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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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(36) ȏ͵ͷȐ ›ƒ––ǡ ǤǤǢ ‹ ‡”•ǡ ǤǤǢ ‘„‡”•‘ǡ ǤǤǢ — Š‡‹–ǡ ǤǤǢ Ž‹ƒ‹–ǡ ǤǢ ‡ƒ‡–•ǡ ǤǢ ƒ˜‹•ǡ ǤǤǢ ƒ›‡”ǡǤǢ „ƒ Šǡ ǤǤǢ ‡”ǡǤ Ǥǡ‘„‹ƒ–‘”‹ƒŽŽ›•‡Ž‡ –‡†‰—ƒ‘•‹‡Ǧ“—ƒ”–‡–•–”— –—”‡‹•ƒ’‘–‡– ‹Š‹„‹–‘”‘ˆŠ—ƒ‹—‘†‡ˆ‹ ‹‡ ›˜‹”—•‡˜‡Ž‘’‡Ǧ‡†‹ƒ–‡† ‡ŽŽˆ—•‹‘ǤProc.Natl.Acad.Sci.USAǡ 1994ǡͻͳǡͳ͵ͷ͸Ǧͳ͵͸Ͳ ȏ͵͸Ȑ‹• Š‘‘ˆǡ ǤǢ ‘ˆˆƒǡǤǡǦ‹†‹‰‘ˆ”—‰••‡†‹‡†‹ ‹ƒŽŠ‡”ƒ’‹‡•ǡCurr.Med.ChemǤ 2002ǡͻǡ͵ʹͳǦ͵Ͷͺ ȏ͵͹Ȑ‡”ƒǡ ǤǡǢ‡‹†‡ŽǡǤǡNucleicacidgeometryanddynamics,1980ǡƒƒ•™ƒ› Ǥƒ”ƒǡ†ǤǢ ‡”‰ƒ‘”‡••ǣ‡™›‘”Ǥ ȏ͵ͺȐ ‡”‡”ǡ Ǥ ǤǢ ”‘‡„‘”ǡ ǤǤǢ Ž‘”‡ǡ ǤǤǡ –‡” ƒŽƒ–‹‘ǡ  ‹‹‰ǡ ƒ† –Š‡ ‘–”‘Ž ‘ˆ –”ƒ• ”‹’–‹‘ǡScience,1996ǡʹ͹ͳǡ͹͹ͺǦ͹ͺͶǤ ȏ͵ͻȐ ƒ‰—Ž‡›ǡ ǤǤǡ ‹Š›†”‘‹•‘“—‹‘Ž‹‘‡•ǣ –Š‡ †‡•‹‰ ƒ† •›–Š‡•‹• ‘ˆ ƒ ‡™ •‡”‹‡• ‘ˆ ’‘–‡– ‹Š‹„‹–‘”•‘ˆ’‘Ž›ȋǦ”‹„‘•‡Ȍ’‘Ž›‡”ƒ•‡ǡAnticancerDrugDes.,1991ǡ͸ǡͳǡͳͲ͹Ǧͳͳ͹Ǥ ȏͶͲȐ ‡‹‡”•–ƒ‰‡”ǡ Ǥ ǤǢ ‡‡”ǡ ǤǤǡ ‘’Ž‡š‡• ‘ˆ –Š‡ ‹‘” ‰”‘‘˜‡ ‘ˆ ǡ Annu. Rev. Biophys. Biomol.Struct.,1995ǡʹͶǡͶ͸͵ǦͶͻ͵Ǥ ȏͶͳȐƒ”ƒŽ†‹ǡǤ ǤǢ‘˜‡”‘ǡǤǢ ”—––ƒ”‘Ž‘ǡ ǤǢ”‡–‹ǡǤǢƒ„”‹œ‹ǡǤǤǢƒ˜ƒ‹ǡǤ ǤǢ‘ƒ‰‘Ž‹ǡǤǡ ‹‘”‰”‘‘˜‡„‹†‡”•ƒ•’‘–‡–‹ƒŽƒ–‹–—‘”ƒ†ƒ–‹‹ ”‘„‹ƒŽƒ‰‡–•ǡMedResRevǡ2004ǡʹͶǡͶ͹ͷǦ ͷʹͺǤ ȏͶʹȐ ‹”ƒ— ǤǢ ‹ƒ™ƒ ǤǢ ƒ™ƒ‹•Š‹ Ǥǡ ‹•–ƒ› ‹ ǡ ƒ ‹‘” ‰”‘‘˜‡ „‹†‡”ǡ Šƒ‰‡• ‡‡†‹›‡Ǧ ‹†— ‡† Ž‡ƒ˜ƒ‰‡•‹–‡•ƒ†‡Šƒ ‡•ƒ’‘’–‘•‹•ǡNucleicAcidssymposiumseriesǡ2002ǡͳǡͻͷǦͻ͸Ǥ ȏͶ͵Ȑ” ƒ‘‡ǡ ǤǢ‡ ‘ǡǤǢ”‡œœ‹ǡǤǢ‹ ‘Ž‡ŽŽƒǤǢ‹”‡ŽŽ‹Ǥǡ–”— –—”‡ƒ†•›–Š‡•‹•‘ˆ†‹•–ƒ› ‹ǡ Natureǡ1964ǡʹͲ͵ǡͳͲ͸ͶǦͳͲ͸ͷǤ ȏͶͶȐ ‡Œ—‰ƒǡ ǤǢ ‡™‹–œǡ ǤǢ Š‹”—†‡ǡ ǤǤǢ ‘†”‹‰—‡œǡ ǤǢ ŠƒŠ‹†ǡǤǢ  ƒŽƒ•—„”ƒƒ‹ƒǡ Ǥ ”‹Ǧ •—„•–‹–—–‡†‹•‘ƒŽŽ‘šƒœ‹‡•ƒ•ƒ‡™ Žƒ••‘ˆ Ǧ“—ƒ†”—’Ž‡š„‹†‹‰Ž‹‰ƒ†•ǣ•ƒŽŽ‘Ž‡ —Ž‡”‡‰—Žƒ–‹‘ ‘ˆ Ǧ‹–‘ ‘‰‡‡‡š’”‡••‹‘.,J.Am.Chem.SocǤǡ2007ǡͳʹͻǡͳʹͻʹ͸Ǧͳʹͻʹ͹Ǥ ȏͶͷȐƒ›‘†ǡǤǢ—ǡǤǢŠ‡ǡǤǦ ǤǢ‹†Ž‡ǡǤǢ‘ ‘ˆˆǡǤǤǡ‰‡–•–Šƒ––ƒ”‰‡––‡ŽÖ‡”ƒ•‡ƒ† –‡ŽÖ‡”‡•ǡCurr.Opin.Biotech,1996.7,ͷͺ͵ǦͷͻͳǤ ȏͶ͸Ȑ ƒŠŽ‡”ǡ ǤǤǢ ‹ŽŽ‹ƒ•‘ǡ ǤǤǢ ‡ Šǡ ǤǤǢ ”‡• ‘––ǡ ǤǤǡ Š‹„‹–‹‘ ‘ˆ –‡ŽÖ‡”ƒ•‡ „› Ǧ“—ƒ”–‡– •–”— –›—”‡•ǡNatureǡ1991,͵ͷͲǡ͹ͳͺǦ͹ʹͲǤ ȏͶ͹Ȑ ‘ Šƒ—† ǤǢ ‡—Žƒ†‡Ǧ ‹ Š‘— ǤǤǡ  Š‹– ŠŠ‹‡”ǯ• ‰—‹†‡ –‘ Ǧ“—ƒ†”—’Ž‡š Ž‹‰ƒ†•ǡ Org. Biomol. Chem.ǡ2008ǡ͸ǡ͸ʹ͹Ǧ͸͵͸Ǥ ȏͶͺȐ ƒ””‹•‘Ǥ ǤǢ ‘™ƒǤǤǢ‡ŽŽƒ†ǤǤǢ‡‹†Ž‡Ǥǡ —ƒ–‡ŽÖ‡”ƒ•‡‹Š‹„‹–‹‘„›•—„•–‹–—–‡† ƒ ”‹†‹‡†‡”‹˜ƒ–‹˜‡•ǡBioorg.Med.Chem.LettǤǡ1999ǡͻǡʹͶ͸͵ǦʹͶ͸ͺǤ ȏͶͻȐ ‰„ƒ†Œ‡ ǤǢ ‡‹• Ǥ ǤǢ  ‡ƒ ǤǢ ‡•œƒ Ǥ ǤǢ ‡‹†Ž‡ Ǥǡ –Š”ƒ ‡‡ǦͻǡͳͲǦ†‹‘‡• ƒ• ’‘–‡–‹ƒŽ ƒ–‹ ƒ ‡” ƒ‰‡–•Ǥ ›–Š‡•‹•ǡ Ǧ„‹†‹‰ǡ ƒ† „‹‘Ž‘‰‹ ƒŽ •–—†‹‡• ‘ ƒ •‡”‹‡• ‘ˆ ʹǡ͸Ǧ †‹•—„•–‹–—–‡††‡”‹˜ƒ–‹˜‡•ǡ1992ǡ͵ͷȋͺȌǡͳͶͳͺǦͳͶʹͻǤ ȏͷͲȐ ‡‘‡––‹ ǤǢ ‘†‡‹ ǤǢ ǯ‰‡Ž‘ ǤǢ ‹œœ‘ ǤǢ ‡ƒ••‹ ǤǢ –‘‡ŽŽ‹ ǤǢ ŽŽ‹ ǤǢ –‡˜‡• Ǥ Ǥ ǤǢ ǯ  ƒŽ ‹ǤǢ—’‹ ǤǢ‹”‘ ‹‘Ǥǡ‹‘Ž‘‰‹ ƒŽƒ –‹˜‹–›‘ˆ–Š‡ Ǧ“—ƒ†”—’Ž‡šŽ‹‰ƒ† Ͷȋ͵ǡͳͳǦ†‹ˆŽ—‘”‘Ǧ ʹͳ.

Figure

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