Els quàdruplex de guanina: Estudis estructurals i diana farmacològica
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(2) . . A 1 . Dzǣ Ö dz . . . ± ʹͲͳʹ. .
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(4) . . . A 1 . Dzǣ Ö dz. Öǣ ± À ǣÀ ïÀ Ǧ ° ʹͲͲͺǦͳͲ ǣǤǤÓ×± ǣǤ ǡʹͲͳʹ.
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(6) . . Ã ǡ Ó×Ǥ ± ǯǯ ȉ Ǥ À ǡǤ.
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(8) Öǯ ° ȋ Ȍ À Ǥ ×Ǥ ° ×ǯǡ ȋǦʹͲͲͺǦͲͲͻ͵ͳͷȌǤ ȋ Ȍǡ°ȋ ȌȋȌ° × ȋͳͲͲͲ ͲͲͲͲʹͺͲǢ ǦʹͲͳͳǦͶͶͶͶͷ Ǧ ǦͳʹǦͲͷʹʹͶȌǤ ȋEuropean Cooperation in Sciencie and TechnologyȌ ȋ Ȍ°Ǥ.
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(10) ÍNDEX A..............................................................................................................................................................................i Aǯ................................................................................................................................................iii A.........................................................................................................................................................vi IntroduccióiObjectius..........................................................................................................................................1 ×..................................................................................................................................................................3 ...................................................................................................................................................................17 ° ...............................................................................................................................................................19 1.Síntesis i caracterització estructrual de quàdruplex de guanina de DNA de gran estabilitat utilitzantelfosforoamidittrebler...................................................................................................................23 2.Espectroscòpiademassesiespectroscòpiademobilitatiònicaaplicadaalsquàdruplexde guanina.Estudidelsefectesdeldissolventenlaformacióienlestransicionsestructuralsdel dímerenlaseqüènciatelomèricadTAGGGTTAGGGT.............................................................................41 3. Estudis estructurals i d’estabilitat del quàdruplex de guanina present en els telòmers humans.Interacciód’aquestquàdruplexamb9aminoacridinesenavaluaciópreclínica......53 4.Síntesisd’oligòmersd’acridinailessevespropietatsd’unióaquàdruplexdeguanina..........89 5.Elsoligòmersd’acridinaiquindolinaunitsmitjançantla4aminoprolina prefereixenlesestructuresdequàdruplexdeguanina.......................................................................115 6.Síntesis,propietatsd’unióalDNAiactivitatantiproliferativadederivatsdel’acridinaidela 5metilacridina...................................................................................................................................................133 7.Discussiógeneraliconclusions................................................................................................................153 ×..................................................................................................................................................153 ............................................................................................................................................................159 Ö..........................................................................................................................................161. . .
(11) .
(12) Aǯ ǣ . Ǧ͵ͺǣÀ ȉ . ǣ . ǣ ° . ʹǣÀ ° ǣ ǯ. ǣͳǦ . ǣȋʹǦȌǦ . ǣÀǯ×. ǣtertǦ . ǣ ×Ö. ǣ × ȉ×ȋCollisioncross. ǣ ÖÖ . sectionȌ. ǣ . ǣ . ǦͳǣÀ ȉ. ǣ Ö ×. °. ǣ . ǣ° . ǣǦȏʹǦȋȌȐ ǦͶǦ. ǣ. . Ö. ǣ . Ǧ ǣ × ×. ǣʹǡʹǦǦʹǦǦͷǦ. Ȃ. . ǣ. ǣ. ǣ . ǣǡǯǦ . ǣ. ǣ. ǣ . ǣͶǦ. ǣ. ǣ ǯ . ǣ . . ǣ Ö. ǣNǡNǦ. ǣ͵ǦȋͶǡͷǦʹǦȌǦʹǡͷǦ. ǣÖ. . ǣͶǡͶǦǦ. Ȁǣ ×Ȁ . ǣ . ǣ. ǣò° ȋ. Ͷ ǣ ǯ. Ȍ. . ǣ ° . ǣ ° . ǣ × . ǣ . ǣ. ǣ Ö . Ǧ͵͵ǣÀ ȉÀ. ǣ°À. . ǣͻǦ . ǣÖ . ǦͶ ǣÀ ȉ . ǣ Ö. ×. ǣ .
(13) ǣ×À. ǣ ××ǡ . ǣ À . . ǣǯ . ǣǡ . à . . ǣ°. ǣ ° . ǣ ȋǦͳǦ. ǣ . Ȍ. ǣ ° . ǣ. ǣ . ǣ . ǣ Ö ×. ǣ × . ǣȋȌ. ǣ . ǣ. ǣ . ǣǦ . ǤǤǣ ǣ ǣ . .
(14) A. . . N O. N. N O. N. N. N. NH NH HN. 2BBA(2012). N. 1BBA(2012). N. N. COO H H N OH O. COOH. N H. N O. acridine9carboxylicacid J.Nucleicacids 1BBA(2011) 1Molecules. 2(acridine9carboxamide) aceticacidJ.Nucleicacids 2BBA(2011). 3BBA(2011). 4BBA(2011). Dimer1J.Nucleicacids Dimer2J.Nucleicacids. Trimer3J.Nucleicacids. Trimer4J.Nucleicacids O. O O. O. N H. N H. NH2. N H. N. N. N. O. O O. NH. NH NH. O. O. O. 8BBA(2011). 6BBA(2011). N. N. N. 5BBA(2011). 7BBA(2011). 9BBA(2011). 10BBA(2011). O. O O. O. N H. N H. NH2. N H. N. N. N. O. O O. NH. NH NH. H N. O. O. O. N. 11BBA(2011). 12BBA(2011). N. 13BBA(2011). N. .
(15) O. O O. O. N H. N H. N H. N. O. NH. N. NH2 N O. O O. N. NH. NH O. O H N. N. N. 14BBA(2011). 15BBA(2011). 17BBA(2011). 16BBA(2011). 10Molecules. 11Molecules. 18BBA(2011). HO. HN OH O N. 2Molecules 5Molecules. 6Molecules. 7Molecules. 3Molecules. 8Molecules. 4Molecules. .
(16) . Introducció iobjectius. ͳ.
(17) . ʹ.
(18) INTRODUCCIÓ Ladiversitatconformacionaldelsàcidsnucleics ǯ ï Ã À Öǡ ͳͻͷ͵ ȏͳȐǡ ° À Ö Ö Ǥ Àǡ ï ° ǡ ǯ × ǯ° Ö ° ǯ × ° ǡ ° ǯ Dz dzȏʹȐǤ ° ǯ ǯ ȋ ͳȌǤ ± Ö ×ǯ ȏ͵ȐǤ Figura1.Enllaçosdepontd’hidrogendetipusWatsonCrickentreATiGC. Ö ǯ °ǡ ǦǡǦǦȋ ʹȌȏ͵ȐǤ . A-DNA. B-DNA. z-DNA. Figura2.ConformacionsbàsiquesdeladoblehèlixdeDNA:BDNA,ADNAiZDNA. . ͵.
(19) × Ã Ǧ ȏ͵Ȑǡ ǡ ± Ǥ ȏͶȐ ± ǯ À Ǧ ȏ͵Ȑǡ ± ï ǯ × × ȏͷȐǤ × ° ǡ ± ± × ȏ͵ȐǤ ° × Ã ȏͷȐǤ ǡ ï Ǧ Ǧ ȏȐǤ ï±± ȏ͵ȐǤ × Ǧ in vivoǡ ǯ° à ȏȐǤ ° ǯ ǡ ± ± °ǡ Àǡ imotifs ȋ ǦȌǤ ± ǯǡǡ ×ǯ À ǯ ȏ͵ȐǤ ǯͳͻͷ ȉ ×ǯ À ȏͺȐ Ǥ ǯ° ͺͲǡ ï ǯ Ö À ȋ Ȍ ǯ×° ×ȋ°ȌȏͻȐ ×° ȏͳͲȐǤÀǡǯ ÖÀǯ ïǦ ǡǯǤÀ ȉ ȉǡ ǯ × ÀǤ ÖÀȋ Ȍǯǯȉ ïǯ ÀȉΪȉ ȋ ͵ȌǤ ǡ ǯ ǯ ȉ À ȉ ȉȋ ͵ȌǤ ×Àȉ Ö ïÖ ǤÖ À ° ǡ Ǧǡ ǯ° à ȏͳͳȐǤ ×Ö ± ǡÖǯ ò° ǯ ± ÃǤ2×ǡǯǯ Ǧ × × ȏͳͳȐǤ. Ͷ.
(20) A. T·AT. C+·GC. B. A·AT G·GC. T·AT. Figura3.A)EstructuresdelestriadesT·ATiC+·GCpresentsenelstriplexparal·lels.B)Estructuresdels triadesA·AT,G·GCiT·ATpresentsenelstríplexantiparal·lels. imotif ȋ ͶȌǤ ǡ ǯ ͳͻͻ͵ ȏͳʹȐ ȉǡïȉ ǯǯ ǯǣΪȋ ͶȌǤ ͶȌǤ . B. . A. ͶǤȌ ǯǦΪǤȌ × imotifǤ . ͷ.
(21) ǯͳͻͳͲǡ × ǯ À ǡÖ ǯ ͳͻʹ ǯ Ǥ ǯ ǡ ò° × ǯ ȏͳ͵ȐǤ ǯ. . Ǧ° ȏͳͶȐ ȋ ͷȌǤ ° × Ǧ ×ǯǤ × ǡǯ ȏͳͶȐǤ± Ǧ° Ǧ ȏͳͶȐǤ Ǧ ǯ ͳͻͻʹ ò° ° Oxytricha ȋ. ͶͶ. Ͷ Ȍ. ȉȏͳͷȐǤ. Figura 5. A) Tètrada formada per quatre guanines B) Quàdruplex tetramolecular C) Quàdruplex bimolecularD)Quàdruplexmonomolecular . Ǥ . ȋ ͷȌ ǡ ǡò° Ǧ° .
(22) ȋ ͷȌ Ǥ ± Ǧ ȋ ͷȌǤ ï ǡ ± Ö ǡ ǯ × ǡ ×synantiǯ À ×ȏͳȐǤ × ȉǡ ǡ ×ȋ ȌǤ. Diagonal. . Propeller. . Lateral. Figura6.Diferentstipusdeunionsperconnectarlesguaninesenunquàdruplex. ° ǡ ° propellers °Ö ȋ ȌǤ ǡ ʹ ǯ ǡ Ö ±ͳ͵ × ° Ǥ ± × ȋ ǡȌ ȋ ǡͳͳͳͳȌǤ ǡ ǡǣǡǤ Figura7.DiferentsestructuresdeGquàdruplexintermolecular,bimoleculariintramolecular.. .
(23) ò° ± ǯ ǡ Ǥ ǡ ǯ ǯ Ö° . ȋ. Ȍ ͵ ȉȏͳȐǤò° ° . ȋ ͺȌ × ǯ ǡǡ ȉȋ ͺȌǤ Ö ȏͳͺǡͳͻȐǤ ǯ ò° ǡ ×ǡdogearedȋ ͺȌǤ . A. B. . C. Figura 8. Estructures de la seqüència telomèrica 24mer. A) Tipus dogeared. B) tipus cistella. C) Paral·lela. ǯ ǯ × ° ǡ ×ǡ ǡ Ǧ°ǡò° ×ȏʹͲȐǤ × × ± ± ǯ × ǯ Ǥ ǯ ° ǣʹΪεΪεΪ̱ʹΪε. ͶΪεʹΪεΪεʹΪ̱Ϊ εεΪ ȏʹͳȐǤ. ± . ×ïǤ Rellevànciabiològicadelsquàdruplex ° Ǧ in vivo ȏʹʹǦʹ͵Ȑ Ö Ǥ Ö ò° Ǥ × ° ± ʹ ͳͲ ò° ȋ. ȌǤ± ò° ͺ.
(24) ° ° Tetrahymena ǯOxytricha nova ȋ Cerevisiae ȋ. ͳǦ͵ ȌǤ. Ȍ S.. Ö × × . ǤǡͷͲǦʹͲͲÖ ± ×ǤǡÖ × ȉǤ ȉ ò° ° ȏʹͶȐǤǯǡ± × ° Ǥ ȉ ò° ° in vitro ȏͳͶȐ ǡ ×ǯ ò° °invitroǯ ° Ǥ Ö ± ǯ Ãǯ ȏʹͷȐǤ Àǡǯò° Ǧǡ × × ° ×Ǥ ×Ǧ cmycȏʹȐǡVEGFȏʹȐǡHIF1ǡȏʹͺȐǡbcl2ȏʹͻȐ cKitȏ͵ͲȐǤ ǯ ǡ ǡ ǯ×° ǯǡ ȉȏ͵ͳȐǤ × × °ȉ À ×Ö × ° Ǥ Ö ×ȋ ͻȌǤ Figura9.EsquemaquerepresentaelroldelGquàdruplexenlaregulaciógènica. Ǧ±À° ǯÃǡ Ö Ǥ × Ö ×invitroǦÖ ȏ͵ʹȐǤ± ±ǯǯȋǡThrombingBinding ͻ.
(25) AptàmerȌǤ Ǧ ȋ ͳͲȌ ȏ͵͵ǡ ͵ͶȐǤ Ö ° × ΪǤ × ǯ . ȏ͵ͷȐǤ . ȉ ± ÃǤ Figura10.L’aptàmerdelatrombina(blau)s’uneixespecíficamentamblaproteïnatrombina(lila). Elsàcidsnucleicscomadianafarmacològica Ö ǡ± ǡǯï À À ǡ ȏ͵ȐǤ ǯ×° ǯǡ ×ǡ × × ȉǤ ° ǯ ǡ ǡ Ö Ǥ ° × ÀǤ × ǡ Ö ï ǡ Ǥ ȉ ǡ Öǡ × Ö ǯï À Ǥ ǯ ±cisǦÀȋ ͳͳȌ Figura11.Representaciódelstipusd’uniócovalentdelcisplatíambelDNA.. ͳͲ.
(26) ǯ ×± ×Ǥ ǯ × À ǡ ǯ ȏ͵ȐǤ ǯ Ö ǡ Ö ȏ͵ͺȐ ǡ ȏ͵ͻȐǤ ǯ ± Ǥ ȋ ͳʹȌ±° À ǯ ȏͶͲȐǤ. O. OH. O. . OH. . O. O. OH. O. O. . OH NH 2. Figura12.Estructuradeladaunomicina ± ° Ǥ × ȏͶͳȐǤ ° ǯ ǡ Ö ò° Ǥ± ȏͶʹǡͶ͵Ȑǡ ǯ Ǥ À ǡʹǦ ȋ ͳ͵Ȍ Figura 13. Estructura tridimensional del complex format per la distamicina (taronja) i un dúplex de DNA(lila). . ͳͳ.
(27) ǯ × × ǯ Ǥïǡ°° Ǧǯ ǡǯ ȏͶͶȐǤ ǡ °ȉǯ ÖǤ ǡ±ǯͺͷΨ °ȉ À ǯ ȏͶͷȐǤ ǯ ± ° Ǥ ° ǯ ± ° ò° °Ǥ ȉǯ × ò° ° ǯ × Ö ȏͶȐǤ ǯ ° ǡ × À ȏͶȐǤǯ ×± ɎǦɎ ° Ǥ × ï ȏͶȐǤ Ö ȏͶȐǤ in situ × ǡ À ǡ Ö Ǥ ± ǯ Ã Ǧͳͻ ȋ ͳͶȌ ǡ ȉ ȏͶͺȐǤ ǯ vs ïǤ À ǡ ± Ǥ Ǧͳͻ Ǧ° Ǥ . N. NH. O. . N. O. N H. N H. N. Figura14.EstructuradelBRACO19.. ͳʹ.
(28) Ǧ Ǧǡ Ö ǯ± ǯ Ǥ ° ɎǦɎǡ Ö Ǥ ± Ͷ ȋ ͳͷȌǡ ǯ ȉǡ Ǧǡ × ǯ× ǯ ȏʹȐǤ×ǡ ȏͶͻȐǤ ȉ ͳͲͷͳȋ ͳͷȌ Ǧ ǡ Ǥ ǯ À Ͷ ȋ ͳͷȌ ± ± × ȉȏͷͲȐǤ . H N. O N. . N. O. . O. B. N. A. N H. HO O. NH. N N. N. OH. C N. F. HN MeO3 SO. . N F. . N. N. Figura15.EstructuresdelA)TMPyP4B)BSU1051C)RHPS4 ȉǦ ȏͷͳȐ × Àǯ ǯ×Ǥ × Ǧ°ǡ × ȉ ×Ǥ Ö ± ǯ × ǦǤ ȉǦ Ͷȋ Ȍȋ ͳȌȏͷʹȐǤ° vsï ×Ǥ× ȉ ȉ ȋ ͳȌ Ǧ ° ȏͷ͵ǡͷͶȐǤ ͳ͵.
(29) N. . A. B. . N N. . Ni N. Cu. N. . N. N. O. O. N. N. O. O. . N. . N. N. O. O. Figura16.EstructuresdelA)CuTMPyP4B)Ni(II)Salphen ȏͷͷȐ ȋ ͳȌ À Ǥ ° Ã Streptomyces annulatus ǯ ʹͲͲͳ Ǥ ǡ ° ǯ × ï Ǥ Ö ± ± Ǧǡ ǡ ǯ ° ǡ À ȋ ͳȌ ǯ ȋ ͳȌȏͷǡͷȐǤ . B. . O O. O. N. N O. N. N. N. N. O. N. N. N. N AcO. N. N. N. N. O. . NH. . O. O. O. O. . . O. O. O. C. A. NH. HN. O. N. N. N. N. N. S. N N. O O. O. O. OAc. O. O N. O. HN. O. O. O O. Figura17.EstructuresdelA)TelomastatinaB)HXDVC)bistrioxazol. l ǯ° vs ï ǯ ȏͷͺȐǤǯ Ǧ À ȏͷͺȐǤ ȋ ͳͺȌ ± ǡ ǦȏͷͻȐǤ ǯ ǦǤ ͳͶ.
(30) Ǧ ȉǡ cmycǡ VEGF T30695 ȏͷͻȐǤ Öǡ Ö× × cmycȏͲȐǤ À ǡ ° ǯ° . Ǧ ï. Ö Ǥ O. . O. F. . N H. . N. N. N. . O. . N N. Figura18.EstructuradelQuarfloxin.. ͳͷ.
(31) ͳ.
(32) OBJECTIUS ǯ ǯ±ǯ ǯ Ö À °Ǥ ͵ ǣ ͳǤǯ ǯ Ö Ǥ ͳǤͳǤ ǯ±Àǯ Ö ÃͶ Ǥǯ × × ȋÀͳȌǤ ͳǤʹǤ ǯǯ × ò° Ö Ǥ ǯ ò° ǣ ȉ ȉȉǤǡ° ǯ ×Ö Öǡ± Ö ȋÀʹȌǤ ʹǤ × ǯ× ǯ × À Ǥ ×° ǡ Ö ǯ ȋÀ͵ȌǤ ͵ǤÀ ǡǯ × Ǥ ï À Ǧ ×Ǥ ǯ ǯ ȋʹǦȌǦ ȋÀ ͶȌǡ ͶǦ ȋÀ ͷȌ Ǧ ȋÀ ȌǤ ǯǯ ǯ ǯï Ǥ . ͳ.
(33) ͳͺ.
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