Para Analogs Research Articles

Iridium Complexes with Bidentate Pyridinylidene/N-Amidate Ligands for Transfer Hydrogenation Catalysis.

A series of iridium pentamethylcyclopentadienyl (Cp*) complexes, [Cp*Ir(κ2-RLp/m)Cl], that contain the strongly coordinating bidentate ligands RLp/m were synthesized. The donor groups of the bidentate ligands were an N-amidate and either a para-pyridinylidene remote N-heterocyclic carbene (RLp) or a meta-pyridinylidene remote N-heterocyclic carbene (RLm). For each type of bidentate ligand, a set of iridium complexes was synthesized, which differed only according to the substituents (R) on the phenyl ring associated with the amidate group. The iridium complexes were all fully characterized and molecular structures were obtained by single-crystal X-ray diffraction studies for representative examples. The complexes were found to be good precatalysts in iso-propanol for the transfer hydrogenation of benzaldehyde to give benzyl alcohol. The catalytic activity correlated with the Hammett σm/p parameters of the phenyl ring substituents, with more electron-donating substituents leading to increased catalytic activity. In all cases, the meta-pyridinylidene complexes, [Cp*Ir(κ2-RLm)Cl], performed better than the corresponding para analogues, [Cp*Ir(κ2-RLp)Cl].

Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity

As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC50 values = 0.015 and 0.005 μM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays.

SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules.

A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibitors of N-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound 4 bound well into the colchicine-binding pocket of tubulin. Indeed, 4 suppressed tubulin polymerization, caused G2/M cell cycle arrest, and induced apoptosis. Also, 4 inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with para analogue 5. In accordance with this, the computed free energy of binding of 5 to tubulin was lower in magnitude than that for 4 and appeared to arise in part from the inability of the para substituent to occupy a tubulin subpocket, which is possible in the meta orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (meta versus para). The meta-substituted isoquinolinone 4 is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features.

Direct Arylation of Dipyrrolonaphthyridinediones Leads to Red‐Emitting Dyes with Conformational Freedom

A series of bis-aryl dipyrrolonaphthyridinediones (DPNDs) with various substitution patterns have been designed and synthesized by direct arylation. This reaction occurs regioselectively at positions 3 and 9, which gives a straightforward entry to unique dyes that absorb in the red/far-red region and emit in the far-red/NIR region. The photophysical properties (absorption and fluorescence wavelength) can be controlled by altering the steric hindrance and electronic character of the peripheral aryl group. The fluorescence quantum yields are moderate in the majority of cases and almost independent of changes in the solvent polarity. DPNDs bearing substituents at the ortho position that prevent free rotation of the phenyl ring emit stronger fluorescence relative to the unhindered para analogues and, at the same time their absorption and emission bands are blueshifted. We have used computational methods to explain why electron-donating substituents have significantly stronger effects than electron-withdrawing substituents on the optical properties by invoking the electron-accepting character of the DPND. Electrochemical measurements revealed that the HOMO and LUMO, as well as the electrochemical band gap, also depend strongly on the electronic character of the peripheral group.

Structural and photophysical characterization of mono- and binuclear Cu(i) complexes based on carbohydrazones: a combined experimental and computational study

Pyridinyl carbohydrazone ligands with different positions between functional groups of –NNHC(O)– and Npy (ortho-, meta- and para-) have been applied for the synthesis of cuprous halide complexes. X-ray crystallography reveals that the ortho analogous ligand, Lo, functions in a chelating mode, adopting a mononuclear structure in complex Co, [CuClLoPPh3], while the meta and para analogs, Lm and Lp, act as ambidentate ligands, coordinating through the Npy atom in halogen-bridged binuclear complexes [Cu(μ-X)LPPh3]2 (X = Cl, Br, I and L = Lm, Lp). The influence of non-covalent intermolecular interactions on the assembly of the final structures has been discussed by geometrical and Hirshfeld analyses. Moreover, the photophysical properties of the complexes have been explored, both experimentally and theoretically. The influence of ligand structure and halide variations on the structural and photophysical aspects of the complexes has been considered in this study.

Halogen-substituted (C-β-d-glucopyranosyl)-hydroquinone regioisomers: Synthesis, enzymatic evaluation and their binding to glycogen phosphorylase

Electrophilic halogenation of C-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl) 1,4-dimethoxybenzene (1) afforded regioselectively products halogenated at the para position to the d-glucosyl moiety (8, 9) that were deacetylated to 3 (chloride) and 16 (bromide). For preparing meta regioisomers, 1 was efficiently oxidized with CAN to afford C-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl) 1,4-benzoquinone 2 which, in either MeOH or H2O–THF containing few equivalents of AcCl, added hydrochloric acid to produce predominantly meta (with respect to the sugar moiety) chlorinated hydroquinone derivatives 5 and 18, this latter being deacetylated to 4. The deacetylated meta (4, 5) or para (3, 16) halohydroquinones were evaluated as inhibitors of glycogen phosphorylase (GP, a molecular target for inhibition of hepatic glycogenolysis under high glucose concentrations) by kinetics and X-ray crystallography. These compounds are competitive inhibitors of GPb with respect to α-d-glucose-1-phosphate. The measured IC50 values (μM) [169.9±10.0 (3), 95 (4), 39.8±0.3 (5) 136.4±4.9 (16)] showed that the meta halogenated inhibitors (4, 5) are more potent than their para analogs (3, 16). The crystal structures of GPb in complex with these compounds at high resolution (1.97–2.05Å) revealed that the inhibitors are accommodated at the catalytic site and stabilize the T conformation of the enzyme. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions with protein residues of the different substituents on the aromatic part of the inhibitors.

Synthesis and biological evaluation of radioiodinated phospholipid ether analogs

Previous work has shown that radioiodinated phospholipid ether analogs with the iodine-125 substituted on the meta position of the aromatic ring readily localized in a variety of animal tumors. In an effort to ascertain the importance of such meta substitution, three phospholipid ether analogs with the iodine-125 in the para position were synthesized for evaluation as potential tumor-localizing imaging agents. 12-( p-Iodophenyl)dodecyl phosphocholine, l- O-[12-( p-iodophenyl)dodecyl]-1,3-propanediol-3-phosphocholine, and 1- O-[12-( p-iodophenyl)dodecyl]-2- O-methyl-3- rac-glycerophosphocholine were synthesized and labeled with iodine-125 via an isotope exchange procedure. Similar to previous results with the meta substituted analogs, tissue distribution studies with the three para analogs demonstrated tumor localization and retention of radioactivity at 24 h after i.v. injection. In all three cases, the para isomers showed greater tumor avidity than the meta isomers and clearance of the radiotracer from the tumor was much slower than the clearance from nontarget tissue. 12-( p-Iodophenyl)dodecyl phosphocholine afforded the greatest tumor-to-nontarget tissue ratio. For example, the tumor-to-blood and tumor-to-liver ratios at 24 h were 10.96 and 1.85, respectively. As a result of such selective tumor retention, it was possible to clearly delineate the tumor using γ-camera scintigraphy.

Reactions of polar dienes with o-quinones

The behaviour of various types of polar dienes towards halogenated ortho quinones has been investigated in a number of representative cases. As compared to the commonly used para analogues, o-quinones provide a wide range of products that indicate a keener response to the nature, number, and position of substituents on both reactants. 3-Halogenated-o-naphthoquinones 1 and 2 react smoothly with a representative vinologous ketene acetal 3, vinylketene acetals 4 and 5, and a monooxygenated diene 6 to provide variously substituted phenanthrenequinones 7–11. Only monooxygenated dienes on the other hand add to o-benzoquinones 14–16 and give convenient syntheses of the corresponding o-naphthoquinones 18–20. Keywords: cycloaddition, o-naphthoquinones, phenanthrenequinones, regiospecificity.

Effect of neighboring pyridinium groups on the basic hydrolysis of arylbenzoate esters

Arylbenzoate esters with a quaternary pyridinium group ortho to the ester function exhibit enhanced reactivity towards basic hydrolysis relative to their para analogs in the order pyridinium < 4-aminocarbonylpyridinium < 3-aminocarbonylpyridinium < 3-aminocarbonylquinolium. In contrast, a trimethylammonium group in the ortho position shows a decelerating effect relative to the para analog. It is concluded that the catalytic effect of a neighboring pyridinium group is based upon interaction of the negatively charged transition state of ester hydrolysis with the electron deficient π-system of the pyridinium ring. For the p -methoxy-phenolate ester containing the 3-aminocarbonylpyridinium group in the ortho position this interaction leads to a change in mechanism from rate limiting hydroxide ion attack to hydroxide ion catalyzed expulsion of the leaving group as became apparent from deviation of the Hammett plot and second-order dependence on OH - concentration. For the p -nitrophenolate ester it was observed that decrease of the solvent polarity by addition of dioxane results in an increase of the rate of hydrolysis and a marked increase of the neighboring group effect.

195Pt, 119Sn and 31P NMR studies of alkyl, aryl and acyl trichlorostannate complexes of platinum(II). The crystal structure of trans-[Pt(SnCl 3)(COC 6H 5)(PEt 3) 2

195Pt, 119Sn and 31P NMR characteristics of the complexes trans-[Pt(SnCl 3)(carbon ligand)(PEt 3) 2] ( 1a- 1e) are reported, (carbon ligand = CH 3 ( 1a), CH 2Ph ( 1b), COPh ( 1c), C 6Cl 5 ( 1d), C 6Cl 4Y ( e); Y = meta- and para-NO 2, CF 3, Br, H, CH 3, OCH 3, or Pt(SnCl 3)(PEt 3) 2. The values of 1 J( 195Pt, 119Sn) vary from 2376 to 11895 Hz with the COPh ligand having the smallest and the C 6Cl 5 ligand the largest value, making a total range for this coupling constant, when the dimer syn- trans-[PtCl(SnCl 3)(PEt 3)] 2 is included, of ca. 33000 Hz. In the meta- and para-substituted phenyl complexes 1 J( 195Pt, 119Sn) (a) is greater for electron-withdrawing substituents, (b) varies more for the meta-substituted derivatives (5634 to 7906 Hz) than for the para analogues (6088 to 7644 Hz) and (c) has the lowest values when the Pt(SnCl 3)(PEt 3) 2 group is the meta- or para-substituent. The direction of the change in 1 J( 195Pt, 119Sn) is opposite to that found for 1 J( 195Pt, 119P). For the aryl complexes linear correlations are observed between δ( 119Sn), 1 J( 195Pt, 119Sn), 1 J( 195Pt, 31P), 1 J( 119Sn, 31P) and the Hammett substituent constant σ n . δ( 119Sn) and 1 J( 195Pt, 119Sn) are related linearly to v(Pt-H) in the complexes trans-[PtH(C 6H 4Y)(PEt 3) 2]; δ( 119Sn) and δ( 1H) (hydride) are also linearly related. Based on 1 J( 195Pt, 119Sn), the acyl ligand is suggested to have a very large NMR trans influence. The differences in the NMR parameters for ( 1a-e) are rationalized in terms of differing σ- and π-bonding abilities of the carbon ligands. The structure of 1c has been determined by crystallographic methods. The complex has a slightly distorted square planar geometry with trans-PEt 3 ligands. Relevant bond lengths (Å) and bond angles (°) are: PtSn, 2.634(1), PtP, 2.324(4) and 2.329(4), PtC, 2.05(1); PPtP, 170.7(6), SnPtC, 173.0(3), SnPtP, 92.1(1), 91.7(1), PPtC, 88.8(4) and 88.3(4). The PtSn bond separation is the longest yet observed for square-planar platinum trichlorostannate complexes, and would be consistent with a large crystallographic trans influence of the benzoyl ligand. The PtSn bond separation is shown to correlate with 1 J( 195Pt, 119Sn).

N-Alkyl Toluamides in Cloth as Repellents for Mosquitoes, Ticks, and Chiggers

Of 37 N -alkyl toluamides synthesized and tested in this study, the ortho, meta , and Para isomers of N,N -diethyltoluamide were the most effective as mosquito repellents, the meta and Para analogs persisting for 39 and 74 days. Against ticks the dibutyltoluamides were the most effective, the N,N -dibutyl Para isomer remainig so for 70 days. Many of the compounds knocked chiggers down rapidly, but only the diisopropyl-, dibutyl-, and diisobutyltoluamides resisted removal from clothing by soap-and-water washing; N,N -diisopropyl- p -toluamide survived seven such washings.