Photochemistry of pentoxifylline: a xanthine derivative
| dc.contributor.advisor | Van der Westhuizen, J. H. | |
| dc.contributor.advisor | Bonnet, S. L. | |
| dc.contributor.author | Han, Ze | |
| dc.date.accessioned | 2016-06-08T17:33:05Z | |
| dc.date.available | 2016-06-08T17:33:05Z | |
| dc.date.issued | 2006-11 | |
| dc.description.abstract | English: Pentoxifylline [1-(5'-oxohexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione], sold under the trade name Trental®, is a methylxanthine derivative used in treatment of peripheral and cerebrovascular diseases and poor regional microcirculation (intermittent claudication). It has recently been investigated as an antitumor agent. It improves tumor perfusion and influences cytokine –mediated inflammation. Our objectives were to synthesise 1-(3-oxobutyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione and some of its derivatives for use as internal standards in the determination of biological fluids by liquid chromatography and for pharmaceutical/ biological screening as enzyme inhibitors. These efforts were hampered by the low reactivity of the N-1 position on the theobromine towards alkylation with electrophiles. As an alternative method to achieve the aforementioned goals, we investigated the photochemistry of pentoxifylline. Of particular interest was the fact that pentoxyphylline has two chromophores, i.e. carbonyl and xanthine, separated by a linear butyl alkyl chain. We now report a series of photochemical reactions of pentoxifylline and reaction conditions that were used to synthesise novel analogues. The carbonyl moiety reacted predictably to yield three products in toluene. Norrish II fission yielded 1-allyl-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (A) in yields of up to 40%, and Yang cyclisation yielded (R*, R*,)-(±)-1-{[2-Hydroxy-2-methylcyclobutyl]methyl}-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione/(B) (10% yield). The ratio of these two products was always 4:1. The expected racemic 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione / lisophylline (C) (6.5% yield) was isolated via photo-reduction of the carbonyl group to an alcohol. From TLC chromatograpy it appeared that tributyltin hydride increased the yield of these three products. A subsequent HPLC analysis proved this to be wrong, but affirmed the 4:1 ratio of A: B. In benzene as solvent, no lisophylline was obtained. This, together with the fact that the highest yield of (A) was obtained in benzene, indicated that the methyl group of toluene acted as a hydrogen donor during reduction of the carbonyl group. The photo-sensitisation and photo-initiation of pentoxifylline in methanol, ethanol and 2-propanol in the absence of oxygen led to the formation of the C-8 α-hydroxylalkyl analogues of pentoxifylline. Yet, in the presence of oxygen all these C-8 substituted products 8-(1-hydroxy-1-methylethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2, 6-dione (D), 8-(1-hydroxymethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihy- dro-1H-purine-2,6-dione (E) and 8-(1-hydroxyethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (F) were not produced, while the carbonyl photo- chemical products A, B and C were formed in the same yields as those in the toluene reaction. These facts can be explained that triplet ground state oxygen quenches a triplet-excited state of xanthine but not the singlet-excited state of the carbonyl functionality. The yield of the reduction product (lisophylline) was not improved by the addition of tri-butyltin hydride (TBTH). This observation indicated that the pentoxifylline carbonyl group reacted via singlet-excited states and yielded products A, B and C. The improvement of the yield from 32 to 48% with naphtalene and the decrease in the yield with benzophenone supports a singlet intermediate in the Norrish II type reaction of the carbonyl moiety in pentoxifylline. The tri N-substituted xanthine moiety coupled photochemically with isopropanol to yield 8-(1'-hydroxy-1-methyl)ethyl pentoxifylline (D). This reaction involves substitution of the aromatic 8-hydrogen with an isopropyl group, probably via radical initiated aromatic substitution. The highest yield of this product (55%) was obtained in the presence of 50% acetone. This supports a triplet mechanism for the excited xanthine chromophore. Several unknown products were isolated in low yields from the 2-propanol, EtOH/acetone photochemical reaction mixtures where further purification and structure elucidation will be performed. These are likely products derived from some new rearrangements of 8-substituted products. We have developed methods to expand the range of derivatives of pentoxifylline that can be synthesised in reasonable yields. These products will be used as internal standards for bio-analytical purposes and in our biological assays. Conditions have been established that selectively encourage reactions at the carbonyl moiety (toluene, triplet quencher) or the xanthine moiety (protic solvents, photosensitiser or radical initiator). | en_ZA |
| dc.description.abstract | Afrikaans: Pentoksifelien (1-(5’-oksoheksiel)-3,7-dimetielxantien), word as Trental® bemark. Dit is ’n metielxantien derivaat wat gebruik word vir priferale en cerebrovaskulere siektes en swak mikrosirkulasie. Dit word ook ondersoek as ’n potensiële antikankermiddel. Dit verbeter tumor perfusie en het ’n effek op sitokien gekoppelde inflammasie. Ons het probeer om pentoksifelien en derivate daarvan te maak vir gebruik as interne standaarde vir die kwantifisering daarvan in ligaamsvloeistowwe met vloeistofchromatografie en om dit te toets vir biologiese aktiwiteit as ensieminhibeerders. Ons pogings het misluk weens die lae reaktiwiteit van die N-1 posisie van xantien teen alkilering met elektrofiele. Ons het gevolglik fotochemiese metodes ondersoek om derivate van pentoksifelien te maak. Dit is nog nooit vantevore gedoen nie. Ons het veral belang gestel in die feit dat pentoksifelien twee chromofore het (karboniel en xantien gedeelte) wat deur ’n lineêre –(CH2)4- alkielketting geskei word. Ons rapporteer nou ’n reeks fotochemiese reaksies van pentoxifelien en die gepaardgaande reaksietoestande wat ons gebruik het om nuwe derivate te maak. Die karbonielgedeelte reageer soos verwag om drie produkte te lewer. Norrish II splyting lewer 1-alliel-3,7-dimetielxantien in opbrengste van tot 50%. Yang siklisering lewer 1-[(2-hidroksie-2-metelsiklobutiel)metiel]-3,7-dimetielxantien (12.5% opbrengs). Die verhouding tussen hierdie twee produkte was altyd 4:1. Ons isoleer ook die verwagte lisofelien (10% opbrengs) weens die reduksie van die karbonielgroep na ’n alkohol. Volgens dunlaagchromatografie het dit gelyk of byvoeging van tributieltinhidried tot verhoogde opbrengste gelei het. Hoëdrukvloeistofchromatografie het egter getoon dat dit nie die geval was nie en ook die 4:1 verhouding onder verskillende reaksietoestande bevestig. In benseen is geen lisofelien verkry nie. Dit dui aan dat tolueen as waterstofdonor optree in die fotochemiese reduksie van die karbonielgroep. Tributieltinhidried het nie as waterstof donor opgetree nie. Byvoeging van naftaleen (singulet sensitiseerder en triplet blusser) verhoog die opbrengs van 1-alliel-3,7-dimetielxantien van 26 tot 40% en bensofenoon (triplet sensitiseerder) verlaag die opbrengs. Dit dui op ’n singulet tussenproduk in die Norrish tipe II eliminasie. Die opbrengsverhoging van 10 na 46% in metanol wanneer die stikstofatmosfeer met ’n lugatmosfeer vervang word ondersteun ook ’n singuletmeganisme omdat triplet grondtoestandsuurstof die triplet xantienchromofoor blus. Die xantiengedeelte tree as ’n interne tripletblusser op wat voorkom dat die karbonielchromofoor vanuit die triplettoestand reageer. Die xantiengedeelte van pentoksifelien koppel fotochemies met isopropanol in die 8-posisie om 8-isopropielgesubstitueerde pentoksifelien te lewer. Die reaksie behels verplasing van die aromatiese 8-waterstof met ’n isopropanol groep waarskynlik via ’n radikaalmeganisme. Die hoogste opbrengs (55%) word in 50% asetoon verkry. Dit dui op ’n tripletmeganisme vir die fotochemie van die xantiengedeelte. Met di-tert-butielperoksied as radikaalinisieerder kon ons ook 8-hidroksiemetiel en 8-hidroksietiel gesubstitueerde pentoksifelien in goeie opbrengste onder fotolitiese toestande isoleer. Ons het kondisies onwikkel om ’n reeks van nuwe derivate van pentoksifelien in redelike opbrengste te maak. Ons benodig hierdie derivate as interne standaarde vir bio-analises en vir biologiese proewe. Ons het toestande ontwikkel om reaksies op die karbonielgroep te laat plaasvind (toluene, triplet blusser) of op die xantiengedeelte te laat plaasvind (polere oplosmiddels, triplet sensitiseerders of radikaalinisieerders). | af |
| dc.description.sponsorship | FARMOVS-PAREXEL | en_ZA |
| dc.description.sponsorship | The Technology and Human Resources for Industry Programme | |
| dc.identifier.uri | http://hdl.handle.net/11660/2727 | |
| dc.language.iso | en | en_ZA |
| dc.publisher | Unversity of the Free State | en_ZA |
| dc.rights.holder | University of the Free State | en_ZA |
| dc.subject | Pentoxifylline | en_ZA |
| dc.subject | Photochemistry | en_ZA |
| dc.subject | Internal standard | en_ZA |
| dc.subject | Synthetic chemistry | en_ZA |
| dc.subject | Xanthine derivatives | en_ZA |
| dc.subject | Medicinal chemistry | en_ZA |
| dc.subject | Cyclobutanol | en_ZA |
| dc.subject | Aromatic radical substitution | en_ZA |
| dc.subject | 1-Allyl-3,7-dimethyl-1-(5-oxohexyl)-3, 7-dihydro-1H-purine-2, 6- dione | en_ZA |
| dc.subject | Diastereoisomer | en_ZA |
| dc.subject | Stereoselectivity | en_ZA |
| dc.subject | Dissertation (M.Sc. (Chemistry))--University of the Free State, 2006 | en_ZA |
| dc.title | Photochemistry of pentoxifylline: a xanthine derivative | en_ZA |
| dc.type | Dissertation | en_ZA |