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| 5. |
- George, Riham F., et al.
(author)
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Design, synthesis and QSAR studies of dispiroindole derivatives as new antiproliferative agents
- 2013
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 68, s. 339-351
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Journal article (peer-reviewed)abstract
- A variety of 4'-ary1-3-(arylmethylidene)-1 ''-[(cyclic-amino)methylene]-1'-methyl-dispiro[cyclohexane-1,3'-pyrrolidine-2',3 ''-[3H]indole]-2,2 ''(1H)-diones 4a-u were prepared via reaction of 2E,6E-bis(arylidene)-1-cyclohexanones 1a-i with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2a-c and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 liver, HELA cervical and PD prostate cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin. QSAR studies revealed good predictive and statistically significant 3 descriptor models (r(2) = 0.903-0.812, r(adjusted)(2) = 0.855-0.672, r(prediction)(2) = 0.773-0.605).
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| 6. |
- Girgis, Adel S., et al.
(author)
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Synthesis and DFT studies of an antitumor active spiro-oxindole
- 2015
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In: New Journal of Chemistry. - : Royal Society of Chemistry (RSC). - 1144-0546 .- 1369-9261. ; 39:10, s. 8017-8027
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Journal article (peer-reviewed)abstract
- An anti-oncological active spiro-oxindole 7 was synthesized regioselectively via a [3+2]-cycloaddition reaction of azomethine ylide to exocyclic olefinic linkage of 4-piperidone 6, exhibiting properties against diverse tumor cell lines including leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. Compound 7 crystallizes in the monoclinic system and P21/c space group with four molecules in the unit cell. The structure was also studied by AM1, PM3 and DFT techniques. DFT studies support the stereochemical selectivity of the reaction and determine the molecular electrostatic potential and frontier molecular orbitals.
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| 7. |
- Girgis, Adel S., et al.
(author)
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Synthesis and QSAR study of novel cytotoxic spiro[3H-indole-3,2 '(1 ' H)-pyrrolo[3,4-c]pyrrole]-2,3 ',5 '(1H,2 ' aH,4 ' H)-triones
- 2012
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 47, s. 312-322
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Journal article (peer-reviewed)abstract
- 1,3-Dipolar cycloaddition reaction of 1-aryl-1H-pyrrole-2,5-diones 1a-e with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a-c and sarcosine (3) in refluxing ethanol, afforded 4'-aryl-5'a,6'-dihydro-1'-methyl-spiro[3H-indole-3,2'(1 ' H)-pyrrolo[3,4-c]pyrrole]-2,3',5'(1H,2'aH,4'H)-triones 4a-o in good yields. Compound 4I exhibited high anti-tumor activity against HEPG2 (liver cancer) cell line (IC50 = 12.16 mu M) compared to that of Doxorubicin (IC50= 7.36 mu M), and the other synthesized compounds revealed moderate anti-tumor properties against HCT116 (colon), MCF7 (breast) and HEPG2 (liver) human tumor cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements controlling the observed anti-tumor properties. It was found that the major structural factors affecting potency of these compounds were related to their basic skeleton.
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- Gołębiewska, Justyna, et al.
(author)
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Second generation of nucleotide analogues
- 2021
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In: Phosphorus Sulfur and Silicon and the Related Elements. - : Informa UK Limited. - 1042-6507 .- 1563-5325. ; 197:5-6, s. 511-514
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Journal article (peer-reviewed)abstract
- The most common type of modification of a phosphorus center is the replacement of one or two non-bridging atoms of the phosphate group with different heteroatoms (e.g., sulfur, selenium) or groups of atoms (e.g., methyl, borane). Such compounds are referred to as the first generation of nucleotide analogues. We were interested in exploring the possibility of further functionalizing of the heteroatoms present in nucleoside phosphorothioates, phosphoroselenoate or boranephosphonates to create a second generation of nucleotide analogues with hopefully new biological properties. Here we report a preliminary account of our work on introducing additional modifications on the sulfur or selenium heteroatom of nucleotide analogues.
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| 13. |
- Jimenez-Halla, J. Oscar C., et al.
(author)
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Computational study of the mechanism and selectivity of palladium catalyzed propargylic substitution with phosphorus nucleophiles
- 2012
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 18:39, s. 12424-12436
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Journal article (peer-reviewed)abstract
- The mechanism and sources of selectivity in the palladium-catalyzed propargylic substitution reaction that involves phosphorus nucleophiles, and which yields predominantly allenylphosphonates and related compounds, have been studied computationally by means of density functional theory. Full free-energy profiles are computed for both H-phosphonate and H-phosphonothioate substrates. The calculations show that the special behavior of H-phosphonates among other heteroatom nucleophiles is indeed reflected in higher energy barriers for the attack on the central carbon atom of the allenyl/propargyl ligand relative to the ligand-exchange pathway, which leads to the experimentally observed products. It is argued that, to explain the preference of allenyl- versus propargyl-phosphonate/phosphonothioate formation in reactions that involve H-phosphonates and H-phosphonothioates, analysis of the complete free-energy surfaces is necessary, because the product ratio is determined by different transition states in the respective branches of the catalytic cycle. In addition, these transition states change in going from a H-phosphonate to a H-phosphonothioate nucleophile.
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| 14. |
- Johansson, Tommy, et al.
(author)
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2-Pyridylphosphonates : A New type of Modification for Nucleotide Analogues
- 2001
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In: Tetrahedron Letters. - : Elsevier. - 0040-4039. ; 42:11, s. 2217-2220
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Journal article (peer-reviewed)abstract
- Suitably protected dithymidine H-phosphonates afforded the corresponding dinucleoside 2-pyridylphosphonates upon treatment with N-methoxypyridinium tosylate in acetonitrile in the presence of 1,8-diazabicylo[5.4.0]undec-7-ene (DBU). The reaction was rapid (ca. 5 min), practically quantitative and proceeded stereospecifically, most likely with retention of configuration at the phosphorus centre. A simple and efficient protocol for the preparation of a new type of oligonucleotide analogue bearing a 2-pyridylphosphonate internucleotide linkage was developed
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| 15. |
- Johansson, Tommy, et al.
(author)
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Nucleoside H-phosphonates. : Part 19. Efficient entry to novel nucleotide analogues with 2-pyridyl and 4-pyridylphosphonothioate internucleotide linkages
- 2004
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In: Tetrahedron. - : Elsevier. - 0040-4020. ; 60:2, s. 389-395
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Journal article (peer-reviewed)abstract
- Synthetic and 31P NMR spectroscopy studies resulted in the development of efficient protocols for the stereospecific synthesis of a novel type of nucleotide analogues, 2-pyridyl- and 4-pyridylphosphonothioates. The underlying chemistry involves formation of the P–C bond via a base-promoted reaction of suitably protected dithymidine H-phosphonothioates with N-methoxypyridinium tosylate in acetonitrile, or with trityl chloride in pyridine, to produce high yields of nucleotide analogues with a 2-pyridyl- or 4-pyridyl moiety directly bound to the phosphorus centre.
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| 16. |
- Johansson, Tommy, 1975-
(author)
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Studies on Transformations of H-Phosphonates into DNA Analogues Containing P-S or P-C Bonds
- 2004
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Doctoral thesis (other academic/artistic)abstract
- In this thesis, mechanistic and synthetic studies on transformations of H-phosphonates into DNA analogues containing P-S or P-C bonds are described. Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated. In light of these studies, the reported stereoselective sulfurisation of dinucleoside H-phosphonates and benzoylphosphonates in the presence of DBU was proved to be incorrect.Efficient protocols for the synthesis of new nucleotide analogues with non-ionic C-phosphonate internucleotide linkages were developed. The synthesis of dinucleoside 2-pyridylphosphonates was successfully performed by a DBU-promoted reaction of H-phosphonate diesters with N-methoxypyridinium salts. The thio analogues, 2-pyridyl- and 4-pyridyl phosphonothioate diesters, could be obtained by modifying the reactions developed for their oxo counterparts. Dinucleoside 3-pyridylphosphonates were prepared via a palladium(0)-catalysed cross coupling strategy that could be extended also to the synthesis of nucleotide analogues with metal-complexing properties, i.e. terpyridyl- and bipyridylphosphonate derivatives.Oligonucleotides modified with pyridylphosphonate internucleotide linkages have been prepared and preliminary studies on their hybridisation properties and resistance towards enzymatic degradation were performed.Finally, nucleotidic units for the incorporation of pyridylphosphonate groups at the 5’-terminus of oligonucleotides were designed. Condensations of such units with a suitably protected nucleoside afforded after oxidation the expected dinucleoside (3’-5’)-phosphates with pyridylphosphonate monoester functions at the 5’-ends.
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| 19. |
- Johansson, Tommy, et al.
(author)
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The Case for Configurational Stability of H-Phosphonate Diesters in the Presence of Diazabicyclo[5.4.0]undec-7-ene (DBU)
- 2001
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In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896. ; 9:9, s. 2315-2322
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Journal article (peer-reviewed)abstract
- Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated using 31P NMR spectroscopy. It was found that under the reaction conditions and irrespective of the type of protecting groups present in the nucleoside moieties, the H-phosphonate diesters investigated did not undergo any detectable epimerisation at the phosphorus centre, and their sulfurisation with elemental sulfur in the presence of DBU, proceeded stereospecifically. Thus, we could not confirm reports from another laboratory on a stereoselective course of sulfurisation of H-phosphonate diesters and the corresponding acylphosphonates in the presence of DBU.
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| 22. |
- Kalek, Marcin, et al.
(author)
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Microwave-assisted palladium-catalyzed cross-coupling of aryl and vinyl halides with H-phosphonate diesters
- 2008
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In: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 10:20, s. 4637-4640
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Journal article (peer-reviewed)abstract
- A general and efficient method for the microwave-assisted formation of the C−P bond was developed. Using a prevalent palladium catalyst, Pd(PPh3)4, a quantitative cross-coupling of various H-phosphonate diesters with aryl and vinyl halides was achieved in less than 10 min. The reactions occurred with retention of configuration at the phosphorus center and in the vinyl moiety. Using this protocol, several C-phosphonates, including those bearing nucleoside and cholesteryl moieties, were prepared in high yields.
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| 23. |
- Kalek, Marcin, 1983-, et al.
(author)
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Novel, stereoselective and stereospecific synthesis of allenylphosphonates and related compounds via palladium-catalyzed propargylic substitution
- 2011
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In: Advanced Synthesis and Catalysis. - : Wiley. - 1615-4150 .- 1615-4169. ; 353:10, s. 1741-1755
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Journal article (peer-reviewed)abstract
- We have developed a novel method for the synthesis of allenylphosphonates and related compounds based on a palladium(0)-catalyzed reaction of propargylic derivatives with H-phosphonate,H-phosphonothioate, H-phosphonoselenoate, and H-phosphinateesters. The reaction is stereoselective and stereospecific, and provides a convenient entry to a vast array of allenylphosphonates and their analogues with diverse substitution patterns in the allenic moiety and at the phosphorus center. Some mechanistic aspects of this new reaction were also investigated.
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| 24. |
- Kalek, Marcin, et al.
(author)
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Palladium-catalyzed C-P bond formation : Mechanistic studies on the ligand substitution and the reductive elimination. An intramolecular catalysis by the acetate group in PdII complexes
- 2008
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In: Organometallics. - : American Chemical Society (ACS). - 0276-7333 .- 1520-6041. ; 27:22, s. 5876-5888
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Journal article (peer-reviewed)abstract
- Ligand substitution and reductive elimination of the palladium-catalyzed C−P bond forming cross-coupling were investigated in depth. It was found that for PhPdII(PPh3)2X (X = I, Br, Cl) complexes, a step commonly referred to as ligand substitution commenced with coordination of an H-phosphonate diester, followed by its deprotonation to form an equilibrium mixture of penta- and tetracoordinate palladiumphosphonate intermediates, from which reductive elimination of the product (diethyl phenylphosphonate) occurred. For the acetate counterpart, PhPdII(PPh3)2(OAc), the incorporation of a phosphonate moiety to the complex was preceded by a rate-determining removal of the supporting phosphine ligand, facilitated by an intramolecular catalysis by the acetate group. Both the reaction steps, i.e., formation of palladiumphosphonate intermediates and reductive elimination, were significantly faster for the acetate versus halides containing PdII complexes investigated. Similar observations were found to be true also for bidentate ligand complexes [(dppp)PdII(Ph)X]; however, in this instance, a single palladiumphosphonate intermediate, (dppp)PdII(Ph)(PO(OEt)2), could be observed by 31P NMR spectroscopy. The synthetic and kinetic studies on the cross-coupling reaction of diethyl H-phosphonate with phenyl halides permitted us to elucidate a crucial catalytic role of an acetate group in PdII complexes and to propose two distinctive catalytic cycles, which complemented traditional Pd0/PdII schemes, for the palladium-mediated C−P bond formation.
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