Palladium-catalyzed synthesis of 2H-pyrano2,3-gisoquinolinones have been described from easily accessible precursor 6-cyanoumbelliferone triflate via sequential of Sonogashira coupling and the ...following annulations with several primary alkylamines under basic conditions The so obtained 6-propargylamino-2H-pyrano2,3-gisoquinolinones were involved in the CuAAC reaction with 2-azidobenzoic acid for obtaining 2H-pyrano2,3-gisoquinoline-benzoic acid hybrid compounds containing a 1,2,3-triazole linker.
A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a ...cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6-8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9-11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.
Synthesis of 7,7.-linked bicoumarins, 3,3.-linked bi(2-isopropyl)psoralens as well as 1H-1,2,3-triazole linked coumarin-2,3-dihydrofurocoumarin and furocoumarin-2,3-dihydrofurocoumarin hybrids was ...performed by two alternative pathways, either involving a catalyzed transformations of the ethynyl derivatives of plant coumarins - peucedanin or peuruthenicin.
The Sonogashira reaction of 7-ethynyl coumarins or 3-ethynyl-2-isopropylpsoralen with the subsequent coumarin triflates led to 7,7´-linked bicoumarins or 3,3´-linked bipsoralens. 1,2,3-Triazole linked coumarin-2,3-dihydrofurocoumarin or furocoumarin-2,3-dihydrofurocoumarin hybrids were synthesized by a regioselective Cu-catalyzed cycloaddition reaction of 2-azidooreoselone with 7-alkynylcoumarins or 3-ethynyl-2-isopropylpsoralen.
Pharmacological screening of synthesized bicoumarins for anticoagulant activity in vivo revealed that coumarin-dihydrofurocoumarin hybrids linked with a 1,2,3-triazole ring 20 and 22 were the most active compounds. The presented prothrombin time (PT) values comparable to the reference drug warfarin in a dose 100 mg/kg. Docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site.
The moderate toxicity of compounds 20 and 22 (LD50 valuewas more than 3000 mg/kg) encouraged the further design of therapeutically relevant analogues based on these novel type of coumarin hybrids.
A series of 2-(4-R-triazolyl)substituted 3-oxo-2,3-dihydrofurocoumarins have been synthesized by a regioselective cycloaddition of 2-azidooreoselone 1 or ...2-azido-9-(4-methylpiperazin-1-yl)methyloreoselone 2 with various alkynes in the presence of Cu(II)/ascorbate in water/methylene chloride reaction medium. The structure of 2-azidooreoselone was established by X-ray structure analysis. The cytotoxicity of 2-substituted dihydrofurocoumarins was determined against three cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Among the tested molecules, most of the analogs displayed better cytotoxic activity then the parent natural furocoumarin peucedanin 3. The activity and selectivity to the cell line increased even further in the series of 2-(4-{2,3-dihydrobenzob1,4dioxine}triazolyl)-3-oxo-2,3-dihydrofurocoumarins and 2-(4-aryltriazolyl)-3-oxo-2,3-dihydrofurocoumarins having the (4-methylpiperazin-1-ylmethyl) substituent in the 9-th position. The most active compound 20 contain the 4-hydroxy-3-methoxybenzamidomethyl substituent in the 4-th position at the triazole ring of 2-(triazol-1-yl)dihydrofurocoumarins. The obtained 2-triazolyl substituted dihydrofurocoumarins were studied as inhibitors of phosphodiesterase (PDE-4B) using docking experiments. As a result of virtual screening 3 compounds are selected based on minimum binding energy. The interactions of the most active compound and amino acid residues in the binding site were studied.
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•2-Azido-2,3-dihydrofurocoumarins were obtained from plant coumarin peucedanin.•Series of 2-triazolyl substituted furocoumarins were prepared using click reaction.•2-Triazolyl furocoumarins possessed high cytotoxicity against cancer cell lines.•Interactions with phosphodiesterase PDE-4B were revealed by docking studies.
Salts of sterically hindered chalcogen‐varied Herz cations with various anions were synthesized. 4,6‐Di‐tert‐butyl‐substituted 1,2,3‐benzothiaselenazolium (2), 2,1,3‐benzothiaselenazolium (3), and ...1,2,3‐benzodiselenazolium (4) were obtained from corresponding 1,2,3‐benzodithiazolium (1) or 2‐bromo‐4,6‐di‐tert‐butylaniline (9) and were isolated as salts with Cl– or/and SbCl6– anions. Reaction of in situ prepared N,N,Te‐tris(trimethylsilyl)‐2‐amino‐3,5‐di‐tert‐butyltellurophenole with SeCl4, S2Cl2, and SOCl2 resulted in elimination of Te and the formation of 42TeCl6, 12Te3Cl14, and 12Te4Cl18 together with N‐sulfinyl‐2‐amino‐3,5‐di‐tert‐butylphenyltellurium trichloride (11); expected 2,1,3‐benzothiatellurazolium (5) and 2,1,3‐benzoselenatellurazolium (6) were not observed. Compounds 1Cl (solvate with CHCl3), 2SbCl6, 3SbCl6, 4SbCl6, 42TeCl6, 12Te3Cl14, 12Te4Cl18, and 11 were structurally defined by X‐ray diffraction. All of the SbCl6– salts were isomorphous, and the Te3Cl142– and Te4Cl182– anions were previously unknown. Compound 11 has a significantly shortened intramolecular Te···O contact.
Sterically hindered 1,2,3‐benzodithiazolium salts and their Se congeners with Cl– and SbCl6– anions are synthesized and structurally defined. Under identical conditions, the Te analogues unexpectedly give salts of Te‐free cations with TeCl62–, Te3Cl142–, and Te4Cl182– anions and a neutral acyclic compound bearing TeCl3 and N=S=O groups in the ortho positions of the benzene ring.
Salts of 1,2,3-benzodithiazolium (1), 2,1,3-benzothiaselenazolium (3), and 1,2,3-benzodiselenazolium (4) (Herz cations), namely, 1BF4, 1SbCl6, 3BF4, 3GaCl4, 3SbCl6, and 4GaCl4, were prepared ...from the corresponding chlorides and NaBF4, GaCl3, or SbCl5. It was found that 1SbCl6 and 3SbCl6 spontaneously transform in MeCN solution to 13SbCl62Cl and 33SbCl62Cl, respectively. 1BF4, 13SbCl62Cl, 3BF4, 33SbCl62Cl, and 4GaCl4 were structurally characterized by X-ray diffraction (XRD). In solution, these BF4− and GaCl4− salts as well as 1GaCl4, 2GaCl4, 3GaCl4, 3Cl, and 4Cl were characterized by multinuclear nuclear magnetic resonance (NMR). The corresponding Herz radicals 1 • –4 • were obtained in toluene and DCM solutions by the reduction of the appropriate salts with Ph3Sb and characterized by EPR. Cations 1–4 and radicals 1 • –4 • were investigated computationally at the density functional theory (DFT) and second-order Møller–Plesset (MP2) levels of theory. The B1B95/cc-pVTZ method was found to satisfactorily reproduce the experimental geometries of 1–4; an increase in the basis set size to cc-pVQZ results in only minor changes. For both 1–4 and 1 • –4 • , the Hirshfeld charges and bond orders, as well as the Hirshfeld spin densities for the radicals, were calculated using the B1B95/cc-pVQZ method. It was found for both the cations and the radicals that replacing S atoms with Se atoms leads to considerable changes in the atomic charges, bond lengths, and bond orders only at the involved and the neighboring sites. According to the calculations, 60% of the positive charge in the cations and 80% of the spin density in the radicals is localized on the heterocycles, with the spin density distributions being very similar for all radicals 1 • –4 • . For the cations 1–4, the NICS values (B3LYP/cc-pVTZ for B1B95/cc-pVTZ geometries) lie in the narrow range from −5.5 ppm to −6.6 ppm for the carbocycles, and from −14.4 ppm to −15.5 ppm for heterocycles, clearly indicating the aromaticity of the cations. Calculations on radical dimers 1 • 2–4 • 2 revealed, with only one exception, positive dimerization energies, i.e., the dimers are inherently unstable in the gas phase.
Twenty-one phenolic compounds (1-21) including dihydrocinnamic acid, isoflavonoids, flavonoids, coumestans, pterocarpans, chalcones, isoflavan and isoflaven, were isolated from the roots of ...Glycyrrhiza pallidiflora Maxim. Phloretinic acid (1), chrysin (6), 9-methoxycoumestan (8), isoglycyrol (9), 6″-O-acetylanonin (19) and 6″-O-acetylwistin (21) were isolated from G. pallidiflora for the first time. Isoflavonoid acetylglycosides 19, 21 might be artefacts that could be produced during the EtOAc fractionation process of whole extract. Compounds 2-4, 10, 11, 19 and 21 were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Isoflavonoid calycosin (4) showed the best potency against human T-cell leukaemia cells MT-4 (CTD
50
, 2.9 μM). Pterocarpans medicarpin (10) and homopterocarpin (11) exhibit anticancer activity in micromolar range with selectivity on the human monocyte cells U-937. The isoflavan (3R)-vestitol (16) was highly selective on the lymphoblastoid leukaemia cells CEM-13 and was more active than the drug doxorubicin
Derivatives of natural diterpenoid methyl lambertianate containing propargyloxy substituents in 16,17-positions were obtained. CuAAC reaction of methyl ...17-propargyloxy-16-(prop-2-yn-1-yloxy)methyllabdadienoate with various diazides in the presence of Cu(II)/sodium ascorbate in methylene chloride/water reaction medium gave chiral macrocyclic compounds connected on the 16 and 17-positions by 1,2,3-triazole rings with methylene, ethyloxyethyl or ethylethoxyethyl units. The obtained macrocyclic structures showed high selectivity and affinity for Hg
2+
ion by the 1,2,3-triazole rings.
The Sonogashira reaction can be applied for the preparation of acetylenic derivatives of betulonic acid where the triterpenoid moiety can serve as either the halo- or the acetylenic component. This ...reaction opened access to the first derivatives of betulonic acid containing either the arylethynyl (С
С-Ar(Het) or the ethynyl (С
СН) moieties. From the fundamental perspective, this work illustrates the possibility of selective Pd-catalyzed cross-coupling at terminal acetylenes in the presence of a terminal alkene. Hepatoprotective and anti-inflammatory properties of selected acetylenic derivatives of betulonic acid were investigated using the CCl
4-induced hepatitis and carrageenan-induced edema models, respectively.
Interaction between Ph3P and 1,3,2,4-benzodithiadiazine (1); its 6,7-difluoro (2), 5,6,8-trifluoro (3) and 5,6,7,8-tetrafluoro (4) derivatives; and 5,6,8-trifluoro-3,1,2,4-benzothiaselenadiazine (5) ...proceeded via a 1:1 condensation to give Ph3PN−R iminophosphoranes (1a−5a, R = corresponding 1,2,3-benzodichalcogenazol-2-yls), which are inaccessible by general approaches based on the Staudinger and Kirsanov reactions. In contrast, neither Ph3As nor Ph3Sb reacted with 1 and 4. Molecular structures of 1a−5a and 5 were confirmed by X-ray diffraction (XRD). The crystals formed by chiral molecules of 2a−5a were racemic, whereas the crystal of 1a was formed by a single enantiomer. In all of the Ph3PN−R derivatives, one of the Ph rings is oriented face-to-face to the hetero ring, R. Upon heating to ∼120 °C in squalane (1a, 3a, 4a) or dissolving in chloroform at ambient temperatures (1a, 2a, 4a), the Ph3PN−R derivatives generated the 1,2,3-benzodithiazolyls (1b−4b, respectively) whose identity was confirmed by electron paramagnetic resonance (EPR). 2,1,3-Benzothiaselenazolyls 5b and 6b were detected by EPR as the main paramagnetic products of solution thermolysis of 5 and its 5,6,7,8-tetrafluoro congener (6), respectively. Passing a chloroform solution of 4a through silica column unexpectedly gave 5-6-6-6 tetracyclic (9) and 6-10-6 tricyclic (10) sulfur−nitrogen compounds, which were characterized by XRD.
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