A novel method for the synthesis of Indolo2,1-aisoquinolines and modelling studies of 3-substituted oxindoles against PfPK5

摘要

Many naturally occurring and synthetically made azapolycyclic aromatic ringudsystems display important biological activities. One class of naturally occurringudazapolycyclic aromatic ring systems is the dibenzopyrrocoline alkaloids, madeudfrom an indole nucleus fused to an isoquinoline system sharing the sameudnitrogen, i.e. the indolo[2,1-a]isoquinoline nucleus. The indolo[2,1-a]isoquinolineudand its analogues have been reported to possess antileukemic, tubulinudpolymerization inhibitory and antitumor activity.udA variety of indolo[2,1-a]isoquinolines have been synthesized in our labs. Thisudincludes, the 5,12-dimethyl-6-phenylindolo[2,1-a]isoquinoline, using the Suzuki-udMiyaura cross-coupling reaction and reaction conditions for the formation ofudaromatic rings (KOBut in DMF) developed in our laboratories. In this dissertation,udwe outline the syntheses of (±)-5,6-dihydro-6-phenylindolo[2,1-a]isoquinolin-5-oludand 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde. We also discuss theudsynthesis and the modelling studies, (docked in silico) of the 3-substitutedudoxindoles in the X-ray crystal structure of the PfPK5 cyclin dependent kinaseud(CDK).udThe synthesis of indolo[2,1-a]isoquinolines started with N-protection of isatin andudbenzimidazole with a benzyl group to afford 1-benzylindoline-2,3-dione and 1-udbenzyl-1H-benzo[d]imidazole, respectively. The next step was the synthesis ofudthe brominated compound, 1-benzyl-2-bromo-1H-indole, and the iodatedudcompound, 1-benzyl-2-iodo-1H-benzo[d]imidazole. 1-Benzyl-2-bromo-1H-indoleudwas synthesized by means of a functional group interconversion of the oxygen inudthe 3-position of isatin to two chlorine atoms initially, followed by removal of thoseudchlorine atoms with activated zinc, followed by the conversion of the carbonyl ofudthe oxindole to give a 2-bromoindole using POBr3. 1-Benzyl-2-iodo-1Hbenzo[udd]imidazole was synthesized in two ways. Firstly, 1-benzyl-1Hbenzo[udd]imidazole was exposed to LDA followed by iodinating the 2-position byud5udexposure of the intermediate to diiodoethane. The second method uses audhalogenating method developed in our labs. 1-Benzyl-1H-benzo[d]imidazole wasudexposed to isopropylmagnesium chloride lithium chloride followed by I2. Havingudobtained the halogenated products, both sets of halogenated precursors wereudcoupled with 2-formylphenylboronic acid using the Suzuki-Miyaura crosscouplingudreaction to obtain the products, 2-(1-benzyl-1H-indol-2-yl)benzaldehydeudand 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde in 98 and 67% yield,udrespectively. Aromatization of 2-(1-benzyl-1H-indol-2-yl)benzaldehyde occurredudeasily using tBuOK in DMF at room temperature to afford (±)-5,6-dihydro-6-udphenylindolo[2,1-a]isoquinolin-5-ol in 75% yield (7:3 ratio of anti-: syn-) butudexposing 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde to the sameudreaction conditions did not afford the desired product. Dehydrating (±)-5,6-uddihydro-6-phenylindolo[2,1-a]isoquinolin-5-ol using methanesulfonyl chloride inudCH2Cl2 was unsuccessful. Further attempts at dehydrating (±)-5,6-dihydro-6-udphenylindolo[2,1-a]isoquinolin-5-ol were prevented due to time constraints.udIn the last part of the project, a library of 3-substituted oxindoles (13 molecules)udwas synthesized successfully and the compounds were docked in silico in theudactive site of an X-ray crystal structure of PfPK5, a cyclin dependent kinase ofudthe Plasmodium falciparum, the agent causing the most severe form of humanudmalaria. Eleven of the thirteen compounds were synthesized by condensation ofudoxindole and a suitable aldehyde in the presence of piperidine. The other two, 3-ud(propan-2-ylidene)indolin-2-one and 5,6-dimethoxy-3-(methylthio)indolin-2-one,udwere synthesized differently. 3-(Propan-2-ylidene)indolin-2-one was synthesizedudby reacting the oxindole with acetone in the presence of HCl and 5,6-dimethoxy-ud3-(methylthio)indolin-2-one was synthesized following Gassman’s methodology.udTwo molecules scored well in the molecular modelling studies using the X-rayudcrystal structure of PfPK5, namely, (E/Z)-3-(3,4-dimethoxybenzylidene)indolin-2-udone and (Z)-3-(4-hydroxybenzylidene)indolin-2-one.ud6udIn conclusion, we managed to synthesize (±)-5,6-dihydro-6-phenylindolo[2,1-uda]isoquinolin-5-ol using the Suzuki Miyaura cross-coupling reaction and reactionudconditions that lead to aromatization (tBuOK in DMF at room temperature) as keyudsteps and 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde using the Suzuki-udMiyaura cross-coupling reaction. A library of 3-substituted oxindoles was madeudand using molecular modelling were docked in silico into the crystal structure ofudthe active site of PfPK5 with 2 compounds showing promise, for further studies.