1,721,036 research outputs found
Pyrimido[5,4-d]Pyrimidine or pyrimidine derivates compounds and uses there of in the treatment of cancer
No full textIn ottemperanza all’articolo 198 CPI si allega:
Relazione in lingua italiana concernente l’invenzione della domanda di brevetto PCT dal titolo “PYRIMIDO[5,4-d]PYRIMIDINE OR PYRIMIDINE DERIVATIVES COMPOUNDS AND USES THEREOF IN THE TREATMENT OF CANCER”, a nome ZOLLO Massimo, GALEONE Aldo, VIRGILIO Antonella, SPANO Daniela, DE ANTONELLIS Pasquale
L’invenzione concerne pirimido[5,4-d]pirimidino o pirimidino derivati e loro usi nel trattamento del cancro. In particolare, l’invenzione concerne pirimido[5,4-d]pirimidino o pirimidino derivati e loro usi nel trattamento del cancro iper-esprimente h-prune, ossia di cancro metastatico, come ad esempio i carcinoma metastatici alla mammella, alla prostata, al colon, al pancreas, ai polmoni, al fegato, medulloblastoma gastrico e esofageo, neuroblastoma, glioma, oligondendrioma, astrocitoma, sarcoma, linfoma, mieloma, leucemie, cancro alle ovaie.
Costituiscono oggetto specifico della presente invenzione pirimido[5,4-d]pirimidino or pirimidino derivati aventi formula (I) e (II), o loro sali, ad esempio cloridrati:
(I)
(II)
in cui X è H o 4-nitrobenzil etano-1,2-diilbis(metilcarbammato).
I gruppi OX possono avere configurazione R o S nella formula I e configurazione R o S uguale o diversa tra loro nella formula II. Preferibilmente, i derivati della presente invenzione sono i seguenti: (R)-1-(4-((4-metossibenzil)ammino)pirimidin-2-il)pirrolidin-3-ol (composto denominato nel testo come AA7.1), (R)-1-(4-((4-metossibenzil)ammino)pirimidin-2-il)pirrolidin-3-il 4-nitrobenzil etan-1,2-diilbis(metilcarbammato) (composto denominato nel testo come AA7.1 hypoxia), (3S,3'S)-1,1'-(4,8-bis(4-metossibenzilammino)pirimido[5,4-d]pirimidin-2,6-diil)dipirrolidin-3-olo (composto denominato nel testo come composto 8 o AA2.9, (3R,3'R)-1,1'-(4,8-bis(4-metossibenzilammino)pirimido[5,4-d]pirimidino-2,6-diil)dipirrolidin-3-olo (composto denominato nel testo come composto 9 o AA2.8).
Nella domanda di brevetto è riportata la descrizione dettagliata degli esperimenti condotti dagli inventori per testare l’efficacia dei composti sopra menzionati, ossia la loro efficacia nell’inibire l’attività PDE di h-prune, la migrazione e la proliferazione cellulare, utilizzando modelli animali di cancro metastatico. In particolare, gli inventori hanno messo a punto un modello animale per l’identificazione e lo studio di composti in grado di inibire l’attività di h-prune. In modo specifico, il modello animale è stato denominato Mouse Loricrin-prune/Vegfr2-luc ed è caratterizzato dal comprendere un transgene di h-prune (GenBank: NM_021222.1 dalla Base 137 alla 1495) con un epitopo flag tag la cui trascrizione è condotta da un promotore della loricrina (GenBank: S77319.1) e un transgene contenente un promotore murino VEGFR2 e un cDNA di luciferasi modificata di lucciola (Promega pGL-3).
L’invenzione concerne anche composizioni farmaceutiche contenenti i composti sopra menzionati e loro usi, oltre al procedimento per la preparazione di detti composti e del modello animale
The Introduction of Inversion of Polarity Sites in DNA G-Quadruplex Structures: Effects and Perspectives
No full textThe natural sequences of nucleic acids generally consist of nucleotides linked together by canonical 3'-5' phosphodiester bonds. An inversion of polarity site (IPS) can be defined as the point of the sequence in which a 3'-3' or a 5'-5' phosphodiester bond occurs. By extending this definition, an IPS can be described as that part of the sequence in which two 3'- or two 5'-hydroxyl groups are connected by a linker, variable in size or in chemical nature. In G-quadruplex structures an IPS can be introduced in three different positions: inside a non G-tract, inside a G-tract and just between a non Gtract and a G-tract. Investigations have been reported concerning all the three types of modification. This review describes the effects of the presence of one or more IPSs in G-quadruplex structures, particularly regarding their topological and structural characteristics, glycosidic bond preference, and thermal stability, with special attention to biologically active Gquadruplex forming aptamers. The perspectives and potential developments of this research area are also discussed
8-Methyl-2'-deoxyguanosine incorporation into parallel DNA quadruplex structures
No full textThis paper concerns the CD and NMR structural studies of the quadruple helix arrangements adopted by three tailored oligodeoxyribonucleotide analogs, namely d(TGMeGGT), d(TGGMeGT) and d(TGGGMeT), where dGMe represents a 8-methyl-2'-deoxyguanosine residue. The results of this study clearly demonstrate that the effects of the incorporation of dGMe instead of a dG residue are strongly dependent upon the positioning of a single base replacement along the sequence. As such, d(TGMeGGT), d(TGGMeGT) have been found to form 4-fold sym. quadruplexes with all strands parallel and equiv. to each other, each more stable than their natural counterpart. NMR expts. clearly indicate that [d(TGMeGGT)]4 possesses a GMe-tetrad with all dGMe residues in a syn-glycosidic conformation while an anti-arrangement is apparent for the four dGMe of [d(TGGMeGT)]4. As the two complexes show a quite different CD behavior, a possible relationship between the presence of residues adopting syn-glycosidic conformations and CD profiles is briefly discussed. As far as d(TGGGMeT) is concerned, NMR data indicate that at 25°C it exists primarily as a single-strand conformation in equil. with minor amts. of a quadruplex structure
A new class of DNA quadruplexes formed by oligodeoxyribonucleotides containing a 3'-3' or 5'-5' inversion of polarity site
No full textUnprecedented DNA quadruplex structures containing a 3′-3′ or 5′-5′ inversion of polarity site in the G-tract are presented; the quadruplexes are characterized by different elements of symmetry and glycosidic angle conformations. © The Royal Society of Chemistry 2005
More than one non-canonical phosphodiester bond in the G-tract: formation of unusual parallel G-quadruplex structures
No full textIn this article, we report an investigation, based on NMR and CD spectroscopic and electrophoretic techniques, of 5′TGGGGT3′ analogues containing two or three 3′-3′ or 5′-5′ inversion sites in the G-run, namely 5′TG3′-3′G5′- 5′GGT3′ (Q350), 5′TG3′-3′GG5′- 5′GT3′ (Q305), 5′TGG3′-3′G5′- 5′GT3′ (Q035), 5′TG3′-3′G5′- 5′G3′-3′GT5′ (Q353) and 3′TG5′- 5′G3′-3′G5′-5′GT3′ (Q535). Although the sequences investigated contain either no or only one natural 3′-5′ linkage in the G-tract, all modified oligodeoxyribonucleotides (ODNs) have been shown to form stable tetramolecular quadruplex structures. The ability of the 3′-3′ or 5′-5′ inversion sites to affect the glycosidic conformation of guanosines and, consequently, base stacking, has also been investigated. The results of this study allow us to propose some generalizations concerning strand arrangements and the glycosidic conformational preference of residues adjacent to inverted polarity sites. These rules could be of general interest in the design of modified quadruplex structures, in view of their application as G-wires and modified aptamers
Effects of 8-Methyl-2'-deoxyadenosine incorporation into quadruplex forming oligonucleotides
No full textIn this paper we report the synthesis and the structural characterization of two modified oligodeoxyribonucleotides (ODNs), namely d(A8MeGGGT) and d(TA8MeGGGT), where A8Me represents a 8-methyl-2'-deoxyadenosine. Both ODNs have been studied by 1H NMR, CD spectroscopy and mol. modeling and shown to form four-folds sym. G-quadruplex structures, with all strands parallel and equiv. to each other. The complexes are characterized by thermal stabilities comparable to that of their natural counterparts. NOE patterns involving 8-Me group in A8Me residues allowed us to define the main structural features at the 5'-end of the complexes. Particularly, inter- and intra-strand NOEs show a syn-orientation and a sym. arrangement of A8Me bases stacking on the adjacent G-tetrad
A novel equilibrium relating to the helix handedness in G-quadruplexes formed by heterochiral oligonucleotides with an inversion of polarity site
No full textInvestigations of heterochiral oligodeoxynucleotides 50-TD1GD2GD3-
30-30-GL3GL2TL1-50 (L33) and 30-TD1GD2GD3-50-50-GL3GL2TL1-30 (L55)
forming quadruplex structures are reported. Data indicate the
presence of enantiomeric left- and right-handed quadruplex
helices. In the case of L55, NMR experiments point to an unusual
equilibrium between them
Structural Investigations on the Anti-HIV G-Quadruplex-Forming Oligonucleotide TGGGAG and Its Analogues: Evidence for the Presence of an A-Tetrad
No full textSeveral anti-HIV aptamers adopt DNA quadruplex structures.
Among these, “Hotoda’s aptamer” (base sequence TGGGAG)
was one of the first to be discovered. Although it has been the topic of some recent research, no detailed structural investigations
have been reported. Here we report structural investigations
on this aptamer and analogues with related sequences,
by using UV, CD, and NMR spectroscopy as well as electrophoretic
techniques. The addition of a 3’-end thymine has allowed
us to obtain a single, investigable quadruplex structure. Data
clearly point to the presence of an A-tetrad. Furthermore, the
effects of the incorporation of an 8-methyl-2’-deoxyguanosine
at the 5’-end of the G-run were investigated
Improved performances of catalytic G-quadruplexes (G4-DNAzymes) via the chemical modifications of the DNA backbone to provide Gquadruplexes with double 3′-external G-quartets
Full text linkHere we report on the design of a new catalytic G-quadruplex-DNA system (G4-DNAzyme) based on the modification
of the DNA scaffold to provide the DNA pre-catalyst with two identical 3′-ends, known to bemore catalytically
proficient than the 5′-ends. To this end, we introduced a 5′-5′ inversion of polarity site in the middle of
the G4-forming sequences AG4A andAG6A to obtain d(3′AGG5′-5′GGA3′) (orAG2-G2A) and d(3′AGGG5′-5′GGGA3′)
(or AG3-G3A) that fold into stable G4 whose tetramolecular nature was confirmed via nuclear magnetic resonance
(NMR) and circular dichroism(CD) investigations. Both AG2-G2AandAG3-G3A display two identical external
G-quartets (3′-ends) known to interact with the cofactor hemin with a high efficiency, making the resulting
complex competent to performhemoprotein-like catalysis (G4-DNAzyme). A systematic comparison of the performances
of modified and unmodified G4s lends credence to the relevance of the modification exploited here
(5′-5′ inversion of polarity site), which represents a new chemical opportunity to improve the overall activity
of catalytic G4s
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