Photochemistry of pentoxifylline: a xanthine derivative

[摘要] 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).

[发布机构] University of the Free State