Síntesi d’inhibidors de la integrasa del VIH

Abstract

La present Tesi tracta sobre el desenvolupament d’inhibidors d’integrasa (INIs) del VIH alternatius. Es va partir de la base existent a la literatura química sobre diverses substàncies quelatants d’ions divalents com a potencials inhibidors del procés de strand transfer catalitzat per la integrasa. Amb aquest concepte en mà, varem pensar que la unió de grups quelatants semblants, però no idèntics, als àcids 2,4-dioxocarbonílics a nucleobases o nucleòsids purínics i pirimidínics podrien millorar les propietats farmacocinètiques dels substrats, tot reduint-ne la toxicitat intrínseca d’alguns dicetoàcids. Al Capítol 1 de la Tesi es duen a terme rutes accessibles i segures cap a la síntesis de tetrazols substituïts mitjançant una reacció de cicloaddició-[3+2] entre azides orgàniques i cianurs d’acil en presència de Cu2(OTf)2. Al Capítol 2 es concentren els nostres esforços cap a la preparació de “dicetotetrazols” juntament amb la síntesi de derivats de timidines i AZT amb subestructures de “dicetotetrazols”. Al Capítol 3 es preparen estructures que contenen nucleòsids o nucleobases units a hidroxiquinolines (com a farmacòfors del tipus “dicetoàcids” o “dicetotetrazols”). Finalment, al Capítol 4, es descriuen les diferents rutes que s’han assajat per arribar a la obtenció de N-hidroxiderivats d’hipoxantina i inosines, així com N-hidroxiderivats de benzopirimidines. En aquest cas, el farmacòfor està relacionat amb el Raltegravir, que és l’únic INI aprovat fins la data per la FDA.

As the initial diketo acids, uncovered by Shionogi and Merck pharmaceutical companies around 2000 as integrase inhibitors, turned out to be toxic, other small molecules were early designed. An obvious replacement of the carboxyl group by its bioisoster tetrazole ring was envisaged by many groups. This posed the question of how to prepare these substrates safely and efficiently. A new method to synthesize 5-acetyl or 5-methoxycarbonyl derivatives of tetrazoles was envisaged in our lab taking advantage of the [3+2]-cycloaddition reaction of organic azides with acyl cyanides and alcoxycarbonyl cyanides (ROCO-CO-CN) in the presence of Cu2(OTf)2 as the catalyst of choice. We achieved to carry out these processes under very mild conditions as described in chapter 1. The most outstanding facts of the second topic may be summarized as follows: 5-acetyl-tetrazole (prepared as reported in topic 1) was linked to N3 of thymidine and of 3’-azido-3’-deoxythymidine (AZT), as model compounds of natural nucleosides and of nucleoside RT inhibitors (NRTIs), respectively, by condensation of the lithium salt of 5-acetyl-1-(4-methoxybenzyl)tetrazole, with nucleoside-derived oxo nitriles. Most of the original activity of AZT was retained. A route for the conjugation of potential NRTIs with pharmacophores of integrase inhibitors (INIs) was disclosed. In the third topic, which we examined in parallel with the preceding one, 8-hydroxy-quinolinecarboxylic acids were linked to position 5 of 5-iodo-2’-deoxy- uridines or 5-iodouracils through spacers that were generated by [3+2]-cycloaddition of TMS–C=C–Ura (where Ura means any uracil derivative), with azides, catalysed by Cu2(OTf)2. This is an example of a click reaction with a non-terminal triple bond, but it was shown that the cleavage of C–Si bond preceded the CuAAC reaction. In topic 4, N-hydroxybenzopyrimidine-2-carboxamides and N-hydroxyhypoxanthine-2-carboxamide with the amide nitrogen substituted by a 4-fluorobenzyl group, containing the essential pharmacophoric elements of HIV-1 integrase inhibitor Raltegravir, were synthesized by means of a sequence that involved a cyclization of amino-hydroxamates with methyl trimetoxiacetate. Other approaches were unsuccessful. Unfortunately, prototypes prepared to date are devoid of integrase inhibition and antiviral activity (IC50 and EC50 > 10 μM).