Els quàdruplex de guanina: Estudis estructurals i diana farmacològica

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(1)Els quàdruplex de guanina: Estudis estructurals i diana farmacològica Rubén Ferreira Aguilera. ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora.. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora.. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized neither its spreading and availability from a site foreign to the TDX service. Introducing its content in a window or frame foreign to the TDX service is not authorized (framing). This rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author..

(2)      .     .    A 1     . DzŽ•“—†”—’Ž‡š†‡‰—ƒ‹ƒǣ•–—†‹•‡•–”— –—”ƒŽ•‹†‹ƒƒ ˆƒ”ƒ ‘ŽÖ‰‹ ƒdz      .          . . —„± ‡””‡‹”ƒ‰—‹Ž‡”ƒ  ʹͲͳʹ. .

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(4)    .      .    .    A 1     . DzŽ•“—†”—’Ž‡š†‡‰—ƒ‹ƒǣ•–—†‹•‡•–”— –—”ƒŽ•‹†‹ƒƒ ˆƒ”ƒ ‘ŽÖ‰‹ ƒdz.   ‡Ö”‹ƒ’”‡•‡–ƒ†ƒ’‡”ǣ   —„± ‡””‡‹”ƒ‰—‹Ž‡”ƒ   ‡”‘’–ƒ”ƒŽ–À–‘Ž†‡‘ –‘”’‡”Žƒ‹˜‡”•‹–ƒ–†‡ƒ” ‡Ž‘ƒ ”‘‰”ƒƒ†‡†‘ –‘”ƒ–ǣ—À‹ ƒ”‰‹ ƒƒŽƒ †ï•–”‹ƒ—À‹ ‘Ǧˆƒ”ƒ °—–‹ ƒ ‹‡‹ʹͲͲͺǦͳͲ     ‹”‹‰‹†ƒ’‡”ǣ”Ǥƒ‘”‹–Œƒƒ•ƒ†‡ŽŽ‹”ƒǤƒ˜‹Óא†”±•     —–‘”ǣ”Ǥ ‘ƒ‘• Šƒ”–‡•  ƒ” ‡Ž‘ƒǡʹͲͳʹ.

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(6)                                    . .  ‘Ž‹ƒ ƒ‰”ƒ‹” ƒ –‘–Š‘ “—‹ Šƒ ‘–”‹„—Ö ’”‘ˆ‡••‹‘ƒŽ‡– ƒ Žƒ –‡•‹•ǡ ‡•’‡ ‹ƒŽ‡– ƒŽ ‡—• •—’‡”˜‹•‘”• ƒ‘ ”‹–Œƒ ‹ ƒ ˜‹Ó×Ǥ ƒ„± ˜‘Ž†”‹ƒ ƒ‰”ƒ‹” ƒŽ• ‡—• ‘’ƒ›• †‡ Žƒ„‘”ƒ–‘”‹ ‹ ƒŽ• ‹˜‡•–‹‰ƒ†‘”• “—‡ ǯŠƒ”‡„—–ƒŽ‡•‡•–ƒ†‡•ƒŽǯ‡•–”ƒ‰‡”‘†—”ƒ–Ž‡• ‘ŽȉŽƒ„‘”ƒ ‹‘•Ǥ  Žƒ‡˜ƒˆƒÀŽ‹ƒ‹ƒŽ•‡—•ƒ‹ •ǡ’‡Ž•‡—•—’‘”–‹‹•Ǥ.

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(8)                         Ž–”‡„ƒŽŽ†‡• ”‹–‡ƒ“—‡•–ƒ‡Ö”‹ƒŠƒ‡•–ƒ–”‡ƒŽ‹–œƒ–ƒŽǯ •–‹–—–†‡‡ ‡” ƒ‹‘°†‹ ƒȋ Ȍ•‹–—ƒ– ƒŽ ƒ”  ‹‡–Àˆ‹  †‡ ƒ” ‡Ž‘ƒ †‡ Žƒ ‹˜‡”•‹–ƒ– †‡ ƒ” ‡Ž‘ƒǤ “—‡•– Šƒ ‰ƒ—†‹– †‡Ž• ƒŒ—–• “—‡ ‡• †‡–ƒŽŽ‡ƒ ‘–‹—ƒ ‹×Ǥ ‡ ƒ’”‡†‘ –‘”ƒŽ†‡Ž‹‹•–‡”‹†‡‹° ‹ƒ‹ ‘˜ƒ ‹×†ǯ•’ƒ›ƒǡ  ȋǦʹͲͲͺǦͲͲͻ͵ͳͷȌǤ‡“—‡•’‡” ”‡ƒŽ‹–œƒ”‡•–ƒ†‡•„”‡—•ƒ‹Žȋ –ƒŽ‹ƒȌǡ‹°‰‡ȋ‡Ž‰‹ ƒȌ‹‹‡ƒ’‘Ž‹•ȋȌ†‡Ž‹‹•–‡”‹†‡‹° ‹ƒ‹ ‘˜ƒ ‹× ȋͳͲͲͲ ͲͲͲͲʹͺͲǢ ǦʹͲͳͳǦͶͶͶͶͷ ‹ Ǧ ǦͳʹǦͲͷʹʹͶȌǤ ‡“—‡• ˆ‹ƒ­ƒ†‡• ’‡Ž  ȋEuropean Cooperation in Sciencie and TechnologyȌ ’‡” ’ƒ”–‹ ‹’ƒ” ƒ — ™‘”•Š‘’ ƒ ’ƒ ȋ‡Ž‰‹ ƒȌ‹—ƒ‡•–ƒ†ƒ„”‡—ƒ‹°‰‡Ǥ.

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(10) ÍNDEX  A†‡š..............................................................................................................................................................................i A†‡š†ǯƒ„”‡˜‹ƒ–—”‡•................................................................................................................................................iii A†‡š†‡ˆ‹‰—”‡•.........................................................................................................................................................vi  IntroduccióiObjectius..........................................................................................................................................1 –”‘†— ‹×..................................................................................................................................................................3 „Œ‡ –‹—•...................................................................................................................................................................17 ‡ˆ‡”° ‹‡•...............................................................................................................................................................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 ‹• —••‹×‰‡‡”ƒŽ..................................................................................................................................................153 ‘ Ž—•‹‘•............................................................................................................................................................159 ‡•—†‡Žƒ‡Ö”‹ƒ..........................................................................................................................................161. . ‹.

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(12) Aǯ   „•ǣ„•‘”„ ‹ƒ. Ǧ͵ͺǣÀ‡ƒ ‡ŽȉŽ—Žƒ”Š—ƒƒ†‡  ‡”. ǣ ‡–‘‹–”‹Ž. ‘Ž‘ ǣ‹”—•†‡Žƒ‹—‘†‡ˆ‹ ‹° ‹ƒŠ—ƒƒ.  ʹǣŠÀ†”‹†ƒ °–‹   –ǣ ‡–ƒ–†ǯ‡–‹Ž. –ǣͳǦ ‹†”‘š‹„‡œ‘–”‹ƒœ‘Ž‡. ‡‰ǣȋʹǦ‹‘‡–‹ŽȌǦ‰Ž‹ ‹ƒ. ǣ”‘ƒ–‘‰”ƒˆ‹ƒŽÀ“—‹†ƒ†ǯƒŽ–ƒ’”‡••‹×. ‘ ǣtertǦ—–‘š‹ ƒ”„‘‹Ž. ǣ‘ ‡–”ƒ ‹×‹Š‹„‹–Ö”‹ƒ. ǣ‡ ‹×‡ˆ‹ ƒ­†‡ ‘ŽȉŽ‹•‹×ȋCollisioncross. ǣ•’‡ –”‘• ֒‹ƒ‹Ö‹ ƒ†‡ƒ••‡•. sectionȌ. ‹” ǣ •‘’”‘’ƒ‘Ž. ǣ‹ ”‘‹•‡ ‹” —Žƒ”. —”ƒ– Ž‘‡͸ǦͳǣÀ‡ƒ ‡ŽȉŽ—Žƒ”Š—ƒƒ†‡. ǣ•’‡ –”‘• ֒‹ƒ†‡ ‘””‡Žƒ ‹×.  ‡”†‡Ž‡— °‹ƒ.  ǣ‹†”‡†‡’‘”—• ‘–”‘Žƒ–.  ǣŽ‰‘”‹–‡‰‡°–‹ †‡ƒƒ” ‹ƒ. ǣǦȏʹǦȋ‹‡–‹Žƒ‹‘Ȍ‡–‹ŽȐƒ ”‹†‹ƒǦͶǦ. ǣ‘Ž—ƒ†‡„ƒ‹š˜‘Ž—’‡”•‹–‡–‹–œƒ”. ƒ”„‘šƒ‹†ƒ. ‘Ž‹‰‘— Ž‡Ö–‹†•. ǣ‹ Ž‘”‘‡–.  Ǧ ǣ ‘‹–œƒ ‹×’‡”†‡•‘” ‹×Žƒ•‡”. ǣʹǡʹǦ‹‡–‹ŽǦʹǦ•‹Žƒ’‡–ǦͷǦ•—Žˆ‘ƒ–†‡. ƒ••‹•–‹†ƒ’‡”ƒ–”‹—Ȃ‡’•†‡˜‘Ž. •‘†‹’‡”†‡—–‡”ƒ–.  ǣ‡–‹Ž„‡œ‹Ž†”‹Žƒ‹ƒ.  ǣ‹‹•‘’”‘’‹Ž‡–‹Žƒ‹ƒ. ǣ‹‹ ƒ‘Ž‡ —Žƒ”.   ǣǡǯǦ‹‹•‘’”‘’‹Ž ƒ”„‘†‹‹‹†ƒ. †‡‰ǣ‹Ž‹‰”ƒ—•.  ǣ‹‹•‘’”‘’‹Ž‡–‹Žƒ‹ƒ. ǣ‡ ‹ ƒ‘Ž‡ —Žƒ”. ǣͶǦ‹‡–‹Žƒ‹‘’‹”‹†‹ƒ. ‡ ǣ‡–ƒ‘Ž. ǣ‡†‹†‡ —Ž–‹—†ǯƒ‰Ž‡‘†‹ˆ‹ ƒ–’‡”. ǣ ‹†”‹„‘— Ž‡‹ ‹••ƒ–‰‡”. —Ž„‡ ‘. ǣ•’‡ –”‘• ֒‹ƒ†‡ƒ••‡•.  ǣNǡNǦ‹‡–‹Žˆ‘”ƒ‹†ƒ. ǣ”‘—”†‡͵ǦȋͶǡͷǦ†‹‡–‹Ž–‹ƒœ‘ŽʹǦ‹ŽȌǦʹǡͷǦ. ǣ‹‡–‹Ž•—ˆÖš‹†. †‹ˆ‡‹Ž–‡–”ƒœ‘Ž. ǣͶǡͶǦǦ‹‡–‘š‹–”‹–‹Ž. Ȁœǣ‡Žƒ ‹×ƒ••ƒȀ ””‡‰ƒ. ǣ ‹††‡•‘š‹”‹„‘— Ž‡‹ . ǣ‘Ž—ƒ†‡‡’Šƒ†‡š.  ǣ‡“ò° ‹ƒ†‡’‘Ž•‘•ȋˆ‹Ž–”‡†‡†‘„Ž‡.  Ͷ ǣ ‡–ƒ–†ǯƒ‘‹. “—ƒ–—Ȍ. . ǣ ‹†‡–‹Ž‡†‹ƒ‹‘–‡–”ƒ °–‹ . ǣ‡••‘ ‹ƒƒ‰°–‹ ƒ— Ž‡ƒ”.  ǣ ‘‹–œƒ ‹×’‡”‡Ž‡ –”‘•’”ƒ‹. ǣˆ‡ –‡˜‡”Šƒ—••‡”— Ž‡ƒ”. – ǣ–ƒ‘Ž. ǣ•’‡ –”‘• ֒‹ƒ’‡”‡ˆ‡ –‡. Ǧ͵͵ǣÀ‡ƒ ‡ŽȉŽ—Žƒ”†‡”ƒ–‘ŽÀ. ǣ°”—ˆ‡–ƒŽ„‘˜À. ˜‡”Šƒ—••‡”— Ž‡ƒ”. ‘ ǣͻǦ Ž—‘”‡‹Ž‡–‘š‹ ƒ”„‘‹Ž. ǣ‡•‹–ƒ–֒–‹ ƒ. ǦͶ Ž‘ǣÀ‡ƒ ‡ŽȉŽ—Žƒ”Š—ƒƒ†‡  ‡”. ǣŽ‹‰‘— Ž‡Ö–‹†. †‡’—Ž×.  ǣŽ‡ –”‘ˆ‘”‡•‹‡‰‡Ž†‡’‘Ž‹ƒ ”‹Žƒ‹†ƒ ‹‹‹.

(13) ǣƒ’׈‘•ˆƒ–•ƒŽÀ. ǣ‘Ž— ‹×–ƒ’׈‘”ƒ†ƒ’‡””‹•ǡ ‡–ƒ–‹. ǣ ‹†— Ž‡‹ ’‡’–À†‹ . . ǣƒ•‡†‡†ƒ†‡•†ǯ‡•–”— –—”‡•. ǣ”‡„Ž‡”ǡ”‡ƒ –‹—’‡”‰‡‡”ƒ”–”‡• ƒ†‡‡•. –”‹†‹‡•‹‘ƒŽ†‡’”‘–‡Ã‡•‹ ‹†•— Ž‡‹ •. †‡. ǣ‘Ž‹‡•–‹”°. ǣ ‹†–”‹ Ž‘”‘ƒ °–‹ . ›ǣ ‡šƒˆŽ—‘”‘ˆ‘•ˆƒ–†‡ȋ„‡œ‘–”‹ƒœ‘ŽǦͳǦ. ǣ ‡–ƒ–†‡–”‹‡–‹Žƒ‘‹. ‹Ž‘š‹Ȍ–”‹’‹””‘Ž‹†‹‘ˆ‘•ˆ‘‹.  ǣ ‹†–”‹ˆŽ—‘”‘ƒ °–‹ . ›”ǣ‹”‹†‹ƒ. ǣ”‘ƒ–‘‰”ƒˆ‹ƒ‡ ƒ’ƒˆ‹ƒ. ǣ‡ ‹ ƒ“—–‹ ƒ. ǣ•’‡ –”‘• ֒‹ƒ†‡ ‘””‡Žƒ ‹×–‘–ƒŽ. ”•†ǣ‡•˜‹ƒ ‹×’‡”Žƒ‹–Œƒƒ“—ƒ†”–‹ ƒ. ”‹•ǣ”‹•ȋŠ‹†”‘š‹‡–‹ŽȌƒ‹‘‡–. ǣ ‹†”‹„‘— Ž‡‹ . ǣŽ–”ƒ˜‹‘Ž‡–ƒ.  ǣ‡†‹‘•™‡ŽŽƒ”‡‘”‹ƒŽ •–‹–—–‡. ǣƒ–•‘Ǧ”‹ . ”Ǥ–Ǥǣ‡’‡”ƒ–—”ƒƒ„‹‡– ƒ”ǣƒ” ‘•‹ƒ ǣ‘†‡ ƒ•—Žˆƒ–†‡‘†‹. ‹˜.

(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  Ž †‡• ‘„”‹‡– †‡ Žǯ‡•–”— –—”ƒ †‡Ž  ‘ — †ï’Ž‡š Š‡Ž‹ ‘ƃŽ †‡ ’‘ŽÀ‡”• †‡ — Ž‡Ö–‹†•ǡ ’‡” ƒ‡• ƒ–•‘ ‹ ”ƒ ‹• ”‹  ‡Ž ͳͻͷ͵ ȏͳȐǡ Šƒ ’‡”°• ƒŽ• ‹‡–Àˆ‹ • ”‡‡šƒ‹ƒ” Žƒ ƒŒ‘”‹ƒ †‡Ž• ˆ‡Ö‡• „‹‘ŽÖ‰‹ •Ǥ ‹šÀǡ ‡ Ž‡• ‹‡• ‹  †° ƒ†‡•ǡ •ǯŠƒ ˆ‘”—Žƒ– —ƒ ˜‹•‹× ‰‡‡”ƒŽ †‡ ŽǯŠ‡”° ‹ƒ „‹‘ŽÖ‰‹ ƒ ‹ †‡ Žƒ –”ƒ•ˆ‡”° ‹ƒ †ǯ‹ˆ‘”ƒ ‹× ‰‡°–‹ ƒǡ “—‡ Šƒ ’‡”°• ‡•–ƒ„Ž‹” Žǯƒ‘‡ƒ– Dz‘‰ƒ ‡–”ƒŽ†‡Žƒ‹‘Ž‘‰‹ƒ‘Ž‡ —Žƒ”dzȏʹȐǤ  ƒ†‘„Ž‡Š°Ž‹š†‡‡•–‡•–ƒ„‹Ž‹–œƒ†ƒ’”‹ ‹’ƒŽ‡–’‡”Ž‡•‹–‡”ƒ ‹‘•†‡’‘–†ǯŠ‹†”‘‰‡“—‡ •ǯ‡•–ƒ„Ž‡‹š‡ ‡–”‡ Ž‡• — Ž‡‘„ƒ•‡• †‡ ƒ†ƒ ƒ†‡ƒ ȋ ‹‰—”ƒ ͳȌǤ –”‡ Ž‡• †—‡• ƒ†‡‡• –ƒ„± ‡• ˆ‘”‡‹–‡”ƒ ‹‘•†‡–‹’—•Š‹†”‘ˆÖ„‹ ‹‹–‡”ƒ ‹×†ǯƒ’‹Žƒ‡–‡–”‡Ž‡•— Ž‡‘„ƒ•‡•ȏ͵ȐǤ       Figura1.Enllaçosdepontd’hidrogendetipusWatsonCrickentreATiGC.  ‡Ž••‹•–‡‡•„‹‘ŽÖ‰‹ ••ǯŠƒ‹†‡–‹ˆ‹ ƒ––”‡• ‘ˆ‘”ƒ ‹‘•ˆ‘ƒ‡–ƒŽ•’‡”Žƒ†‘„Ž‡Š°Ž‹š†‡ǡ ƒ‘‡ƒ†‡•ǦǡǦ‹Ǧȋ ‹‰—”ƒʹȌȏ͵ȐǤ           . A-DNA. B-DNA. z-DNA.  Figura2.ConformacionsbàsiquesdeladoblehèlixdeDNA:BDNA,ADNAiZDNA. . ͵.

(19) ƒ ‘ˆ‘”ƒ ‹× Š‡Ž‹ ‘ƃŽ Ǧ ȏ͵Ȑǡ †‡• ”‹–ƒ ’‡” ƒ‡• ƒ–•‘ ‹ ”ƒ ‹• ”‹ ǡ ±• Žƒ ˆ‘”ƒ ’”‡†‘‹ƒ– ‡ ‡Ž• ‘”‰ƒ‹•‡• ˜‹—•Ǥ ƒ ˆ‘”ƒ  ȏͶȐ ±• ƒ†‘’–ƒ†ƒ ’‡Ž• ˆ”ƒ‰‡–• †‡ †‘„Ž‡ ƒ†‡ƒ †ǯ ‹ ‡••‡ ‹ƒŽ‡– ’‡Ž• ŠÀ„”‹†• Ǧ ȏ͵Ȑǡ –ƒ„± ‡• ’‘– †‘ƒ” ‡ †ï’Ž‡š• †‡  ‡ ‘†‹ ‹‘• †ǯƒŽ–ƒ ‘ ‡–”ƒ ‹× †‡ ƒ–‹‘• ‘ „ƒ‹šƒ Š‹†”ƒ–ƒ ‹× ȏͷȐǤ ƒ ‘ˆ‘”ƒ ‹×  ’”‡•‡–ƒ †‹ˆ‡”° ‹‡• ”‡•’‡ –‡ Žƒ ǡ ±• ±• ‘’ƒ –ƒ ‹ ‡Ž• •‘Ž • •× †‹ˆ‡”‡–• ȏ͵ȐǤ “—‡•–‡• †‹ˆ‡”° ‹‡• •× ”— ‹ƒŽ• ’‡Ž ”‡ ‘‡‹š‡‡– †‡ ‡”–‡• ’”‘–‡Ã‡• ȏͷȐǤ Ž ’”‹‡” ”‹•–ƒŽŽ †‡  “—‡ ‡• ˜ƒ ƒ ‘•‡‰—‹” ”‡•‘Ž†”‡ǡ ˜ƒ ‘•–”ƒ” — †ï’Ž‡š Ž‡˜‘‰‹” ‹ ’‡” Žƒ •‡˜ƒ ˆ‘”ƒ ‡ œ‹‰Ǧœƒ‰ ˜ƒ •‡” ƒ‘‡ƒ– Ǧ ȏ͸ȐǤ “—‡•–†ï’Ž‡šŽ‡˜‘‰‹”±•ƒŽŽƒ”‰ƒ–‹’”‹‹‘±•’”‡•‡–ƒ—•‘Ž ‡•–”‡–‹’”‘ˆ—†ȏ͵ȐǤƒ ‘ˆ‘”ƒ ‹× †‡ Ǧ ‡š‹•–‡‹š in vivoǡ ‘‘ Š‘ †‡‘•–”ƒ Žǯ‡š‹•–° ‹ƒ †‡ ’”‘–‡Ã‡• “—‡ ‡Ž ”‡ ‘‡‹š‡ ƒ„ —ƒ ‰”ƒƒˆ‹‹–ƒ–‹‡•’‡ ‹ˆ‹ ‹–ƒ–ȏ͹ȐǤ  ƒ ‘–ƒ„Ž‡ ˆŽ‡š‹„‹Ž‹–ƒ– ‘ˆ‘”ƒ ‹‘ƒŽ †‡Ž•  ‹†• — Ž‡‹ • ‡Ž• Šƒ ’‡”°• ˆ‘”ƒ” —ƒ ‰”ƒ ˜ƒ”‹‡–ƒ– †ǯ‡•–”— –—”‡•ǡ ƒ ±• ƒ ±• †‡ Žƒ †‘„Ž‡ Š°Ž‹šǡ ‘ ƒ”ƒ ‡Ž• –”À’Ž‡šǡ ‡Ž• imotifs ‹ ‡Ž• “—†”—’Ž‡š †‡ ‰—ƒ‹ƒ ȋ Ǧ“—†”—’Ž‡šȌǤ “—‡•–ƒ ˆŽ‡š‹„‹Ž‹–ƒ– ’”‘˜± ‡ ‰”ƒ ’ƒ”– †‡ Žƒ ŽŽ‹„‡”–ƒ– ‘ˆ‘”ƒ ‹‘ƒŽ †‡ Žǯƒ‡ŽŽ†‡”‹„‘•ƒ‹ǡ‡‡‘”‰”ƒ—ǡ†‡Žƒ”‘–ƒ ‹×‡–‘”Žǯ‡ŽŽƒ­‰Ž‹ ‘•À†‹ ‹Ž‡•”‘–ƒ ‹‘•†‡Žǯ‡•“—‡Ž‡– ˆ‘•ˆƒ–ȏ͵ȐǤ  ǯƒ›ͳͻͷ͹‹ Š‹ ‘ŽȉŽƒ„‘”ƒ†‘”•˜ƒ†‡‘•–”ƒ”Žƒˆ‘”ƒ ‹×†ǯ‡•–”— –—”‡•†‡–”‹’Ž‡ ƒ†‡ƒ‘–”À’Ž‡š †‡  ȏͺȐ ‡ ‡• Ž‡• †‡ ’‘Ž‹—”‹†‹‡• ‹ ’‘Ž‹ƒ†‡‹‡•Ǥ ǯ‹–‡”°• ’‡” ƒ“—‡•–‡• ‡•–”— –—”‡• ˜ƒ ƒ—‰‡–ƒ” ƒ ˆ‹ƒŽ• †‡Ž• ͺͲǡ †‡‰—– ƒŽ ’‘–‡ ‹ƒŽ ï• †ǯ‘Ž‹‰‘— Ž‡Ö–‹†• “—‡ ’‘†‡ ˆ‘”ƒ” –”À’Ž‡š ȋ Ȍ ‘ƒ‰‡–•‹Š‹„‹†‘”•†‡Žǯ‡š’”‡••‹×‰°‹ ƒƒ‹˜‡ŽŽ†‡–”ƒ†— ‹×ȋ‡•–”ƒ–°‰‹ƒƒ–‹‰‡ȌȏͻȐ‹ ‘ƒ‡‹‡• ‡Žƒ‹˜‡•–‹‰ƒ ‹×„‹‘°†‹ ƒȏͳͲȐǤ‡Ž–”À’Ž‡š†‡ǡŽǯ‘Ž‹‰‘— Ž‡Ö–‹†“—‡ˆ‘”ƒ‡Ž–”À’Ž‡š•ǯ—‡‹šƒŽ •‘Ž ƒŒ‘”†‡Ž†ï’Ž‡š‡•–†ƒ”†ƒ–•‘Ǧ”‹ ǡ‹–Œƒ­ƒ–‡ŽŽƒ­‘•†ǯŠ‹†”‘‰‡ǤŽ•–”À’Ž‡š’‘†‡•‡” ’ƒ”ƒŽȉŽ‡Ž• ‘ ƒ–‹’ƒ”ƒŽȉŽ‡Ž•ǡ •‡‰‘• Žǯ‘”‹‡–ƒ ‹× †‡ Žƒ –‡” ‡”ƒ ƒ†‡ƒ “—‡ ˆ‘”ƒ ‡Ž –”À’Ž‡šǤ Ž• ‘Ž‹‰‘— Ž‡Ö–‹†•ˆ‘”ƒ†‘”•†‡–”À’Ž‡šȋ Ȍ†ǯŠ‘‘’‹”‹‹†‹‡••ǯ—‡‹š‡’ƒ”ƒŽȉŽ‡Žƒ‡–ƒŽƒ ƒ†‡ƒ †‡’—”‹ƒ†‡Ž†ï’Ž‡š’‡”‡ŽŽƒ­‘•†ǯŠ‹†”‘‰‡ ‘‘‰•–‡‡’‡”ˆ‘”ƒ”‡Ž•–”À’Ž‡–•ȉ‹Ϊȉ ȋ ‹‰—”ƒ ͵ȌǤ  ƒ˜‹ǡ ‡Ž   †ǯŠ‘‘’—”‹‡• •ǯ—‡‹š‡ ƒ–‹’ƒ”ƒŽȉŽ‡Žƒ‡– ‹–Œƒ­ƒ– ‡ŽŽƒ­‘• ‘‘‰•–‡ ”‡˜‡”•‘•‹ˆ‘”‡‡Ž•–”À’Ž‡–• ȉ ‹ȉȋ ‹‰—”ƒ͵ȌǤƒˆ‘”ƒ ‹×†‡–”À’Ž‡š’ƒ”ƒŽȉŽ‡Ž”‡“—‡”‡‹š’   ‹†•’‡”’”‘–‘ƒ”Žƒ ‹–‘•‹ƒ‹ƒ‹šÖ‡Žˆƒ’‘ Ž‡‡–‘”•ˆ‹•‹‘ŽÖ‰‹ •Ǥ‡Ž„‹‘ŽÖ‰‹ ‡•’‘†‡ ˆ‘”ƒ” –”À’Ž‡š Š°Ž‹š• Ž‘ ƒŽ•ǡ ƒ‘‡ƒ†‡• Ǧǡ ‡ •‹–—ƒ ‹‘• †ǯ‡•–”°• •—’‡”Š‡Ž‹ ‘ƃŽ ‘ ƒ „ƒ‹š ’  ȏͳͳȐǤƒ•‡˜ƒˆ— ‹×„‹‘ŽÖ‰‹ ƒ‘±• Žƒ”ƒǡ’‡”ÖŽǯƒ„—† ‹ƒ†‡•‡“ò° ‹‡•ˆ‘”ƒ†‘”‡•†ǯƒ“—‡•–‘–‹— ±• ‘Ž– ƒŒ‘” ‡ ‡— ƒ”‹‘–‡• “—‡ ‡ ’”‘ ƒ”‹‘–‡• ‹ ‡ ‰‡‡”ƒŽ ‡• –”‘„‡ ‡ ‹–”‘• ‘ ”‡‰‹‘• ‘ –”ƒ†—Ƈ•Ǥ2•’‡”ƒ“—‡•–ƒ”ƒ×ǡ“—‡•ǯŠƒŠ‹’‘–‡–‹–œƒ–“—‡Žǯ Ǧ’‘––‡‹”—’ƒ’‡”‹’‘”–ƒ– ‘ƒ •‡›ƒŽ”‡‰—Žƒ†‘”†‡Žƒ”‡’Ž‹ ƒ ‹×‘‡Žƒ–”ƒ• ”‹’ ‹×‡‡— ƒ”‹‘–‡•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.  ‡• ƒ†‡‡•”‹“—‡•‡ ‹–‘•‹‡•’‘†‡ˆ‘”ƒ”—ƒ‡•–”— –—”ƒ†‡“—ƒ–”‡ ƒ†‡‡•ƒ‘‡ƒ†ƒimotif ȋ ‹‰—”ƒ ͶȌǤ “—‡•–‡• ‡•–”— –—”‡•ǡ “—‡ ˜ƒ”‡ •‡” †‡• ‘„‡”–‡• ƒ Žǯƒ› ͳͻͻ͵ ’‡” ‡Š”‹‰ ȏͳʹȐ ‹ ‘ŽȉŽƒ„‘”ƒ†‘”•ǡ”‡˜‡Ž‡“—‡†‘•†ï’Ž‡š’ƒ”ƒŽȉŽ‡Ž•‡•’‘†‡‹–‡” ƒŽƒ”Žǯ—ƒ„ŽǯƒŽ–”‡‹–Œƒ­ƒ–’‘–• †ǯŠ‹†”‘‰‡ǣΪȋ ‹‰—”ƒͶȌǤ ͶȌǤ . B.  . A.          ‹‰—”ƒͶǤȌ –‡”ƒ ‹‘•’‡”’‘–•†ǯŠ‹†”‘‰‡‡ǦΪǤȌ‡’”‡•‡–ƒ ‹×‡•“—‡–‹ ƒ†‡ŽimotifǤ . ͷ.

(21) ǯƒ›ͳͻͳͲǡƒ‰˜ƒ’—„Ž‹ ƒ”“—‡—ƒ•‘Ž— ‹× ‘ ‡–”ƒ†ƒ†ǯ ‹†‰—ƒÀŽ‹ ˆ‘”ƒ˜ƒ—‰‡Žǡ’‡”֐‘˜ƒ •‡” ˆ‹• Žǯƒ› ͳͻ͸ʹ “—‡ ‡ŽŽ‡„‡”– ˜ƒ †‡–‡”‹ƒ” “—‡ ‡• –”ƒ –ƒ˜ƒ †ǯ—ƒ ‡•–”— –—”ƒ †‡ “—†”—’Ž‡šǤ ǯƒŽ–”ƒ „ƒ†ƒǡ ‡ ƒ† ‹Ž„‡”– ˜ƒ”‡ ‘„•‡”˜ƒ” “—‡ •‡“ò° ‹‡• ”‹“—‡• ‡ ‰—ƒ‹‡• ’”‡•‡–ƒ˜‡ —ƒ ‡Ž‡ –”‘ˆ‘”‡•‹• ‡ ‰‡Ž ‹—•—ƒŽ ‹ ˜ƒ”‡ ’”‡†‹” “—‡ ’‘†”‹ƒ •‡” †‡‰—– ƒ Žƒ ˆ‘”ƒ ‹× †ǯ‡ŽŽƒ­‘• ‘‘‰•–‡ ȏͳ͵ȐǤ  ”‡ƒŽ‹–ƒ– Ž‡• ‰—ƒ‹‡• ’‘†‡ ‡•–ƒ„Ž‹” —• ‡ŽŽƒ­‘• †ǯŠ‹†”‘‰‡. ‘‘‰•–‡ ˆ‘”ƒ– —‡•. ‡•–”— –—”‡• ƒ‘‡ƒ†‡• Ǧ–°–”ƒ†‡• ȏͳͶȐ ȋ ‹‰—”ƒ ͷȌǤ “—‡•–‡• –°–”ƒ†‡• •× — ƒ””ƒŒƒ‡– ‘Ǧ ’Žƒƒ”‘ ƒ†ƒ‰—ƒ‹ƒƒ ‡’–ƒ‹†×ƒ†‘•‡ŽŽƒ­‘•†ǯŠ‹†”‘‰‡Ǥ“—‡•–ƒ†‹•’‘•‹ ‹×ˆ‘”ƒ—ƒ ƒ˜‹–ƒ– ‡–”ƒŽ“—‡’‡”‡–‹ ‘”’‘”ƒ”—‡–ƒŽŽǡ“—‡‡•–ƒ„‹Ž‹–œƒŽǯ‡•–”— –—”ƒȏͳͶȐǤ—ƒ†‘•‘±• Ǧ–°–”ƒ†‡• ‡•–ƒ ƒ’‹Žƒ†‡• ‡• ˆ‘”‡ —‡• ‡•–”— –—”‡• ƒ‘‡ƒ†‡• Ǧ“—†”—’Ž‡š ȏͳͶȐǤ ƒ ’”‹‡”ƒ ‡•–”— –—”ƒ ”‡•‘Ž–ƒ †‡ Ǧ“—†”—’Ž‡š ˜ƒ •‡” ’—„Ž‹ ƒ†ƒ Žǯƒ› ͳͻͻʹ ’‡” Žƒ •‡“ò° ‹ƒ –‡Ž‘°”‹ ƒ †‡ Žƒ Oxytricha ȋ. ͶͶ. Ͷ Ȍ’‡”. ”‹•–ƒŽȉŽ‘‰”ƒˆ‹ƒ‹’‡”ȏͳͷȐǤ.                     Figura 5. A) Tètrada formada per quatre guanines B) Quàdruplex tetramolecular C) Quàdruplex bimolecularD)Quàdruplexmonomolecular  Ž• “—†”—’Ž‡š ‡• ’‘†‡ ˆ‘”ƒ” ƒ„ ˜”‹‡• ‡•–‡“—‹‘‡–”‹‡• †‡. ƒ†‡ƒǤ Ž• “—†”—’Ž‡š. ‹–”ƒ‘Ž‡ —Žƒ”•ȋ ‹‰—”ƒͷȌ‡•ˆ‘”‡ƒ„—ƒ ƒ†‡ƒ•‡œ‹ŽŽƒǡ ‡ ƒ˜‹ǡ—ƒ•‡“ò° ‹ƒƒ„†—‡• ’ƒ”–•”‹“—‡•‡‰—ƒ‹‡•’‘†‡ˆ‘”ƒ”—ƒˆ‘”“—‡–ƒ‹ƒ••‘ ‹ƒ”Ǧ•‡’‡”‰‡‡”ƒ”—“—†”—’Ž‡š†‹°”‹  ͸.

(22) ȋ ‹‰—”ƒ ͷȌ ‹–‡”‘Ž‡ —Žƒ”Ǥ —ƒ–”‡ ƒ†‡‡• •‡’ƒ”ƒ†‡• –ƒ„± ’‘†‡ ‘„‹ƒ”Ǧ•‡ ‹ ˆ‘”ƒ” — “—†”—’Ž‡š–‡–”ƒ‘Ž‡ —Žƒ”ȋ ‹‰—”ƒͷȌǤ ‡• ïŽ–‹’Ž‡• ‡•–”— –—”‡• †‡–‡”‹ƒ†‡• ˆ‹• ƒŽ ‘‡– ’”‡•‡–ǡŠƒ ‘•–”ƒ– “—‡ ‡Ž “—†”—’Ž‡š †‡ ‰—ƒ‹ƒ ±• ƒŽ–ƒ‡– ’‘Ž‹Ö”ˆ‹ ǡ ƒ„ †‹ˆ‡”‡–• –‘’‘Ž‘‰‹‡• ”‡•’‡ –‡ ƒŽ ‘„”‡ ‹ Žǯ‘”‹‡–ƒ ‹× †‡ Ž‡• ƒ†‡‡•ǡ ‘ˆ‘”ƒ ‹×syn‘anti†‡Žǯ‡ŽŽƒ­‰Ž‹ ‘•À†‹ †‡Ž‡•‰—ƒ‹‡•‹†‹•’‘•‹ ‹×†‡Ž•‡ŽŽƒ­‘•ȏͳ͸ȐǤ ‡–”‡“—‡‡Ž•“—†”—’Ž‡š‹–‡”‘Ž‡ —Žƒ”•‘”ƒŽ‡––‡‡Ž‡•“—ƒ–”‡ ƒ†‡‡•‡—ƒ‘”‹‡–ƒ ‹× ’ƒ”ƒŽȉŽ‡Žƒǡ‡Ž•„‹‘Ž‡ —Žƒ”•‹‡Ž•‹–”ƒ‘Ž‡ —Žƒ”•’‘†‡’”‡•‡–ƒ”†‹ˆ‡”‡–•–‘’‘Ž‘‰‹‡•ǡ†‡ˆ‹‹†‡•’‡Ž –‹’—•†‡—‹×ȋ ‹‰—”ƒ͸ȌǤ. Diagonal.  . Propeller.     . Lateral. Figura6.Diferentstipusdeunionsperconnectarlesguaninesenunquàdruplex.  ‡•—‹‘•Žƒ–‡”ƒŽ• ‘‡ –‡Ž‡•„ƒ•‡•†‡Žƒƒ–‡‹šƒ–°–”ƒ†ƒ“—‡ ‘’ƒ”–‡‹š‡‡ŽŽƒ­‘•ǡŽ‡•—‹‘• †‹ƒ‰‘ƒŽ• ‘‡ –‡ Ž‡• „ƒ•‡• †‡ Žƒ ƒ–‡‹šƒ –°–”ƒ†ƒ “—‡ ‘ ‡•–ƒ —‹†‡• ’‡” ‡ŽŽƒ­‘• ‹ Ž‡• —‹‘• propellers ‘‡ –‡‰—ƒ‹‡•“—‡‘‡•–ƒ‡Žƒƒ–‡‹šƒ–°–”ƒ†ƒ’‡”Ö•‹‡‡Žƒ–‡‹š•‘Ž ȋ ‹‰—”ƒ͸ȌǤ  ‡Ž ƒ• †‡Ž• “—†”—’Ž‡š —‹‘Ž‡ —Žƒ”•ǡ •‡‰‘• ‡Ž –‹’—• †‡ —‹‘• ‡• ’‘†”‹‡ ˆ‘”ƒ” ʹ͹ –‹’—• †ǯ‡•–”— –—”‡•ǡ ’‡”Ö ‘±•ͳ͵ •× ‡•–°”‹ ƒ‡– ’‡”‡•‡•Ǥ ‡• ‘ˆ‘”ƒ ‹‘• ±• ‘—‡••× Ž‡• †‡ ƒ†‹”ƒȋ ‹‰—”ƒ͹ǡ͸ƒ‹͸„Ȍ‹Ž‡•†‡ ‹•–‡ŽŽƒȋ ‹‰—”ƒ͹ǡͳͳƒ‹ͳͳ„ȌǤŽ‡•‡•–”— –—”‡•†‡“—†”—’Ž‡šǡ‡Ž• ‡ŽŽƒ­‘•ˆ‘•ˆ‘†‹‡•–‡”†‡ˆ‹‡‹š‡‡Ž••‘Ž •ǡ“—‡’‘†‡•‡”†‡–”‡•–‹’—•ǣ‰”ƒǡ‹–Œƒ‘’‡–‹–Ǥ             Figura7.DiferentsestructuresdeGquàdruplexintermolecular,bimoleculariintramolecular.. ͹.

(23)  ‘Ž–‡• •‡“ò° ‹‡• ’‘†‡ ˆ‘”ƒ” ±• †ǯ—ƒ ‡•–”— –—”ƒ †‡ “—†”—’Ž‡šǡ ƒ–‘”‰ƒ– ƒŽ• “—†”—’Ž‡š — ‰”ƒ ’‘Ž‹‘”ˆ‹•‡Ǥ ‡” ‡š‡’Ž‡ǡ •ǯŠƒ †‡• ”‹– †‹ˆ‡”‡–• ‡•–”— –—”‡• ‹–”ƒ‘Ž‡ —Žƒ”• ’‡” Žǯ‘Ž‹‰‘— Ž‡Ö–‹†–‡Ž‘°”‹ . ȋ. Ȍ ͵ ’‡”‘”‹•–ƒŽȉŽ‘‰”ƒˆ‹ƒȏͳ͹ȐǤƒ•‡“ò° ‹ƒ–‡Ž‘°”‹ ƒ. ’”‡•‡–ƒ —ƒ ‡•–”— –—”ƒ –‹’—• ‹•–‡ŽŽƒ ȋ ‹‰—”ƒ ͺȌ ‡ —ƒ •‘Ž— ‹× †‡ •‘†‹ ’‡”  ‡–”‡ “—‡ Žǯ‡•–”— –—”ƒ†‡Ž ”‹•–ƒŽŽǡ‡’‘–ƒ••‹ǡ’”‡•‡–ƒ—ƒ‡•–”— –—”ƒ’ƒ”ƒŽȉŽ‡Žƒȋ ‹‰—”ƒͺȌǤ•–—†‹•’‘•–‡”‹‘”• ‘•–”‡ “—‡ Ž‡• †—‡• ‡•–”— –—”‡• ‡• ’‘†‡ ’”‡•‡–ƒ” ƒŽŠ‘”ƒ ‡ ‘†‹ ‹‘• ’”‘’‡”‡• ƒ Ž‡• ˆ‹•‹‘ŽÖ‰‹“—‡•‹‡•’‘†‡‹–‡” ‘˜‡”–‹”‡—ƒ‡• ƒŽƒ†‡–‡’•†‡‹—–•ȏͳͺǡͳͻȐǤ‡ ‡–‡–•ǯŠƒ †‡• ”‹–’‡”ƒ“—‡•–ƒ•‡“ò° ‹ƒ—ƒŽ–”ƒ‡•–”— –—”ƒǡ‡•‘Ž— ‹×†‡’‘–ƒ••‹ǡ†‡Ž–‹’—•dogearedȋ ‹‰—”ƒ ͺȌǤ  . A. B. . C.   Figura 8. Estructures de la seqüència telomèrica  24mer. A) Tipus dogeared. B) tipus cistella. C) Paral·lela.  ǯ‡•–ƒ„‹Ž‹–ƒ– †ǯ—ƒ ‘ˆ‘”ƒ ‹× †‡’° †‡ ‘Ž–• ˆƒ –‘”•ǡ ‘ ƒ”ƒ Žƒ ‘ ‡–”ƒ ‹×ǡ ‡Ž ‘„”‡ †‡ ƒ†‡‡•ǡ‡Ž‘„”‡†‡ Ǧ–°–”ƒ†‡•ǡ‡Ž–‹’—•‹•‡“ò° ‹ƒ†‡Ž‡•—‹‘•‹Ž‡• ‘†‹ ‹‘•†‡•‘Ž— ‹×ȏʹͲȐǤŽ –‹’—• ‹ Žƒ ‘ ‡–”ƒ ‹× †‡Ž ƒ–‹× ±• — †‡Ž• ˆƒ –‘”• ±• ‹ˆŽ—‡– ‡ Žǯ‡•–ƒ„‹Ž‹–œƒ ‹× †ǯ—ƒ ‡•–”— –—”ƒ ’ƒ”–‹ —Žƒ” †‡ “—†”—’Ž‡šǤ ǯ‡•–ƒ„‹Ž‹–ƒ– ‰‡‡”ƒŽ †‡Ž• “—†”—’Ž‡š ’‡Ž• ƒ–‹‘• •‡‰—‡‹š ƒ“—‡•–ƒ –‡†° ‹ƒǣ”ʹΪεΪε„Ϊ̱ƒʹΪε. ͶΪεƒʹΪεƒΪε‰ʹΪ̱•Ϊ εε‹Ϊ ȏʹͳȐǤŽ•. ƒ–‹‘•–ƒ„±’‘†‡ƒˆ‡ –ƒ”. ‡Ž’‘Ž‹‘”ˆ‹•‡†‡Ž•“—†”—’Ž‡š‹ƒˆƒ˜‘”‹”Žƒ ‘˜‡”•‹×†‡†ï’Ž‡šƒ“—†”—’Ž‡šǤ  Rellevànciabiològicadelsquàdruplex  ‹ Šƒ ‡˜‹†° ‹‡• “—‡ ‡Ž• Ǧ“—†”—’Ž‡š ‡• ˆ‘”‡ in vivo ȏʹʹǦʹ͵Ȑ ‹ “—‡ ’”‡•‡–‡ —ƒ ‰”ƒ ”‡ŽŽ‡˜ ‹ƒ„‹‘ŽÖ‰‹ ƒǤ  Ž•–‡ŽÖ‡”•‡•–”‘„‡ƒŽˆ‹ƒŽ†‡Ž• ”‘‘•‘‡•†‡Ž•‡— ƒ”‹‘–‡•‹ ‘–‡‡—–†‡†‡•‡“ò° ‹‡• ”‹“—‡• ‡ ‰—ƒ‹‡• ‘ ‘†‹ˆ‹ ƒ„Ž‡•Ǥ ƒ ”‡’‡–‹ ‹× –‡Ž‘°”‹ ƒ ‡ ‡Ž• Š—ƒ• ±• ‡–”‡ ʹ ‹ ͳͲ „ †‡ Ž‘‰‹–—†‹ ‘•‹•–‡‹š‡”‡’‡–‹ ‹‘•†‡Žƒ•‡“ò° ‹ƒȋ. ȌǤƒ„±‡• ‘‡‹š‡ƒŽ–”‡••‡“ò° ‹‡• ͺ.

(24) –‡Ž‘°”‹“—‡• ‡ ƒŽ–”‡• ‡•’° ‹‡• ‘ ƒ”ƒ Žƒ Tetrahymena ‹ ŽǯOxytricha nova ȋ Cerevisiae ȋ. ͳǦ͵ ȌǤ. Ȍ ‘ Žƒ S.. Ž• –‡ŽÖ‡”• ƒŒ—†‡ ƒ ’”‡˜‡‹” Žƒ †‡‰”ƒ†ƒ ‹× ‹ Žƒ ˆ—•‹× †‡Ž• ‡š–”‡• †‡Ž•. ”‘‘•‘‡•ǤŠ—ƒ•ǡƒ’”‘š‹ƒ†ƒ‡–‡–”‡ͷͲǦʹͲͲ’ƒ”‡ŽŽ•†‡„ƒ•‡•‡‡Ž•–‡ŽÖ‡”•‡•’‡”†‡ †‡•’”±•†‡ ƒ†ƒ ‹ Ž‡†‡”‡’Ž‹ ƒ ‹×Ǥ‡‰—–ƒƒ“—‡•–ˆ‡–ǡ‡Ž•–‡ŽÖ‡”•–‡‡—’ƒ’‡”‹’‘”–ƒ–‡Žƒ ”‡‰—Žƒ ‹× †‡ Žƒ Ž‘‰‡˜‹–ƒ– ‹ Žƒ ‘”– ‡ŽȉŽ—Žƒ”Ǥ ƒ ‘”– ‡ŽȉŽ—Žƒ” ’”‘‰”ƒƒ†ƒ ‡• ’‘– ’”‘†—‹” “—ƒ Žƒ •‡“ò° ‹ƒ–‡Ž‘°”‹ ƒ‡•”‡†—‡‹šƒ—ƒ†‡–‡”‹ƒ†ƒŽ‘‰‹–—†ȏʹͶȐǤǯƒŽ–”ƒ„ƒ†ƒǡŽƒ–‡Ž‘‡”ƒ•ƒ±•— ‡œ‹ “—‡ ‹•‡”‡‹š —ƒ ”‡’‡–‹ ‹× –‡Ž‘°”‹ ƒ ƒ††‹ ‹‘ƒŽ ƒŽ Ǥ ‹ŽŽ‹ƒ•‘ ‹ ‘ŽȉŽƒ„‘”ƒ†‘”• ˜ƒ ‘„•‡”˜ƒ” “—‡ Ž‡• •‡“ò° ‹‡• –‡Ž‘°”‹“—‡• ˆ‘”‡ ‡•–”— –—”‡• †‡ “—†”—’Ž‡š in vitro ȏͳͶȐ ‹ †‡• †‡ ŽŽƒ˜‘”•ǡŽƒˆ‘”ƒ ‹×†ǯ‡•–”— –—”‡•†‡“—†”—’Ž‡š’‡”•‡“ò° ‹‡•–‡Ž‘°”‹“—‡•invitro•ǯŠƒ‡•–—†‹ƒ– ’‡”†‹˜‡”•‡•–° ‹“—‡•Ǥ   ƒŽ–”‡ –”‡– •‘„”‡ Žƒ ”‡ŽŽ‡˜ ‹ƒ „‹‘ŽÖ‰‹ ƒ †‡Ž• “—†”—’Ž‡š ±• “—‡ •ǯŠƒ ‘„•‡”˜ƒ– — ‘„”‡ ‹’‘”–ƒ–†‡’”‘–‡Ã‡•“—‡•ǯ—‡‹š‡ƒŽ‡•‡•–”— –—”‡•†‡“—†”—’Ž‡šȏʹͷȐǤ  ‹šÀƒ–‡‹šǡ•ǯŠƒ–”‘„ƒ–•‡“ò° ‹‡•“—‡’‘†‡ˆ‘”ƒ” Ǧ“—†”—’Ž‡š‡œ‘‡•’”‘‘–‘”‡•†‡‰‡•ǡ •—‰‰‡”‹– “—‡ Žƒ •‡˜ƒ ˆ— ‹× ’‘†”‹ƒ ‡•–ƒ” ”‡Žƒ ‹‘ƒ†ƒ ƒ„ Žƒ ”‡‰—Žƒ ‹× ‰°‹ ƒ ƒ ‹˜‡ŽŽ †‡ Žƒ –”ƒ• ”‹’ ‹×Ǥ “—‡•– Šƒ ‡•–ƒ– ‡Ž ’—– †‡ ’ƒ”–‹†ƒ †‡ ‘Ž–‡• ‹˜‡•–‹‰ƒ ‹‘• •‘„”‡ ‡Ž ’ƒ’‡” †‡Ž “—†”—’Ž‡š‡Žƒ”‡‰—Žƒ ‹×†‡’”‘–‘Ǧ‘ ‘‰‡• ‘‡Žcmycȏʹ͸ȐǡVEGFȏʹ͹ȐǡHIF1ǡȏʹͺȐǡbcl2ȏʹͻȐ‘ cKitȏ͵ͲȐǤ ‹ Šƒ ‡•–—†‹• “—‡ †‡‘•–”‡ “—‡ ‡Ž ‹˜‡ŽŽ †ǯƒŽ‰—• ‹‘•ǡ ‘ ‡Ž ’‘–ƒ••‹ ‘ ‡Ž •‘†‹ǡ ’‘†‡ ƒˆ‡ –ƒ” Žǯ‡š’”‡••‹×‰°‹ ƒ‘Žǯƒ’‘’–‘•‹•ǡ‹‡•–”‘„‡ƒŽ–‡”ƒ–•‡ƒŽ‰—•–—‘”• ‡ŽȉŽ—Žƒ”•ȏ͵ͳȐǤƒ‘†‹ˆ‹ ƒ ‹× †‡ Žƒ ”‡Žƒ ‹× ‡–”‡ ƒ“—‡•–• ƒ–‹‘• ‡ Ž‡• °ŽȉŽ—Ž‡• ƒ ‡”À‰‡‡• ’‘†”‹‡ ’”‘˜‘ ƒ” ƒ˜‹• ‘ˆ‘”ƒ ‹‘ƒŽ•‡Ž‡•‡•–”— –—”‡•†‡“—†”—’Ž‡š‹ƒŽ–‡”ƒ”Žƒˆ— ‹×†‡Ž•–‡ŽÖ‡”•‘Žƒ–”ƒ• ”‹’ ‹× ‰°‹ ƒǤ • ’‘– Š‹’‘–‡–‹–œƒ” “—‡ Ž‡• ‡•–”— –—”‡• †‡ “—†”—’Ž‡š ’‘†”‹‡ ƒ –—ƒ” ‘ ƒ ‹–‡””—’–‘”• „‹‘ŽÖ‰‹ •‡Žƒ–”ƒ• ”‹’ ‹×ȋ ‹‰—”ƒͻȌǤ       Figura9.EsquemaquerepresentaelroldelGquàdruplexenlaregulaciógènica.  Ž• Ǧ“—†”—’Ž‡š•–ƒ„±ˆ‘”‡’ƒ”–†‡ŽƒˆƒÀŽ‹ƒ†‡„‹‘‘Ž° —Ž‡•ƒ –‹˜‡•“—‡•ǯ—‡‹š‡ƒ’”‘–‡Ã‡•ǡ ƒ“—‡•–• ‘Ž‹‰‘— Ž‡Ö–‹†• ‡• ‘‡‹š‡ ‘ ƒ’–‡”•Ǥ Ž• ƒ’–‡”• •× ‘Ž‹‰‘— Ž‡Ö–‹†• “—‡ Šƒ ‡•–ƒ– •‡Ž‡ ‹‘ƒ–•‹–Œƒ­ƒ–—• ‹ Ž‡•”‡’‡–‹–‹—•†‡•‡Ž‡ ‹×invitro’‡”—‹”Ǧ•‡ƒ—‡•†‹ƒ‡•„‹‘ŽÖ‰‹“—‡• ȏ͵ʹȐǤ†‡Ž•ƒ’–‡”•±• ‘‡‰—–±•Žǯƒ’–‡”“—‡•ǯ—‡‹šƒŽƒ–”‘„‹ƒȋǡThrombingBinding ͻ.

(25) AptàmerȌǤ Ž  ˆ‘”ƒ — “—†”—’Ž‡š ‹–”ƒ‘Ž‡ —Žƒ” ƒ„ †‘• Ǧ–‡–”†‡• ‹ –”‡• †‹ˆ‡”‡–• —‹‘• ȋ ‹‰—”ƒ ͳͲȌ ȏ͵͵ǡ ͵ͶȐǤ ƒ •‡˜ƒ ‡•–”— –—”ƒ ‹ ƒ –‹˜‹–ƒ– „‹‘ŽÖ‰‹ ƒ †‡’° †‡ Žƒ ‘ ‡–”ƒ ‹× †‡ ΪǤ Ž–”‡• ‡š‡’Ž‡• •× ‡Ž• ƒ’–‡”• †‡  “—‡ ‹Š‹„‡‹š‡ Žǯ‹–‡‰”ƒ•ƒ †‡Ž.  Š— ȏ͵ͷȐǤ •–—†‹•. ”‹•–ƒŽȉŽ‘‰”ˆ‹ • ‘•–”‡ “—‡ Žƒ –‘’‘Ž‘‰‹ƒ †‡Ž• “—†”—’Ž‡š ±• ”— ‹ƒŽ ’‡Ž ”‡ ‘‡‹š‡‡– ƒ„ Žƒ ’”‘–‡ÃƒǤ       Figura10.L’aptàmerdelatrombina(blau)s’uneixespecíficamentamblaproteïnatrombina(lila).  Elsàcidsnucleicscomadianafarmacològica  ‡‰—–ƒŽƒ‰”ƒ”‡ŽŽ‡˜ ‹ƒ„‹‘ŽÖ‰‹ ƒ†‡Žǡ‘±••‘”’”‡‡–“—‡‡š‹•–‡‹š‹ˆ”ƒ •ǡ†ǯï• ŽÀ‹ ‘ ‡ ˆƒ•‡• ŽÀ‹“—‡• ƒ˜ƒ­ƒ†‡•ǡ ”‡Žƒ ‹‘ƒ–• ƒ„ ‡Ž•  ‹†• — Ž‡‹ • ȏ͵͸ȐǤ Ž• ‘’‘•–‘• “—‡ ‹–‡”ƒ ‹‘‡ƒ„‡Ž• ‹†•— Ž‡‹ •’‘†‡ƒŽ–‡”ƒ”Žǯ‡š’”‡••‹×‰°‹ ƒ‘‹†—‹”Žǯƒ’‘’–‘•‹•ǡ†‡‰—–ƒ“—‡ ‹–‡”ˆ‡”‡‹š‡ ‡ ‡Ž• ’”‘ ‡••‘• †‡ ”‡’Ž‹ ƒ ‹×ǡ –”ƒ• ”‹’ ‹× ‘ –”ƒ†— ‹× ‡ŽȉŽ—Žƒ”Ǥ ‡• ƒ’Ž‹ ƒ ‹‘• –‡”ƒ’°—–‹“—‡• †‡ ˆ”ƒ • “—‡ ‹–‡”ƒ ‹‘‡ ƒ„ ‡Ž  ’‘†‡ ’”‡•‡–ƒ” — ƒ’Ž‹ ‡•’‡ –”‡ †ǯƒ –‹˜‹–ƒ–• ‘ ƒ”ƒ ƒ–‹˜‹”‹ƒŽǡ ƒ–‹ˆ—‰‹ ‹†ƒǡ ƒ–‹„‹Ö–‹ ƒ ‘ ƒ–‹‡‘’Ž•–‹ ƒǤ ‡• ‘Ž° —Ž‡• “—‡ ‹–‡”ƒ ‹‘‡ƒ„‡Ž•×’ƒ”–‹ —Žƒ”‡–‹’‘”–ƒ–• ‘ƒ‰‡–•ƒ–‹ ƒ ‡”À‰‡•Ǥ  ‘”ƒŽ‡– Ž‡• ‹–‡”ƒ ‹‘• †‡ ‘Ž–• ‘’‘•–‘• ƒ„ ‡Ž  •× ‘˜ƒŽ‡–• ‹ ‹””‡˜‡”•‹„Ž‡•ǡ ’‡”Ö ’‘†‡ •‡” Ž• ‡ –”ƒ –ƒ‡–• †‡ –—‘”•ǡ ’”‘ ‡••‘• ˜‹”ƒŽ• ‘ „ƒ –‡”‹ƒ•Ǥ “—‡•–• ‘’‘•–‘• ’”‘˜‘“—‡ Žƒ ‘”– ‡ŽȉŽ—Žƒ” †‡‰—– ƒ Ž‡• Ž‡•‹‘• ’”‘˜‘ ƒ†‡• ƒŽ ǡ ’‡”Öǡ ‰‡‡”ƒŽ‡– •× –Öš‹ • ‹ ’‘†‡ –‡‹” ‡ˆ‡ –‡• •‡ —†ƒ”‹• ‹’‘”–ƒ–• “—‡ ”‡†—‡‹š‡ Žǯï• ŽÀ‹ Ǥ  ‡š‡’Ž‡ †‡ ˆ”ƒ  ƒ–‹ ƒ ‡”‹‰‡“—‡•ǯ—‡‹š ‘˜ƒŽ‡–‡–±•‡ŽcisǦ’Žƒ–Àȋ ‹‰—”ƒͳͳȌ        Figura11.Representaciódelstipusd’uniócovalentdelcisplatíambelDNA.. ͳͲ.

(26) ƒƒŽ–”ƒˆ‘”ƒ†ǯ‹–‡”ƒ ‹×ƒ„‡Ž±•‹–Œƒ­ƒ–Žƒ‹–‡” ƒŽƒ ‹×ǤŽ• ‘’‘•–‘•“—‡•ǯ‹–‡” ƒŽ‡ ƒŽ  ‘”ƒŽ‡– •× •‹•–‡‡• ’‘Ž‹ À Ž‹ •ǡ ƒ”‘–‹ • ‹ ’Žƒ• “—‡ •ǯ‡ ƒ‹š‡ ‡–”‡ ‡Ž• ’ƒ”‡ŽŽ• †‡ „ƒ•‡• †‡Ž  ȏ͵͹ȐǤ š‹•–‡‹š‡ — ‘•‹†‡”ƒ„Ž‡ ‘„”‡ †ǯ‹–‡” ƒŽƒ–• ƒ„ ’‘–‡ ‹ƒŽ ˆƒ”ƒ ‘ŽÖ‰‹  ƒ–‹˜‹”ƒŽǡ ƒ–‹„‹Ö–‹  ȏ͵ͺȐ ‘ ƒ–‹–—‘”ƒŽǡ ‘ ƒŽ‰—‡• ƒ ”‹†‹‡• ȏ͵ͻȐǤ  ‡š‡’Ž‡ †‡ ˆ”ƒ  “—‡ •ǯ‹–‡” ƒŽƒƒŽ±•Žƒ†ƒ—‘‹ ‹ƒǤƒ†ƒ—‘‹ ‹ƒȋ ‹‰—”ƒͳʹȌ±•—ƒ‰‡–“—‹‹‘–‡”ƒ’°—–‹ †‡Žƒ ˆƒÀŽ‹ƒ†‡Ž‡•ƒ–”ƒ ‹ Ž‹‡•—–‹Ž‹–œƒ–’‡Ž–”ƒ –ƒ‡–†ǯƒŽ‰—•  ‡”•ȏͶͲȐǤ. O. OH. O.  . OH.  . O. O. OH. O. O.  . OH NH 2. Figura12.Estructuradeladaunomicina ƒ„± ‡š‹•–‡‹š‡ ‘Ž° —Ž‡• “—‡ ‹–‡”ƒ ‹‘‡ ƒŽ •‘Ž  ƒŒ‘” ‘ ‡‘” †‡Ž Ǥ ‘”ƒŽ‡– •× ƒ‡ŽŽ••‹’Ž‡•‘ˆ—•‹‘ƒ–• ‘‡ –ƒ–•’‡”‡ŽŽƒ­‘•ƒ„ŽŽ‹„‡”–ƒ–†‡‘˜‹‡–ȏͶͳȐǤ“—‡•–•ŽŽ‹‰ƒ†• ’‘†‡†‡•’Žƒ­ƒ”‡Ž• ƒ–‹‘•‘Ž‡•‘Ž° —Ž‡•†ǯƒ‹‰—ƒ†‡Ž••‘Ž •‹‹–‡”ƒ ‹‘ƒ”ƒ„‡Ž’ƒ”‡ŽŽ†‡„ƒ•‡•ǡ ƒ‹šÖˆƒ“—‡’—‰—‹•‡”•‡Ž‡ –‹—•‡‡Ž”‡ ‘‡‹š‡‡–†‡Žƒ•‡“ò° ‹ƒǤ‡š‡’Ž‡±•Žƒ†‹•–ƒ‹ ‹ƒ ȏͶʹǡͶ͵Ȑǡ—’”‘†— –‡ƒ–—”ƒŽˆ‘”ƒ–’‡”–”‡•ƒ‡ŽŽ•†‡’‹””‘Ž“—‡•ǯ—‡‹šƒŽ•‘Ž ’‡–‹–†‡ŽǤŽ‰”—’ –‡”‹ƒŽƒ‹†À‹ •‡”˜‡‹š’‡”ƒ–”ƒ—”‡‡Ž ‘’‘•–ƒŽ ƒ””‡‰ƒ–‡‰ƒ–‹˜ƒ‡–ǡ‹‡Ž‰”—’ʹǦƒ‹‘‡Ž• Š‹’”‘’‘” ‹‘ƒ—ƒ•‡Ž‡ –‹˜‹–ƒ–’‡Ž’ƒ”‡ŽŽ†‡„ƒ•‡•ȋ ‹‰—”ƒͳ͵Ȍ          Figura 13. Estructura tridimensional del complex format per la distamicina (taronja) i un dúplex de DNA(lila). . ͳͳ.

(27) ǯ‡•–ƒ„‹Ž‹–œƒ ‹× †‡Ž “—†”—’Ž‡š ’‘†”‹ƒ ‡•–ƒ” ”‡Žƒ ‹‘ƒ†ƒ ƒ„ Žƒ ”‡‰—Žƒ ‹× –”ƒ• ”‹’ ‹‘ƒŽ †ǯƒŽ‰—• ‰‡•Ǥ‡Ž•‹•ƒ›•ǡŠƒ•‘”‰‹–—‰”ƒ‹–‡”°•‡‡Ž†‹••‡›†‡‘Ž° —Ž‡•“—‡–‡‡ƒˆ‹‹–ƒ–’‡Ž• Ǧ“—†”—’Ž‡š’”‡•‡–•‡‡Ž•’”‘‘–‘”•†ǯ‘ ‘‰‡•ǡ’‡”–ƒŽ†ǯ‘„–‡‹”‘—•ˆ”ƒ • ‘–”ƒ‡Ž  ‡” ȏͶͶȐǤ ‡”—ƒƒŽ–”ƒ„ƒ†ƒǡŽƒƒŒ‘”‹ƒ†‡Ž‡• °ŽȉŽ—Ž‡••‘–‹“—‡•–‡‡—„ƒ‹š‹˜‡ŽŽ†‡Žǯ‡œ‹–‡Ž‘‡”ƒ•ƒ ‹ ‡••‡†‡’”‘Ž‹ˆ‡”ƒ”“—ƒ‡Ž•–‡ŽÖ‡”•ƒ””‹„‡ƒ—ƒ†‡–‡”‹ƒ†ƒŽ‘‰‹–—†Ǥ ƒ˜‹ǡ±•†ǯ—ͺͷΨ †‡ Ž‡• °ŽȉŽ—Ž‡• ƒ ‡”À‰‡‡• ’”‡•‡–‡ — ‰”ƒ ‹˜‡ŽŽ †ǯƒ“—‡•– ‡œ‹ ȏͶͷȐǤ Š‹„‹” Žǯƒ –‹˜‹–ƒ– †‡ Žƒ –‡Ž‘‡”ƒ•ƒ ±• —ƒ ‡•–”ƒ–°‰‹ƒ ’‡Ž †‹••‡› †‡ ˆ”ƒ •Ǥ ƒ  ‡•–”ƒ–°‰‹ƒ ’‡” †‹••‡›ƒ” ‹Š‹„‹†‘”• †‡ Žǯ‡œ‹ ±• ’”‡†”‡ ‘ ƒ †‹ƒƒ –‡”ƒ’°—–‹ ƒ Ž‡• ‡•–”— –—”‡• †‡ “—†”—’Ž‡š “—‡ ‡• ˆ‘”‡ ƒ„ Ž‡• •‡“ò° ‹‡•–‡Ž‘°”‹“—‡•ǤƒŠŽ‡”‹ ‘ŽȉŽƒ„‘”ƒ†‘”•˜ƒ‘„•‡”˜ƒ”“—‡Žǯ‡•–ƒ„‹Ž‹–œƒ ‹×†‡Ž‡•‡•–”— –—”‡• †‡ “—†”—’Ž‡š ˆ‘”ƒ†‡• ’‡” •‡“ò° ‹‡• –‡Ž‘°”‹“—‡• ‹Š‹„‹ƒ Žǯ‡Ž‘‰ƒ ‹× †‡Ž• –‡ŽÖ‡”• ’‡” Žƒ –‡Ž‘‡”ƒ•ƒȏͶ͸ȐǤ  ‡‰—– ƒ Žǯ‡•–”— –—”ƒ ’Žƒƒ †‡ Ž‡• –°–”ƒ†‡• †‡ ‰—ƒ‹ƒǡ ‡Ž• ‘’‘•–‘• “—‡ ‹–‡”ƒ ‹‘‡ ƒ„ Ž‡• ‡•–”— –—”‡•†‡“—†”—’Ž‡š•×‘”ƒŽ‡–ŽŽ‹‰ƒ†•ƒ”‘–‹ •’‘Ž‹ À Ž‹ •ƒ„†‹˜‡”•‡••—„•–‹–— ‹‘• ȏͶ͹ȐǤǯ‡•–ƒ„‹Ž‹–œƒ ‹×†‡Ž“—†”—’Ž‡š’‡Ž•ŽŽ‹‰ƒ†•‰‡‡”ƒŽ‡–±•†‡‰—†ƒ’‡”Ž‡•‹–‡”ƒ ‹‘•ɎǦɎ‡ Žƒ–°–”ƒ†ƒ†‡‰—ƒ‹ƒ‹’‡”Ž‡•‡Ž‡ –”‘•––‹“—‡•‡‡Ž••‘Ž •†‡Ž“—†”—’Ž‡šǤƒ‹–‡”ƒ ‹×‡š–‡”‹‘”†‡Ž ŽŽ‹‰ƒ†ƒ„‡Ž“—†”—’Ž‡š•‡„Žƒ•‡”Žƒ ƒƒ‡”ƒ†‡”‡ ‘‡‹š‡‡–‡•–”— –—”ƒŽ’‡Ž“—†”—’Ž‡š ȏͶ͹ȐǤ Ž• ŽŽ‹‰ƒ†• •‡Ž‡ –‹—• ƒ “—†”—’Ž‡š ‡• ’‘†”‹‡ Žƒ••‹ˆ‹ ƒ” ‡ “—ƒ–”‡ ƒ–‡‰‘”‹‡• •‡‰‘• Žƒ •‡˜ƒ ƒ–—”ƒŽ‡•ƒ ƒ–‹Ö‹ ƒȏͶ͹ȐǤ  Ž• ŽŽ‹‰ƒ†• ’”‘–‘ƒ„Ž‡• in situ •× ‘’‘•–‘• “—‡ ’”‡•‡–‡ ƒ†‡‡• •‡ —†”‹‡•ǡ ‘”ƒŽ‡– †‡ ƒ–—”ƒŽ‡•ƒ ƒÀ‹ ƒǡ “—‡ ‡ ‡†‹ ˆ‹•‹‘ŽÖ‰‹  ‡• –”‘„‡ ’”‘–‘ƒ†‡•Ǥ  ‡š‡’Ž‡ ±• Žǯƒ ”‹†‹ƒ –”‹•—„•–‹–—ƃ Ǧͳͻ ȋ ‹‰—”ƒ ͳͶȌ ‘’–‹‹–œƒ†ƒ ’‡” ‡‹†‡Žǡ —”Ž‡› ‹ ‘ŽȉŽƒ„‘”ƒ†‘”• ȏͶͺȐǤ “—‡•– ‘’‘•– ‡•–ƒ„‹Ž‹–œƒ ˆ‘”–ƒ‡– Žǯ‡•–”— –—”ƒ †‡ “—†”—’Ž‡š ‹ ’”‡•‡–ƒ —ƒ ‰”ƒ —ƒ •‡Ž‡ –‹˜‹–ƒ– ’‡Ž “—†”—’Ž‡š vs †ï’Ž‡šǤ ‹šÀ ƒ–‡‹šǡ ±• — ’‘–‡– ‹Š‹„‹†‘” †‡ Žƒ –‡Ž‘‡”ƒ•ƒ ‹ ’”‡•‡–ƒ ƒ –‹˜‹–ƒ– ƒ–‹–—‘”ƒŽǤ ƒ ’ƒ”– ƒ”‘–‹ ƒ †‡Ž Ǧͳͻ ‹–‡”ƒ ‹‘ƒ ƒ„ Ž‡• Ǧ–°–”ƒ†‡• ‡–”‡ “—‡ Ž‡• –”‡• ƒ†‡‡•Š‘ˆƒ’‡Ž••‘Ž •†‡Ž“—†”—’Ž‡šǤ  . N.  NH.  O.  . N. O. N H. N H. N.  Figura14.EstructuradelBRACO19.. ͳʹ.

(28) ‡Ž•ŽŽ‹‰ƒ†•ƒœƒǦƒ”‘–‹ •Ǧ‡–‹Žƒ–•ǡ‡Ž ƒ” –‡” ƒ–‹Ö‹ †‡ŽŽŽ‹‰ƒ†•ǯ‘„–±’‡Ž‹–”‘‰‡“—ƒ–‡”ƒ”‹ †‡ Žǯƒ‡ŽŽ ƒ”‘–‹ Ǥ “—‡•–ƒ ‡•–”ƒ–°‰‹ƒ ’‡”‡– ‘„–‡‹” ‘’‘•–‘• Š‹†”‘•‘Ž—„Ž‡• ƒ„ —ƒ ‰”ƒ Šƒ„‹Ž‹–ƒ–’‡”ˆ‘”ƒ”‹–‡”ƒ ‹‘•ɎǦɎǡ”‡†—‹–Žƒ†‡•‹–ƒ–‡Ž‡ –”֐‹ ƒ†‡Žƒ’ƒ”–ƒ”‘–‹ ƒǤ‡š‡’Ž‡ ±• ‡Ž ›Ͷ ȋ ‹‰—”ƒ ͳͷȌǡ ’Ž‹ƒ‡– ‡•–—†‹ƒ†ƒ ’‡” —”Ž‡›ǯ• ‹ ‘ŽȉŽƒ„‘”ƒ†‘”•ǡ “—‡ ’”‡•‡–ƒ —ƒ ‰”ƒ ƒˆ‹‹–ƒ– ’‡Ž• Ǧ“—†”—’Ž‡šǡ —ƒ ‡ˆ‹ ‹‡– ‹Š‹„‹ ‹× †‡ Žƒ –‡Ž‘‡”ƒ•ƒ ‹ ”‡‰—Ž‡ Žǯ‡š’”‡••‹× †ǯ‘ ‘‰‡•ȏʹ͹ȐǤƒŽ–”‡‡š‡’Ž‡•×Ž‡•ƒ–”ƒ“—‹‘‡•ǡ ‘’‘•–‘•†‡•‡˜‘Ž—’ƒ–•‘”‹‰‹ƒŽ‡–’‡” ‹–‡”ƒ ‹‘ƒ” ƒ„ ‡Ž  ‹ “—‡ ’”‡•‡–‡ ƒ –‹˜‹–ƒ– ƒ–‹–—‘”ƒŽ ȏͶͻȐǤ — ‹ ‘ŽȉŽƒ„‘”ƒ†‘”• ˜ƒ †‡‘•–”ƒ”“—‡Žƒƒ–”ƒ“—‹‘ƒͳͲͷͳȋ ‹‰—”ƒͳͷȌ‹–‡”ƒ ‹‘ƒ‹‡•–ƒ„‹Ž‹–œƒŽ‡•‡•–”— –—”‡•†‡ Ǧ “—†”—’Ž‡šǡ ‹Š‹„‹– Žƒ –‡Ž‘‡”ƒ•ƒǤ ǯƒ ”‹†‹ƒ ’‡–ƒ À Ž‹ ƒ  Ͷ ȋ ‹‰—”ƒ ͳͷȌ –ƒ„± ±• — ’‘–‡– ‹Š‹„‹†‘”†‡Žƒ–‡Ž‘‡”ƒ•ƒ‹‹Š‹„‡‹šŽƒ’”‘Ž‹ˆ‡”ƒ ‹× ‡ŽȉŽ—Žƒ”ȏͷͲȐǤ   . 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  Ž• ŽŽ‹‰ƒ†• ‡–ƒŽȉŽ‘Ǧ‘”‰‹ • ȏͷͳȐ •× ‹–‡”‡••ƒ–• †‡‰—– ƒ “—‡ ‡• ’‘†‡ ‘„–‡‹” ˆ ‹Ž‡– ’‡” •À–‡•‹‹•ǯŠƒ†‡‘•–”ƒ–“—‡’‘†‡–‡‹”—ƒ„‘ƒ ƒ’ƒ ‹–ƒ–†ǯ—‹×ƒ“—†”—’Ž‡š†‡‰—ƒ‹ƒǤŽ‡–ƒŽŽ †‡Ž ŽŽ‹‰ƒ† ’‘†”‹ƒ ‘ —’ƒ” Žƒ ’‘•‹ ‹× ‡–”ƒŽ †‡ Žƒ Ǧ–°–”ƒ†ƒǡ ƒˆƒ˜‘”‹– Žƒ ‹–‡”ƒ ‹× ‹–Œƒ­ƒ– “—‡ŽȉŽƒ ‹×Ǥ “—‡•–ƒ ƒ–—”ƒŽ‡•ƒ ƒ–‹Ö‹ ƒ ‘ ƒŽ–ƒ‡– ’‘Žƒ”‹–œƒ†ƒ ±• — Žƒ” ƒ˜ƒ–ƒ–‰‡ ’‡” ’”‘‘—”‡ Žǯƒ••‘ ‹ƒ ‹× ƒ„ ‡Ž Ǧ“—†”—’Ž‡šǤ  †‡Ž• ’”‹‡”• ŽŽ‹‰ƒ†• ‡–ƒŽȉŽ‘Ǧ‘”‰ƒ‹ • ’—„Ž‹ ƒ–• ˜ƒ •‡” ‡Ž ›Ͷƒ„—ȋ Ȍȋ ‹‰—”ƒͳ͸ȌȏͷʹȐǤ“—‡•–’”‡•‡–ƒ—ƒ’”‡ˆ‡”° ‹ƒ’‡Ž“—†”—’Ž‡švs‡Ž†ï’Ž‡š‹ —ƒ‘†‡•–ƒ‹Š‹„‹ ‹×†‡Žƒ–‡Ž‘‡”ƒ•ƒǤƒŽ–”‡‡š‡’Ž‡•×‡Ž• ‘’Ž‡š‡•‡–ŽȉŽ‹ •†‡•‡˜‘Ž—’ƒ–• ’‡” ‹Žƒ” ‹ ‘ŽȉŽƒ„‘”ƒ†‘”• ȋ ‹‰—”ƒ ͳ͸Ȍ “—‡ ‹–‡”ƒ ‹‘‡ ƒ„ ‡Ž• Ǧ“—†”—’Ž‡š –‡Ž‘°”‹ • ‹ ’”‡•‡–‡ƒ –‹˜‹–ƒ–ƒ–‹–—‘”ƒŽ‹‹Š‹„‹†‘”ƒ†‡Žƒ–‡Ž‘‡”ƒ•ƒȏͷ͵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  ƒ –‡Ž‘ƒ•–ƒ–‹ƒ ȏͷͷȐ ȋ ‹‰—”ƒ ͳ͹Ȍ ‡•– ‹ Ž‘•ƒ ‡ Žƒ ƒ–‡‰‘”‹ƒ †‡Ž• ŽŽ‹‰ƒ†• ƒ ”‘ À Ž‹ •Ǥ “—‡•–ƒ ‘Ž° —Žƒ ƒ–—”ƒŽ ˜ƒ •‡” ƒÃŽŽƒ†ƒ †‡Ž Streptomyces annulatus Žǯƒ› ʹͲͲͳ ’‡Ž ‰”—’ †‡Ž Š‹›ƒǤ ‘•–‡”‹‘”‡–˜ƒ•‡”‘Ž–‡•–—†‹ƒ†ƒ’‡Ž•‡—’‘–‡ ‹ƒŽ ‘ƒŽŽ‹‰ƒ††‡“—†”—’Ž‡šǡ†‡‰—–ƒŽƒ•‡˜ƒ ‘’Ž‡–ƒ ƒ„•° ‹ƒ †ǯ‹–‡”ƒ ‹× ƒ„ ‡Ž †ï’Ž‡š ‹ ’‡” ‹Š‹„‹” Žƒ –‡Ž‘‡”ƒ•ƒǤ ‡”Ö ‡Ž •‡— ‹ ‘˜‡‹‡– ±• ‰”ƒ ±• Žƒ †‹ˆ‹ —Ž–ƒ– ’‡” ‘„–‡‹”ǦŽƒǡ ’‡” –ƒ–ǡ •ǯŠƒ †‡•‡˜‘Ž—’ƒ– ƒŽ–”‡• †‡”‹˜ƒ–• •‹–°–‹ • †‡ Žƒ –‡Ž‘‡•–ƒ–‹ƒǡ ‘ ‡Ž ƒ ”‘ À Ž‹  Š‡šƒ‘šƒœ‘Ž  ȋ ‹‰—”ƒ ͳ͹Ȍ ‘ Žǯƒ ‡–ƒ– †‡ „‹•–”‹‘šƒœ‘Ž ȋ ‹‰—”ƒ ͳ͹Ȍȏͷ͸ǡͷ͹ȐǤ . 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.  lŽ–‹ƒ‡– Žǯ‹–‡”°• ’‡” ‘„–‡‹” ŽŽ‹‰ƒ†• ƒ’ƒ­‘• †‡ †‹• ”‹‹ƒ” ‡–”‡ “—†”—’Ž‡š vs †ï’Ž‡š •ǯŠƒ †‡•’Žƒ­ƒ–’‡Ž†‹••‡›†‡ ‘’‘•–‘• ƒ’ƒ­‘•†‡†‹ˆ‡”‡ ‹ƒ”‡–”‡†‹˜‡”•‡•–‘’‘Ž‘‰‹‡•†‡“—†”—’Ž‡š ȏͷͺȐǤŽ‰—•†ǯƒ“—‡•–•ŽŽ‹‰ƒ†••‡Ž‡ –‹—•ƒ Ǧ“—†—’Ž‡š–‡‡—‰”ƒ’‘–‡ ‹ƒŽ’‡”‡–”ƒ”‡‡•–—†‹• ŽÀ‹ •ȏͷͺȐǤ  Ž —ƒ”ˆŽ‘š‹ ȋ ‹‰—”ƒ  ͳͺȌ ±• — †‡”‹˜ƒ– †‡Ž ‘”ˆŽ‘šƒ ‹ǡ —ƒ ˆŽ—‘”‘“—‹‘Ž‘ƒ “—‡ ’”‡•‡–ƒ ƒˆ‹‹–ƒ– ’‡”Žƒ–‘’‘‹•‘‡”ƒ•ƒ ‹’‡Ž• Ǧ“—†”—’Ž‡šȏͷͻȐǤ›Ž‡‡Šƒ”ƒ ‡—–‹ ƒŽ‡Ž˜ƒ‘’–‹‹–œƒ”’‡”‡Ž‹‹ƒ” Žǯƒ –‹˜‹–ƒ– ‹Š‹„‹†‘”ƒ †‡ Žƒ –‘’‘‹•‘‡”ƒ•ƒ  ‹ ƒš‹‹–œƒ” Žƒ •‡Ž‡ –‹˜‹–ƒ– ’‡Ž• Ǧ“—†”—’Ž‡šǤ Ž ͳͶ.

(30) —ƒ”ˆŽ‘š‹ ’”‡•‡–ƒ —ƒ ‰”ƒ •‡Ž‡ –‹˜‹–ƒ– ’‡” –‘–• ‡Ž• Ǧ“—†”—’Ž‡š ’ƒ”ƒŽȉŽ‡Ž•ǡ ‘ ‡Ž• ˆ‘”ƒ–• ƒŽ• ’”‘‘–‘”• cmycǡ VEGF ‹ T30695 ȏͷͻȐǤ ‘– ‹ ƒ‹šÖǡ ‡•–—†‹• ’‘•–‡”‹‘”• †‡‘•–”‡ “—‡ Ž‡• ’”‘’‹‡–ƒ–• „‹‘ŽÖ‰‹“—‡•†‡Ž—ƒ”ˆŽ‘š‹•×†‡‰—†‡•ƒŽƒ‹–‡”ƒ ‹×ƒŽ ‘’Ž‡š’”‘–‡‹ †‡Ž“—†”—’Ž‡šcmycȏ͸ͲȐǤ  ƒ”ƒ“—‡‡Ž—ƒ”ˆŽ‘š‹‘˜ƒ•—’‡”ƒ”‡Ž•‡•–—†‹• ŽÀ‹ •†‡ ƒ•‡ ’‡”Žƒ•‡˜ƒ„‹‘†‹•’‘‹„‹Ž‹–ƒ–ǡ‡Ž •‡— ’‡”ˆ‹Ž –‡”ƒ’°—–‹  ƒ˜‹˜ƒ Žǯ‹–‡”°• ’‡” ‘’–‹‹–œƒ” ‡Ž• ŽŽ‹‰ƒ†• †‡. Ǧ“—†”—’Ž‡š ’‡Ž •‡— ï•. ˆƒ”ƒ ‘ŽÖ‰‹ Ǥ   O. . O. F. . N H. . N. N. N. . O.   . N N.  Figura18.EstructuradelQuarfloxin.. ͳͷ.

(31) ͳ͸.

(32) OBJECTIUS  ǯ‘„Œ‡ –‹—‰‡‡”ƒŽ†ǯƒ“—‡•–ƒ–‡•‹•±•Žǯ‡•–—†‹‡•–”— –—”ƒŽ†ǯ‘Ž‹‰‘— Ž‡Ö–‹†•“—‡ˆ‘”‡“—ƒ†”—’Ž‡š†‡ ‰—ƒ‹ƒ ‹ Žƒ •À–‡•‹• †‡ ŽŽ‹‰ƒ†• •‡Ž‡ –‹—•’‡” ƒ“—‡•–‡•‡•–”— –—”‡• ƒ„ ˆ‹ƒŽ‹–ƒ–•–‡”ƒ’°—–‹“—‡•Ǥ Ž• ‘„Œ‡ –‹—•‡•’‘†‡”‡•—‹”‡͵‘„Œ‡ –‹—•’”‹ ‹’ƒŽ•ǣ  ͳǤǯ‡•–—†‹‡•–”— –—”ƒŽ†ǯ‘Ž‹‰‘— Ž‡Ö–‹†•ƒ–—”ƒŽ•‹‘†‹ˆ‹ ƒ–•“—‡ˆ‘”‡“—†”—’Ž‡š†‡‰—ƒ‹ƒǤ  ͳǤͳǤ‘ ”‡–ƒ‡–—†‡Ž•‘„Œ‡ –‹—•†ǯƒ“—‡•–ƒ–‡•‹±•Žƒ•À–‡•‹†ǯ—•‘Ž‹‰‘— Ž‡Ö–‹†•”ƒ‹ˆ‹ ƒ–•“—‡ ‡•–ƒ ‘•–‹–—Ö•’‡”Ͷ ƒ†‡‡•”‹“—‡•‡‰—ƒ‹ƒŽŽ‹‰ƒ†‡•’‡”—†‡Ž•‡š–”‡•Ǥǯƒ“—‡•–ƒƒ‡”ƒ‡• ’‡”•‡‰—‡‹š’”‘†—‹”‡•–”— –—”‡•†‡“—†”—’Ž‡š—‹‘Ž‡ —Žƒ”•ƒŽ–ƒ‡–‡•–ƒ„‹Ž‹–œƒ†‡•†‡ ‘ˆ‘”ƒ ‹× ‹ƒ••‘ ‹ƒ ‹×‹–‡”‘Ž‡ —Žƒ””‡•–”‹‰‹†ƒȋƒ’À–‘ŽͳȌǤ  ͳǤʹǤ•‡‰‘‘„Œ‡ –‹—•‡•„ƒ•ƒ‡Žǯ‡•–—†‹†‡Žǯƒ••‘ ‹ƒ ‹×„‹‘Ž‡ —Žƒ”†‡•‡“ò° ‹‡•†‡ƒ–—”ƒŽ• ’”‡•‡–• ‡ ‡Ž• –‡ŽÖ‡”• Š—ƒ•Ǥ  ǯŠƒ †‡• ”‹– “—‡ ƒ“—‡•–‡• •‡“ò° ‹‡• ˆ‘”‡ “—†”—’Ž‡š †‡ ‰—ƒ‹ƒ“—‡’‘†‡•‡”†‡†‘•–‹’—•†‹ˆ‡”‡–•ǣ—ƒˆ‘”ƒ‡Žƒ“—‡Ž‡•“—ƒ–”‡ ƒ†‡‡••‘’ƒ”ƒŽȉŽ‡Ž‡•‹ —ƒƒŽ–”ƒ‡Žƒ“—‡Š‹Šƒ†‘• ƒ†‡‡•’ƒ”ƒŽȉŽ‡Ž‡•‹†‘•ƒ–‹’ƒ”ƒŽȉŽ‡Ž‡•Ǥ“—‡•–‡“—‹Ž‹„”‹ǡ†‡‰”ƒ‹–‡”°• ’‡”Žǯ‡•–ƒ„‹Ž‹–ƒ–‹ˆ— ‹×„‹‘ŽÖ‰‹ ƒ†‡Ž•–‡ŽÖ‡”•ǡ±•‡•–—†‹ƒ–‡†‡–ƒŽŽ’‡”‡•’‡ –”‘• ֒‹ƒ†‡ƒ••‡•‹ †‹ ”‘‹•‡ ‹” —Žƒ”ȋƒ’À–‘ŽʹȌǤ  ʹǤ ˜ƒŽ—ƒ ‹× †‡ Ž‡• ’”‘’‹‡–ƒ–• †ǯ—‹× ƒŽ  †ǯ‹Š‹„‹†‘”• †‡ Ž‡• –‘’‘‹•‘‡”ƒ•‡• “—‡ ‡•–ƒ ‡ ƒ˜ƒŽ—ƒ ‹×’”‡ ŽÀ‹ ƒǤ“—‡•–‘„Œ‡ –‹—Šƒ ‘’‘”–ƒ–Žƒ—–‹Ž‹–œƒ ‹×†‡–° ‹“—‡•†‡†‹Ž‹•‹• ‘’‡–‹–‹˜ƒǡ ‡•’‡ –”‘• ֒‹ƒ†‡‹‘†‡Žƒ–‰‡‘Ž‡ —Žƒ”’‡”–ƒŽ†‡†‡ˆ‹‹”Žǯ‡•–”— –—”ƒ†‡Ž ‘’Ž‡šˆ‘”ƒ–’‡Ž “—†”—’Ž‡š†‡‰—ƒ‹ƒ‹‡Ž•‹Š‹„‹†‘”•ȋƒ’À–‘Ž͵ȌǤ  ͵ǤÀ–‡•‹•†‡‘—• ‘’‘•–‘•ƒ„ƒˆ‹‹–ƒ–’‡Žǡ‡•–—†‹†‡Žǯƒˆ‹‹–ƒ–‹‡Ž— ‹†ƒ ‹×‡•–”— –—”ƒŽ†‡Ž• ‘’Ž‡š‡•ˆ‘”ƒ–•ǤŽ–”‡– ‘ï“—‡–‡‡‡Ž• ‘’‘•–‘•‡•–—†‹ƒ–•‡•“—‡‡•–ƒˆ‘”ƒ–•’‡”†‹˜‡”•‡• —‹–ƒ–• †‡ ‘’‘•–‘• Š‡–‡”‘ À Ž‹ • “—‡ ’‘†‡ —‹”Ǧ•‡ ƒŽ  ’‡” ‹–‡” ƒŽƒ ‹×Ǥ ‡” –ƒŽ †ǯ—‹” ‡Ž• ‘’‘•–‘• ‹–‡” ƒŽƒ–• •ǯŠƒ ‡•–—†‹ƒ– †‹˜‡”•‘• ‡•’ƒ‹ƒ†‘”• ‘ ’‡” ‡š‡’Ž‡ ȋʹǦƒ‹‘‡–‹ŽȌǦ‰Ž‹ ‹ƒ ȋƒ’À–‘Ž ͶȌǡ ͶǦƒ‹‘’”‘Ž‹ƒ ȋƒ’À–‘Ž ͷȌ ‹ –”‡‘‹‘ŽǦˆ‘•ˆƒ– ȋƒ’À–‘Ž ͸ȌǤ “—‡•–• ‡•’ƒ‹ƒ†‘”• –‡‡ Žƒ ’ƒ”–‹ —Žƒ”‹–ƒ–†ǯ—‹”†‡”‹˜ƒ–•†ǯƒ ”‹†‹ƒ‹“—‹†‘Ž‹ƒƒ—ƒ†‹•–ƒ ‹ƒ ‘’ƒ–‹„Ž‡ƒ„‡Ž†‡†‘„Ž‡ ƒ†‡ƒ’‡”–ƒŽ†ǯƒ ‘•‡‰—‹”Žǯƒ’‹Žƒ‡–ïŽ–‹’Ž‡†‡Ž‡•—‹–ƒ–•‹–‡” ƒŽƒ–•Ǥ   . ͳ͹.

(33) ͳͺ.

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Figure

Figura�3.�A)�Estructures�de�les�triades�T·AT�i�C+·GC�presents�en�els�triplex�paral·lels.�B)�Estructures�dels��triades�A·AT,�G·GC�i�T·AT�presents�en�els�tríplex�antiparal·lels.�
Figura�3.�A)�Estructures�de�les�triades�T·AT�i�C+·GC�presents�en�els�triplex�paral·lels.�B)�Estructures�dels��triades�A·AT,�G·GC�i�T·AT�presents�en�els�tríplex�antiparal·lels.� p.20
Figura� 5.� A)� Tètrada� formada� per� quatre� guanines� B)� Quàdruplex� tetramolecular� C)� Quàdruplex�b�imolecular�D)�Quàdruplex�monomolecular�
Figura� 5.� A)� Tètrada� formada� per� quatre� guanines� B)� Quàdruplex� tetramolecular� C)� Quàdruplex�b�imolecular�D)�Quàdruplex�monomolecular� p.21
Figura�7.��Diferents�estructures�de�G�quàdruplex�intermolecular,�bimolecular�i�intramolecular.�
Figura�7.��Diferents�estructures�de�G�quàdruplex�intermolecular,�bimolecular�i�intramolecular.� p.22
Figura�10.�L’aptàmer�de�la�trombina�(blau)��s’uneix�específicament�amb�la�proteïna�trombina�(lila).
Figura�10.�L’aptàmer�de�la�trombina�(blau)��s’uneix�específicament�amb�la�proteïna�trombina�(lila). p.25
Figura�13.�Estructura�tridimensional�del�complex�format�per�la�distamicina�(taronja)�i�un�dúplex�de��DNA�(lila).�
Figura�13.�Estructura�tridimensional�del�complex�format�per�la�distamicina�(taronja)�i�un�dúplex�de��DNA�(lila).� p.26
Figure 2. Left: ESI-MS of a quadruplex formed by oligonucleotides 1 (a), 2 (b) and 3 (c) and the distribution of the number of NH4+ ions preserved in the G-quadruplex at �6 charge state; the mass spectra were smoothed using a mean function, 2*10 channels,

Figure 2.

Left: ESI-MS of a quadruplex formed by oligonucleotides 1 (a), 2 (b) and 3 (c) and the distribution of the number of NH4+ ions preserved in the G-quadruplex at �6 charge state; the mass spectra were smoothed using a mean function, 2*10 channels, p.45
Figure 3. Top: General scheme of a tetra-end-linked quadruplex showing the numeration of the residues as mentioned in the text

Figure 3.

Top: General scheme of a tetra-end-linked quadruplex showing the numeration of the residues as mentioned in the text p.46
Figure 4. Fragments of NOESY spectra (250 ms mixing time) of oligonucleo-tide 1 at 58C (bottom) and 458C (top) in 10 mm potassium phosphate(pH 7).

Figure 4.

Fragments of NOESY spectra (250 ms mixing time) of oligonucleo-tide 1 at 58C (bottom) and 458C (top) in 10 mm potassium phosphate(pH 7). p.47
Figure S1. Native gel electrophoresis of A) oligonucleotide 3 and B) oligonucleotides 1

Figure S1.

Native gel electrophoresis of A) oligonucleotide 3 and B) oligonucleotides 1 p.52
Figure S2. Imino proton region of the NOESY (100ms mixing time) spectra of oligonucleotide 1 in H2O (5mM K+ concentration, pH 7, T= 5 ºC)

Figure S2.

Imino proton region of the NOESY (100ms mixing time) spectra of oligonucleotide 1 in H2O (5mM K+ concentration, pH 7, T= 5 ºC) p.53
Figure S3. CD spectra of sequences 3-5 registered at different temperatures in the range

Figure S3.

CD spectra of sequences 3-5 registered at different temperatures in the range p.54
Fig. 1. Schematic structures of the dimer of dTAGGGTTAGGGT in the antiparallelfold (A) and in the parallel fold (B), according to Ref
Fig. 1. Schematic structures of the dimer of dTAGGGTTAGGGT in the antiparallelfold (A) and in the parallel fold (B), according to Ref p.61
Fig. 2. Electrospray mass spectra of 5recorded 1 day at room temperature after preparation in (A) 20/80 (v:v) EtOH/aqueous NHACN/aqueous NH lM telomeric sequence dTAGGGTTAGGGT4OAc 100 mM, (B) 40/60 (v:v) EtOH/aqueous NH4OAc 100 mM, (C) 60/40 (v:v) EtOH/aqu
Fig. 2. Electrospray mass spectra of 5recorded 1 day at room temperature after preparation in (A) 20/80 (v:v) EtOH/aqueous NHACN/aqueous NH lM telomeric sequence dTAGGGTTAGGGT4OAc 100 mM, (B) 40/60 (v:v) EtOH/aqueous NH4OAc 100 mM, (C) 60/40 (v:v) EtOH/aqu p.62
Fig. 3. Illustration of the utility of drift time separation in the ion mobility cell to distinguish single-stranded monomer (M) and G-quadruplex dimer (D(NHthe latter were acquired after 1 day of folding
Fig. 3. Illustration of the utility of drift time separation in the ion mobility cell to distinguish single-stranded monomer (M) and G-quadruplex dimer (D(NHthe latter were acquired after 1 day of folding p.64
Fig. 4. Comparison between the dimers formed in ethanol and methanol, as a function of folding time
Fig. 4. Comparison between the dimers formed in ethanol and methanol, as a function of folding time p.65
Fig. 6. 2D plot of ammonium ion distribution and collision cross section of thedimers observed on the Synapt G2 HDMS spectrometer (bias = 35 V), formed after1 day in (A) 60% methanol or (B) 60% ethanol.
Fig. 6. 2D plot of ammonium ion distribution and collision cross section of thedimers observed on the Synapt G2 HDMS spectrometer (bias = 35 V), formed after1 day in (A) 60% methanol or (B) 60% ethanol. p.66
Fig. 5. Influence of the bias voltage of the Synapt G1 HDMS instrument (from 10 Vat the top to 25 V at the bottom) on the ammonium ion distribution and on thecollision cross section of the dimers formed (A–D) after 1 day in 60% methanol or(E–H) after 1 day
Fig. 5. Influence of the bias voltage of the Synapt G1 HDMS instrument (from 10 Vat the top to 25 V at the bottom) on the ammonium ion distribution and on thecollision cross section of the dimers formed (A–D) after 1 day in 60% methanol or(E–H) after 1 day p.66
Table�1.�Oligonucleotides�sequences�used�in�this�study
Table�1.�Oligonucleotides�sequences�used�in�this�study p.87
Table�3.�1H�chemical�shift�assignments�for�Htel�(�)�in�the�presence�of�1�and�2a
Table�3.�1H�chemical�shift�assignments�for�Htel�(�)�in�the�presence�of�1�and�2a p.89
Table�5.�Logarithm�of�the�binding�constants�calculated�using�Equispec�program.�n.d.�not�determinded�due�to�lack�of�changes�in�the�fluorescence�spectra.�
Table�5.�Logarithm�of�the�binding�constants�calculated�using�Equispec�program.�n.d.�not�determinded�due�to�lack�of�changes�in�the�fluorescence�spectra.� p.90
Figure�3.�as�well�as�the�aromatic�protons�at�different�R�=�[mM�KH1H�NMR�spectra�(11.5�10.2�ppm�and�9.0�7.0�ppm),�acquired�at�T=25°C�in�H2O,�containing�25�2PO4,�KCl�150�mM�and�EDTA�1�mM�(pH�6.7),�showing�resonance�of�imino�protons�G4,�G5�and�G6�1]/Htel.�
Figure�3.�as�well�as�the�aromatic�protons�at�different�R�=�[mM�KH1H�NMR�spectra�(11.5�10.2�ppm�and�9.0�7.0�ppm),�acquired�at�T=25°C�in�H2O,�containing�25�2PO4,�KCl�150�mM�and�EDTA�1�mM�(pH�6.7),�showing�resonance�of�imino�protons�G4,�G5�and�G6�1]/Htel.� p.91
Figure�4.�and�G6�as�well�as�the�aromatic�protons�at�different�R�=�[1H�NMR�spectra�(11.5�10.2�ppm�and�9.0�7.0�ppm)�showing�resonance�of�imino�protons�G4,�G5�2]/Htel.�
Figure�4.�and�G6�as�well�as�the�aromatic�protons�at�different�R�=�[1H�NMR�spectra�(11.5�10.2�ppm�and�9.0�7.0�ppm)�showing�resonance�of�imino�protons�G4,�G5�2]/Htel.� p.91
Figure�5.�Selected�region�of�2D�NOESY�spectra�of�Htel/��1�(a)�and�Htel/2�(b)�complexes�at�25°C�in�H2O,�containing�25�mM�KH2PO4,�KCl�150�mM�and�EDTA�1�mM�(pH�6.7).�The�weakness�of�H8A3/H2”T2�and�of�H8A3/MeT2��(total�lack�in�the�case�of�Htel/1)�confirms�a�slight�distortion�at�these�level�in�the�sequence.�The�peaks�A,�B�and�C�are�intermolecular�NOEs,�(A)�H1�or�H4�with�CH3T2,�(B)�H1�or�H4�with�H2’,�H2”�A3,�(C)�H3�with�H2’,H2”�A3,�(D)�Ar�with�MeT2�(E)�Ar�with�H2’,H2”T2�(F)�Ar�with�H2’,H2”A3.�
Figure�5.�Selected�region�of�2D�NOESY�spectra�of�Htel/��1�(a)�and�Htel/2�(b)�complexes�at�25°C�in�H2O,�containing�25�mM�KH2PO4,�KCl�150�mM�and�EDTA�1�mM�(pH�6.7).�The�weakness�of�H8A3/H2”T2�and�of�H8A3/MeT2��(total�lack�in�the�case�of�Htel/1)�confirms�a�slight�distortion�at�these�level�in�the�sequence.�The�peaks�A,�B�and�C�are�intermolecular�NOEs,�(A)�H1�or�H4�with�CH3T2,�(B)�H1�or�H4�with�H2’,�H2”�A3,�(C)�H3�with�H2’,H2”�A3,�(D)�Ar�with�MeT2�(E)�Ar�with�H2’,H2”T2�(F)�Ar�with�H2’,H2”A3.� p.92
Figure�6.�Imino�protons�regions�of�the�NMR�spectra�of�Htel�(a)�Htel/1(b)�and�Htel/2�(c)�at�different�temperatures.��
Figure�6.�Imino�protons�regions�of�the�NMR�spectra�of�Htel�(a)�Htel/1(b)�and�Htel/2�(c)�at�different�temperatures.�� p.92
Figure�7.�Lateral�(A)�and�upper�(B)�views�of�the�best�docked�conformations�for�green�stick�and�1�and�2.�1�is�shown�in�2�in�yellow�stick.�In�DNA,�the�base�pairs�are�shown�using�the�ladder�representation,�with�the�backbones�displayed�as�arrows.�
Figure�7.�Lateral�(A)�and�upper�(B)�views�of�the�best�docked�conformations�for�green�stick�and�1�and�2.�1�is�shown�in�2�in�yellow�stick.�In�DNA,�the�base�pairs�are�shown�using�the�ladder�representation,�with�the�backbones�displayed�as�arrows.� p.93
Figure�8.�Time�dependence�of�hydrogen�bond�distances�observed�between�G�quadruplex�and�ligand�and�HN2G25�(red).�B)�1.�Hi�and�OaA17�(blue)�2.�Hi�and�OPA17�(red).�C)�1.�Hb�and�N1A10�(blue)�2.�Nc�and�HN6A10�(red)�3.�Hf�and�OPA10�(green)�D)�1.�Hb�and�N2G11�(blue)�2.�Hb�and�N7A17�(red)�3.�Od�and�and�B)�and�1�(A�2�(C�and�D).�A)1.�Hb�and�N1A10�(cyan)�2.�Hb�and�N3A10�(green)�3.�Hf�and�OPA10�(blue)�4.�Od�HN2G25�(green).�
Figure�8.�Time�dependence�of�hydrogen�bond�distances�observed�between�G�quadruplex�and�ligand�and�HN2G25�(red).�B)�1.�Hi�and�OaA17�(blue)�2.�Hi�and�OPA17�(red).�C)�1.�Hb�and�N1A10�(blue)�2.�Nc�and�HN6A10�(red)�3.�Hf�and�OPA10�(green)�D)�1.�Hb�and�N2G11�(blue)�2.�Hb�and�N7A17�(red)�3.�Od�and�and�B)�and�1�(A�2�(C�and�D).�A)1.�Hb�and�N1A10�(cyan)�2.�Hb�and�N3A10�(green)�3.�Hf�and�OPA10�(blue)�4.�Od�HN2G25�(green).� p.94
Figure�10.�[ds26]�/[1H�NMR�spectra�showing�NH�of�indole�moiety�and�aromatic�protons�of�1�in�the�free�state�(R�=�1]=0)�and�at�different�R.�High�and�low�R�values�must�be�related�to�the�free�and�bound�state�of�1�in�solution�respectively.��
Figure�10.�[ds26]�/[1H�NMR�spectra�showing�NH�of�indole�moiety�and�aromatic�protons�of�1�in�the�free�state�(R�=�1]=0)�and�at�different�R.�High�and�low�R�values�must�be�related�to�the�free�and�bound�state�of�1�in�solution�respectively.�� p.95
Figure�9.�1H�decoupled�31P�NMR�spectra�of�(a)�ds6�at�T�=�25°C,�(b)�R�=�[1]/[DNA]=�3.0�
Figure�9.�1H�decoupled�31P�NMR�spectra�of�(a)�ds6�at�T�=�25°C,�(b)�R�=�[1]/[DNA]=�3.0� p.95
Figure�11.�Time�dependence�of�the�RMSD�of�ligand�respectively)�and�A�and�G�quartet�heavy�atoms�(blue)�with�ligand�atoms�(1�and�2�on�the�complex�(cyan�and�yellow,�1�and�2�are�shown�in�red�and�green,�respectively)�at�298K.�
Figure�11.�Time�dependence�of�the�RMSD�of�ligand�respectively)�and�A�and�G�quartet�heavy�atoms�(blue)�with�ligand�atoms�(1�and�2�on�the�complex�(cyan�and�yellow,�1�and�2�are�shown�in�red�and�green,�respectively)�at�298K.� p.96
Figure�12.��Per�residue�interaction�energy�in�Kcal/mol�between�compound�piperazine�(red)�and�piperidine�(green)��in�compound�(blue),�piperazine�(red)�and�tryptophan�(green)�moiety�in�compound�1�and�2�(A),�between�acridine�1�(B)�and�between�acridine�(blue),�2�(C).�
Figure�12.��Per�residue�interaction�energy�in�Kcal/mol�between�compound�piperazine�(red)�and�piperidine�(green)��in�compound�(blue),�piperazine�(red)�and�tryptophan�(green)�moiety�in�compound�1�and�2�(A),�between�acridine�1�(B)�and�between�acridine�(blue),�2�(C).� p.97

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