Analogues 1a Research Articles

Specific Targeting of Peripheral Serotonin 5-HT3Receptors. Synthesis, Biological Investigation, and Structure−Activity Relationships

The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.

Asymmetric and Symmetric Dipole−Dipole Interactions Drive Distinct Aggregation and Emission Behavior of Intramolecular Charge-Transfer Molecules

Three intramolecular charge-transfer (ICT) compounds with dithiole−nitrofluorene strong push−pull diads have been synthesized and fabricated into well-formed and morphology-controllable supramolecular self-assemblies. Although the difference in chemical structures of the compounds is slight, they exhibit rather distinct self-assembly behaviors driven by asymmetric or symmetric dipole−dipole interactions. The morphologies of the microsized suprastructures can be easily tuned by changing main operation parameters and the morphologies are observed to transit from kinetically to thermodynamically stable supraarchitectures. UV−vis spectra of the compounds are aggregation-dependent and the trinitro-substituted analogue (1a) is observed to be AIE active. The red emitting behavior of the well-formed hierarchical structured supraarchitectures endows the material with potential applications in the fields of OLEDs, molecular probes, biolabels, and so on.

Syntheses, X-ray structures, and redox behaviour of the group 14 bis-boraamidinates M[PhB(μ-N-t-Bu)2]2 (M = Ge, Sn) and Li2M[PhB(μ-N-t-Bu)2]2 (M = Sn, Pb)

The solid-state structures of the complexes M[PhB(μ-N-t-Bu)2]2 (1a, M= Ge; 1b, M = Sn) were determined to be spirocyclic with two orthogonal boraamidinate (bam) ligands N,N′-chelated to the group 14 centre. Oxidation of 1b with SO2Cl2 afforded the thermally unstable, blue radical cation {Sn[PhB(μ-N-t-Bu)2]2}•+, identified by electron paramagnetic resonance (EPR) spectroscopy supported by density functional theory (DFT) calculations, whereas the germanium analogue 1a was inert towards SO2Cl2. The reaction between Li2[PhB(μ-N-t-Bu)2]2 and SnCl2 or PbI2 in 2:1 molar ratio in diethyl ether produced the novel heterotrimetallic complexes Li2Sn[PhB(μ-N-t-Bu)2]2 (2b) and (Et2O·Li)LiPb[PhB(μ-N-t-Bu)2]2 (2c·OEt2), respectively. By contrast, treatment of Li2[PhB(μ-N-t-Bu)2]2 with C4H8O2·GeCl2 yielded the germanium(IV) complex 1a via a redox process. The X-ray structures of 2b and 2c·THF revealed polycyclic arrangements in which one bam ligand is N,N′-chelated to the Sn(II) or Pb(II) atom and one of the Li+ cations, while the second bam ligand exhibits a unique bonding mode, bridging all three metal centres. The fluctional behaviour of 2b was investigated by variable temperature, multinuclear NMR spectroscopy.

Structure-based design and synthesis of macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors

The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a– h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.

Preparation and Chemical Properties of 5-Dialkylaminomethylhydantoins and 2-Thio-Analogues

An efficient procedure for the preparation of 5-dialkylaminomethylhydantoins 3, which are easily obtained from cyclization of the corresponding urea derivatives 2 starting with beta-aminoalanines 1, is described. Methylenehydantoin and the corresponding 2-thio analogue (4a, 4b) were obtained from hydantoins 3a and 3b, respectively. Some new chemical properties of these hydantoin derivatives are reported.

Aqueous syntheses of [(Cp-R)M(CO) 3] type complexes (Cp = cyclopentadienyl, M = Mn, 99mTc, Re) with bioactive functionalities

We describe reactions of [ 99mTc(H 2O) 3(CO) 3)] + ( 1) with Diels–Alder products of cyclopentadiene such as “Thiele’s acid” (HCp-COOH) 2 ( 2) and derivatives thereof in which the corresponding [(Cp-COOH) 99mTc(CO) 3)] ( 3) complex did form in water. We propose a metal mediated Diels–Alder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR) 2 ( 4a–c) ( 4a, R = benzyl amine; 4b, R = N α-Boc- l-2,3-diaminopropionic acid and 4c, R = glycine). The corresponding 99mTc complexes [( 4a) 99mTc(CO) 3)] 6a, [( 4b) 99mTc(CO) 3)] 6b and [( 4c) 99mTc(CO) 3)] 6c have been prepared along the same route as for Thiele’s acid in aqueous media demonstrating the general applicability of this synthetic strategy. The authenticity of the 99mTc complexes on the no carrier added level have been confirmed by chromatographic comparison with the structurally characterized manganese or rhenium complexes. Studies of the reaction of 1 with Thiele’s acid bound to a solid phase resin demonstrated the formation of [(Cp-COOH) 99mTc(CO) 3)] 3 in a heterogeneous reaction. This is the first evidence for the formation of no carrier added 99mTc radiopharmaceuticals containing cyclopentadienyl ligands via solid phase syntheses. Macroscopically, the manganese analogue 5a and the rhenium complexes 5b–c have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P2 1/ c, a = 9.8696(2) Å, b = 25.8533(4) Å, c = 11.8414(2) Å, β = 98.7322(17)°) in order to unambiguously assign the authenticity of the corresponding 99mTc complexes.

Imidazol-2-yl Complexes of Cp*Ir as Bifunctional Ambident Reactants

Loss of chloride ion from imidazol-2-yl complex 4a activates the H-H bond of dihydrogen or the C-H bond of acetylene, forming an Ir(III) N-heterocyclic carbene (NHC) complex (3b or 9). Deprotonation of Ir(III) hydride 4b gives one new species, formulated as Ir(I) carbene complex 5. Protonation or alkylation of 5 occurs at the metal, returning the Ir(III) core of 6a,b. Deprotonation of cationic NHC complex 3a gives neutral imidazol-2-yl analogue 4a; as seen by X-ray diffraction, the Ir-C bond in 3a is shorter than that in 4a. These and other comparisons and interconversions of NHC complexes with an NH function and related imidazol-2-yl species expand the potential of NHC complexes by showing their bifunctional character.

Chemistry of mixed-ligand methoxy bonded oxidovanadium(V) complexes with a family of hydrazone ligands containing VO 3+ core and their substituent controlled methoxy-bridged dimeric forms

[V IVO(acac) 2] reacts with an equimolar amount of benzoyl hydrazones of 2-hydroxyacetophenone (H 2L 1), 2-hydroxy-5-methylacetophenone (H 2L 2) and 5-chloro-2-hydroxyacetophenone (H 2L 4) in methanol to afford the penta-coordinated mixed-ligand methoxy bonded oxidovanadium(V) complexes [V VO(L 1)(OCH 3)] ( 1), [V VO(L 2)(OCH 3)] ( 2), and [V VO(L 4)(OCH 3)] ( 4), respectively, whereas, the similar reaction with the benzoyl hydrazone of 2-hydroxy-5-methoxyacetophenone (H 2L 3) producing only the hexa-coordinated dimethoxy-bridged dimeric complex [V VO(L 3)(OCH 3)] 2 ( 3A). Similar type of hexa-coordinated dimeric analogue of 1 i.e., [V VO(L 1)(OCH 3)] 2 ( 1A) was obtained from the reaction of [V IVO(acac) 2] with the equimolar amount of H 2L 1 in presence of half equivalent 4,4′-bipyridine in methanol while the decomposition of [V IVO(L 2)(bipy)] complex in methanol afforded the dimeric analogue of 2 i.e., [V VO(L 2)(OCH 3)] 2 ( 2A). All these dimeric complexes 1A– 3A react with an excess amount of imidazole in methanol producing the respective monomeric complex. The X-ray structural analysis of 1–3 and their dimeric analogues 1A– 3A indicates that the geometry around the vanadium center in the monomeric form is distorted square-pyramidal while that of their respective dimeric forms is distorted octahedral, where the ligands are bonded to vanadium meridionally in their fully deprotonated enol forms. Due to the formation of bridge, the V–O(methoxy) bond in the dimeric complexes is lengthened to such an extent that it becomes equal in length with the V–O(phenolate) bond in 3A and even longer in 1A and 2A, which is unprecedented. The 1H NMR spectra of the complexes 1A– 3A in CDCl 3 solution, indicates that these dimeric complexes are converted appreciably into their respective monomeric form. Complexes are electro-active displaying one quasi-reversible reduction peak near +0.25 V versus SCE in CH 2Cl 2 solution. The E ½ values of the complexes show linear relationship with the Hammett parameter ( σ) of the substituents. All these VO 3+-complexes are converted to the corresponding complexes with V 2 O 3 4 + motif simply on refluxing them in acetone and to the complexes with VO 2 + motif on reaction with KOH in methanol.

1,1′-Binaphthylazepine-based ligands for the enantioselective dialkylzinc addition to aromatic aldehydes

The new 1,1′-binaphthylazepine ligand 1c has been prepared and tested in the enantioselective addition of Et 2Zn to arylaldehydes, allowing us to reach ee’s up to 97% and giving extremely rapid reactions (10–20 min). Aminoalcohol 1c and the analogous compounds 1a and 1b were then tested in the enantioselective addition of Bu 2Zn and Me 2Zn to arylaldehydes. All of the ligands efficiently catalyze the Bu 2Zn addition to benzaldehyde, providing good yields in short reaction times (2–4 h) and high ee (up to 96%). In the enantioselective methylation of arylaldehydes ligands 1b and 1c gave high yields (88–97%) and good to high (80–90%) ee’s.

Terpene Conjugates of Diaminedichloridoplatinum(II) Complexes: Antiproliferative Effects in HL‐60 Leukemia, 518A2 Melanoma, and HT‐29 Colon Cancer Cells

Twenty-eight [6-(aminomethyl)nicotinate]dichloridoplatinum(II) complexes 1 esterified with various terpene alcohols either directly or via alkyl spacers were tested for antiproliferative activity in human 518A2 melanoma and HL-60 leukemia cells. Generally, conjugates with menthanes and polycyclic sesquiterpenes attached via propane-1,2-diyl spacers were most active. In the melanoma cells, the propane-1,2-diyl-spacered conjugates of (-)-menthol (1a(2')), (+)-neomenthol (1b(2')), (-)-carvomenthol (1h(2')), and (-)-isolongifolol (1n(2')) displayed growth inhibition at IC(50)<4 microM which is ten times smaller than that of cisplatin. The stationary diamino ligand was also crucial. The (-)-menthyl ester complexes with 2,3-diaminopropanoate (9a) and 2,4-diaminobutanoate (10a) ligands caused a greater and persistent growth inhibition in HT-29 colon cancer cells upon long-term exposure when compared to the 6-(aminomethyl)nicotinate analogue 1a. The cedrenyl ester 1l and the menthoxyisopropyl ester 1a(2') proved most efficacious in all three tumor cell lines. The DNA binding of complexes 1 was assessed by electrophoretic band-shift experiments and found correlated to the terpene structure but not to the observed antiproliferative activities.

Synthesis and biological evaluation of novel 3′-N-tert-butylsulfonyl analogues of docetaxel

Novel 3′-N-tert-butylsulfonyl analogues 10a–c of docetaxel were synthesized and their biological evaluation in cytotoxicity in vitro against several human tumor cell lines were presented. The biologically tested results showed that N-oxide pyridyl substituted10b–c had potent cytotoxicities against human tumor cell lines Eca-109, SKOV3, SMMC-7721, HCT-8, PC3, MCF-7, HeLa and KB.

Synthesis and pharmacological evaluation of pentacyclic 6a,7-dihydrodiindole and 2,3-dihydrodiindole derivatives as novel melatoninergic ligands

The synthesis of novel melatonin analogues 3a and 4a– c designed as melatonin receptor ligands is described. Among the newly synthesized ligands, 2-(( S)-2-hydroxymethylindolin-1-ylmethyl)-melatonin 4b displayed the highest affinity for MT 1 receptors ( K i = 9.8 nM) and for MT 2 subtype ( K i = 7.8 nM), whereas the rigid pentacyclic ligand 3 showed the highest selectivity towards the MT 2 receptor subtype ( K i = 319.3 nM for MT 1 and K i = 65.2 nM for MT 2).

Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors: Synthesis, SAR analysis, and biological activity

A series of nitrogen-containing flavonoid analogues were designed and synthesized by Mannich reaction, and screened for the inhibitory activities of cyclin-dependent kinases using a FRET-based biochemical assay method. The results showed that C-8 nitrogen-containing baicalein analogues 3a– 3f exhibited potent CDK1/Cyclin B inhibitory activities. 5,6,7-Trihydroxy-8-(dimethylaminomethyl)-2-phenyl-4 H-chromen-4-one 3a, 5,6,7-trihydroxy-8-(pyrrolid inylmethyl)-2-phenyl-4 H-chromen-4-one 3b, and 5,6,7-trihydroxy-8-(piperidinylmethyl)-2-phenyl-4 H-chromen-4-one 3c (IC 50 1.05–1.28 μM) were about sixfold more potent than baicalein 2 (IC 50 6.53 μM). 5,6,7-Trihydroxy-8-(morpholinomethyl)-2-phenyl-4 H-chromen-4-one 3d, 5,6,7-trihydroxy-8-(thiomorpholinomethy)-2-phenyl-4 H-chrom en-4-one 3e, and 5,6,7-trihydroxy-8-(4-methylpiperazinylmethyl)-2-phenyl-4 H-chromen-4-one 3f (IC 50 0.27–0.38 μM) were about 20-fold more potent than baicalein, and were at the same level as flavopiridol (IC 50 0.33 μM).

Preparation of new pyrido[3,4- b]thienopyrroles and pyrido[4,3- e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles ( 1a, b and 2a, b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4- b]thieno[2,3- and 3,2- d]pyrroles ( 1a, b) and pyrido[4,3- e]thieno[2,3- and 3,2- c]pyridazines ( 2a, b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids ( 3, 4) and 4-bromo-3-pyridylpivaloylamide ( 9) afforded the biaryl coupling products ( 10, 11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product ( 12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine ( 15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues ( 1a, b) were obtained via the nitrene by thermal decomposition of the azido precursors ( 14, 15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72–83%, 2a, b) were afforded.

Antiangiogenic and growth inhibitory effects of synthetic novel 1, 5-diphenyl-1,4 pentadiene-3-one-3-yl-ethanone pyridine curcumin analogues on Ehrlich ascites tumor in vivo

In the present investigation we have synthesized novel substituted dienone pyridine ethanone curcumin analogues 3a and 3b by nucleophilic substitution reactions with 2-bromo-1-pyridine-3-yl ethanone and characterized by 1H nuclear magnetic resonance (NMR), infrared IR, mass, and CHNS analysis. The compounds demonstrated tumor growth inhibition and antiangiogenic effects against mouse Ehrlich ascites tumor in vivo and suppressed neovascularization in a chorio allantoic membrane model.

Synthesis and cytotoxic activity of novel curcumin analogues

Five novel curcumin analogues bearing different substituents at 4-position of phenyl group were synthesized. Their structures were confirmed by NMR and HRMS spectrum. Their cytotoxic activities against six tumor cell lines were tested by the standard MTT assay in vitro. The results indicated that four analogues ( 1A–1C, 1E) with solubilizing moieties showed selective potent cytotoxicity against HepG2, HeLa and CT26 cell lines, and analogue 1A and 1C exhibited more potent cytotoxicity than curcumin against CT26 cell line. It was suggested that introduction of appropriate substituents to 4-position of phenyl group might be a potential option for structural modification of curcumin.

A new series of nematic and smectic liquid crystals with negative dielectric anisotropy: the effect of terminal chain substitution on thermal and electro‐optical properties

Two alkyl (1b and 1c) and four fluoroalkyl derivatives (1d–1f) of 4‐arylbutyric acid (1c, 1d and 1e) and 4‐arylbutanol (1b, 1f and 1g) [aryl = 2′,3′‐difluoro‐4′‐(2‐(E‐4‐pentylcyclohexyl)ethyl)‐biphenyl‐1‐yl] were prepared and investigated in the pure form as nematic materials (1b and 1c) and as additives to a ferroelectric liquid crystal (FLC) host (1d–1f). A comparison of 1b and 1c with the decyl analogue 1a demonstrates the effect of terminal chain modification on thermal and electro‐optical properties. The substitution of the –CH2O– (1b) or –COO– (1c) for –CH2CH2– in 1a destabilized the N and SmA phases or completely eliminated the smectic behaviour (1c). Dielectric analysis revealed that the chain modification increased the negative Δε, reduced elastic constant K 11 and moderately decreased rotational viscosity γ1. The temperature dependence of the key electro‐optical parameters was analysed for ester 2, the methyl analogue of 1c, which exhibits a 45 K wide N phase. All four fluoroalkyl derivatives 1d–1f showed enantiotropic SmA phases and 1e also exhibited a monotropic SmC phase. Solutions of 1d–1f in a FLC host (0.2 mmol g−1) increased the tilt angle Θ (up to 45° for 1g), reduced rotational viscosity γ1 and the risetime τ. The most dramatic changes were observed for 1g, which contains 15 fluorine atoms.

1,2,3,4-Tetrahydro-2-thioxopyrimidine analogs of combretastatin-A4

Eleven 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs of combretastatin-A4 (CA-4) were synthesized and their cytotoxicity against the growth of two murine cancer cell lines (B16 melanoma and L1210 leukemia) in culture was determined using an MTT assay. Two 2-thioxopyrimidine analogs 8f and 9a exhibited significant activity (IC 50 < 1 μM for L1210 and <10 μM for B16 cells). Exposure of A-10 cells to 8f and 9a produced a significant reduction in cellular microtubules in interphase cells, with an EC 50 value of 4.4 and 2.9 μM, respectively, for microtubule loss. Molecular modeling studies using MacSpartan indicated that the two active 2-thioxopyrimidine analogs preferably adopt a twisted conformation, similar to CA-4, affirming that conformation and structure are connected to activity.

Synthesis, nicotinic acetylcholine receptor binding, and pharmacological properties of 3′-(substituted phenyl)deschloroepibatidine analogs

A series of 3′-(substituted phenyl)deschloroepibatidine analogs ( 5a– j) were synthesized. The α4β2 ∗ and α7 nicotinic acetylcholine receptor (nAChR) binding properties and functional activity in the tail-flick, hot-plate, locomotor, and body temperature tests in mice of 5a– j were compared to those of the nAChR agonist, nicotine ( 1), epibatidine ( 4), and deschloroepibatidine ( 13), the partial agonist, varenicline ( 3), and the antagonist 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs ( 7a– j). Unlike epibatidine and deschloroepibatidine, which are potent agonists in the tail-flick test, 5a– k show no or very low antinociceptive activity in the tail-flick or hot-plate test. However, they are potent antagonists in nicotine-induced antinociception in the tail-flick test, but weaker than the corresponding 2′-fluoro-3′-(substituted phenyl)deschloroepibatidines.

Synthesis and antiviral activity of new dimeric inhibitors against HIV-1

This paper describes the synthesis and the antiviral activities of dimeric compounds derived from homo and asymmetric combinations of N-1 propynyloxymethyl analogues 1a, b of MKC-442, an N-1 4-iodobenzyloxymethyl analogue of TNK-651 5, potent contraceptive norgestrel and AZT. They were obtained by Sonogashira reaction, ‘click’ chemistry or Pd-catalyzed oxidative coupling. The iodo precursor 5 turned out as a potent compound against wild type and mutated HIV-1 virus. All dimeric compounds showed lower activity against HIV-1 than MKC-442, except the asymmetric dimer of AZT and 1a which showed an activity comparable to MKC-442.