pyrimidine core of one side stacks more or less face-to-face on opposite side of the same molecule while in earlier compounds ( 1a– 1g & 2) there is no intramolecular stacking between pyrazolo portions and only pyrimidine portions partially stack with each other. Surprisingly, ethyl analog ( 1i) of 1h again shows U-motif conformation similar to earlier related ten symmetrical compounds ( 1a– 1g & 2). Supramolecular structures of both compounds ( 1h & 1i) are stabilized by weak intermolecular C H…O, C H…N and π–π interactions.

The preparation, characterization and X-ray structural analysis of tetrakis[1-methyl-3-(2-propyl)-2(3H)-imidazolethione]zinc(II) tetrafluoroborate and tetrakis[1-methyl-3-(1-butyl)-2(3H)- imidazolethione]zinc(II) tetrafluoroborate

Two compounds, [Zn(mipit)4][BF4]2 (1) and [Zn(mnbit)4][BF4]2 (2) have been synthesized and characterized via standard solid and solution state methods including single crystal X-ray crystallography (mipit: 1-methyl-3-(2-propyl)-2(3H)-imidazolethione and mnbit: 1-methyl-3-(1-butyl)-2(3H)-imidazolethione). Compound 1 crystallizes in monoclinic space group P21/n with a = 11.804(2) A, b = 16.710(3) A, c = 25.763(5) A, γ = 90.14(3)° and Z = 4, whereas compound 2 crystallizes in tetragonal space group $${\rm I}\bar{4}$$ with a = b = 11.6517(16) A, c= 16.820(3) A, and Z = 2. Both complexes are high melting, colorless water soluble 2:1 electrolyte solids that state have flattened tetrahedral ZnS4 coordination geometry. The isopropyl analog is slightly more distorted than the n-butyl analog, and the degree of distortion is not directly related to the steric bulk of the ligand.

Controlling Both Ground- and Excited-State Thermal Barriers to Bergman Cyclization with Alkyne Termini Substitution

The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd0 catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c-e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a-d undergo zinc insertion upon treatment with Zn(OAc)2.2H2O in CHCl3/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a-d) in 70-92% yields. Thermal Bergman cyclization of 1a-e and 2a-d was studied in chlorobenzene and approximately 35-fold 1,4-cyclohexadiene at 120-210 degrees C. Compounds 1b and 2b with R = H react at lower temperature (120 degrees C) and produce cyclized products 3b and 4b in higher yields (65-70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the -TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 degrees C in chlorobenzene/CHD for 24 h. Photolysis (at lambda >/= 395 nm) of 1b and 2b at 10 degrees C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 degrees C in the dark. Unlike thermolysis at 125 degrees C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c: 5%; 4c: 8% based on 1H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 degrees C with lambda >/= 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the porphyrin electronic transitions leads to sufficient distortion to generate photoproduct even with long wavelength excitation.

A sensitive internal standard method for the determination of melatonin in mammals using precolumn oxidation reversed-phase high-performance liquid chromatography

A sensitive and accurate internal standard method to determine melatonin in mammalian tissues and physiological fluids has been described. This method includes the oxidation of melatonin to a highly fluorescent compound, N-[(6-methoxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl]acetamide (6-MOQMA), and the determination of 6-MOQMA by a reversed-phase HPLC system. For the accurate and reliable determination, several melatonin analogs were designed and utilized as the internal standards, and ethyl and isopropyl analogs (having the corresponding alkyl group via the amide bond of melatonin instead of the methyl group) were found to be promising. Using these internal standards, highly accurate and sensitive determination could be accomplished using rat pineal gland samples, and the clear circadian rhythms are demonstrated. This method was also successfully applied to the determination of melatonin in a small amount (20 μL) of human saliva.

A sensitive internal standard method for the determination of melatonin in mammals using precolumn oxidation reversed-phase high-performance liquid chromatography

A sensitive and accurate internal standard method to determine melatonin in mammalian tissues and physiological fluids has been described. This method includes the oxidation of melatonin to a highly fluorescent compound, N-[(6-methoxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl]acetamide (6-MOQMA), and the determination of 6-MOQMA by a reversed-phase HPLC system. For the accurate and reliable determination, several melatonin analogs were designed and utilized as the internal standards, and ethyl and isopropyl analogs (having the corresponding alkyl group via the amide bond of melatonin instead of the methyl group) were found to be promising. Using these internal standards, highly accurate and sensitive determination could be accomplished using rat pineal gland samples, and the clear circadian rhythms are demonstrated. This method was also successfully applied to the determination of melatonin in a small amount (20 μL) of human saliva.

New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5–10 mg/kg) and tocainide (7–20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2–4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.

General Preference for Alkyl/Phenyl Folded Conformations. Relevance of the CH/π and CH/O Interactions to Stereochemistry as Evidenced by Ab Initio MO Calculations

Abstract Ab initio MO calculations were carried out, at the MP2/6-311G(d,p)//MP2/6-31G(d) level, to determine the conformational energy of alkyl 1-phenylethyl sulfoxides, CH3CH(C6H5)–S(O)–R (R = CH3, C2H5, i-C3H7, and t-C4H9). In every case, a geometry (rotamer a, R/C6H5 torsion angle φ ∼ 60°) where the alkyl group (R) is gauche to the C6H5 (Ph) and anti to the benzylic methyl group (Me) has been found to be the most stable. Rotamer b (φ ∼ 300°), where R is flanked by Me and Ph, has been shown the next most stable in every case except for isopropyl and t-butyl analogue with the threo configuration. The R/Ph anti conformation (rotamer c: φ ∼ 180°) has been found the least stable. Interatomic distances (CH/π as well as CH/O) at the stable geometries are found to be very short. These results are interpreted in the context of the attractive CH/π and CH/O hydrogen bonds and the unfavorable electrostatic interaction between the S–O dipole and the quadrupole of the phenyl group. In view of the above result and of previous findings, the alkyl/phenyl congested folded conformation of aralkyl compounds has been suggested to be a general phenomenon.