Diol epoxides conformational

Epoxidation of 10 with m-chloroperbenzoic acid yielded the chrysene anti-1,2-diol-3,4-epoxide, whereas similar reaction of 11 gave a mixture of the corresponding anti and syn diol epoxides in a 5 3 ratio (57,59). These findings are in accord with previous observations that dihydrodiols free to adopt the diequatorial conformation undergo anti stereospecific epoxidation, whereas bay region diaxial dihydrodiols yield mixtures of anti and syn diastereomers. The syn-... 

In contrast to 21, the diol epoxide derivative of the 8,9-dihydrodiol of DMBA was relatively stable. Although only the anti isomer was isolated and identified from epoxidation of the 8,9-dihydrodiol with m-chloroperbenzoic acid (84), it is likely that the syn isomer may also be formed in this reaction. The 8,9-dihydrodiol exists predominantly in the diaxial conformation as a consequence of steric interaction between the 8-hydroxyl and 7-methyl groups (88). 

The existence of isomeric polycyclic aromatic diol epoxide compounds provides rich opportunities for attempting to correlate biological activities with the physico-chemical reaction mechanisms, and conformational and biochemical properties of the covalent DNA adduct8 which are formed. 

Figure 18. Conformations of diol epoxides of BP. (a) Diagrams of the anti- and syn-isomers of a diol epoxide showing the possibility for internal hydrogen-bonding in the syn-diol epoxide.

Figure 19. Perpendicularity of the PAH and the base. Conformations of trans-diols. The steric hindrance in a bay region will cause hydroxyl or other substituents (such as DNA) to lie in an axial orientation. Sites where this occurs are marked "a". Those sites where there is no steric hindrance are marked "ae" (axial or equatorial). The conclusion is that when a diol epoxide alkylates DNA the base on DNA will be bonded axially to the PAH group.

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

The conformations of the 1- and 3-nitro-BaP metabolites were determined through analysis of their NMR spectra (145-146). Both 1- and 3-nitro-BaP-trans-7,8-dihydrodiols existed predominantly in quasi-diequatorial conformations, which corresponds to the preferred conformation of the proximate carcinogen BaP-trans-7,8-dihy-drodiol (149). This suggests that these dihydrodiol metabolites may be converted into electrophilic diol epoxides and in support of this contention, the stereochemistries of 1- and 3-nitro-BaP-... 

DNA binds and reacts with carcinogenic and similar compounds which alkylate it through cationic intermediates, in some cases extraordinarily fast 1371 and can in the process catalyse the hydrolysis of some substrates, like the bay-region diol epoxides derived from benzpyrene.1381 In the context of enzyme mimics these reactions are primarily of curiosity value DNA lacks the conformational flexibility and the chemical functionality to offer the prospect of efficient catalysis for ordinary reactions. 

A 3.1 A crystal structure of human topoisomerase I in complex with DNA containing 8-oxo-dG at the +1 position in the scissile strand shows the enzyme active site to be rearranged into an inactive conformation." A primer-template duplex in complex with the lesion-bypass polymerase Dpo4 is studied in which there is a benzo[a]pyrene diol epoxide adduct of dA (183) base paired with thymidine in the enzyme active site. Two conformations of the adduct are observed, one in which it is intercalated between base pairs, and the other in... 

The pH-independent reaction of diol epoxide 81 is quite different from that of diol epoxide 80, although their chemical structures are similar. Subtle differences in conformation clearly are sufficient to cause different pH-independent mechanisms. Whereas one of the pH-independent reaction pathways of 80 involves a carbocation intermediate, carbocation 83 cannot be detected in the pH-independent reaction of 81.89 The mechanism of the diol-forming reactions in the pH-independent reactions of 81 are not clear, but may involve concerted reactions of 81 with solvent. 

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