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Lakshman MK , Kole PL , Chaturvedi S , Saugier JH , Yeh HJC , Glusker JP , Carrell HL , Katz AK , Afshar CE , Dashwood WM , Kenniston G , Baird WM
Methyl group-induced helicity in 1,4- dimethylbenzo c phenanthrene and its metabolites: Synthesis, physical, and biological properties
Journal of the American Chemical Society. 2000 Dec 27;122(51) :12629-12636
PMID: ISI:000166045000003   
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1,4-Dimethylbenzo[c]phenanthrene (1,4-DMBcPh) is the dimethylated analogue of the benzo[c]phenanthrene (BcPh), where one of its two methyl groups resides in the highly congested fjord-region. A comparative X-ray crystallographic analysis, described herein, shows that BcPh is distorted out-of-plane so that there is an angle of 27 degrees between the outermost rings. The additional methyl groups in I,4-DMBcPh increase this nonplanarity to an angle of 37 degrees. This methyl group- induced disruption of planarity results in P and M enantiomers of 1,4-DMBcPh, and this helicity is observed in a pronounced manner in its putative metabolites, the dihydrodiol and diol epoxide. Synthetically, photochemical cyclization offers convenient access to 1,4-DMBcPh as well as its metabolites. For this, Wittig reaction of 2,5-dimethylbenzyltriphenylphosphoninm chloride and 2-naphthaldehyde provided a cis/trans mixture of alkenes which, when subjected to photolysis, provided],4- DMBcPh. Despite the high steric congestion in the fjord-region, this reaction proceeds with respectable yields. Correspondingly, a Wittig reaction of the same phosphonium chloride derivative with 6-methoxy-2-naphthaldehyde afforded an alkene mixture that, upon photochemical ring closure, provided 10-methoxy-1,4-dimethylbenzo[c]phenanthrene. The methoxy group was cleaved and the resulting phenol oxidized to the o-quinone. Reduction of the o-quinone with NaBH4 under an oxygen atmosphere provided the dihydrodiol, (+/-)-trans-9, 10- dihydroxy-9, 10-dihydro-1,4-dimethylbenzo[c]phenanthrene. This dihydrodiol was found to be an approximately 3:1 mixture of diastereomers, which was produced as follows. Reduction of the quinone proceeds in a stereoselective manner producing both the (R,R)- and (S,S)-trans-diols. However, this factor, when coupled with the P, M atropisomerism of the hydrocarbon, results in two diastereomeric pairs of enantiomeric dihydrodiols. Due to steric constraints imposed by the fjord- region methyl group, the P --> M interconversion is slow, making the proton resonances of the diastereomeric dihydrodiols distinctly observable by NMR. Assignment of major and minor dihydrodiol isomers has been achieved by NOESY experiments. Finally, epoxidation provides a mixture of diol epoxides that reflects the dihydrodiol ratio. The metabolic activation of these compounds to reactive intermediates was studied through analysis of their binding to DNA. DNA binding data using human mammary carcinoma MCF-7 cells reveal that the level of DNA binding of BcPh is not statistically different from that of 1,4-DMBcPh. However, there is an Ii-fold increased activation of BcPh dihydrodiol as compared to the 1,4-DMBcPh dihydrodiol. In contrast to the planar benzo[a]pyrene, BcPh is only poorly adducted to DNA in culture cells. Thus, it appears that increasing the nonplanarity in this type of PAH lowers its ability to be metabolically activated to form DNA-damaging adducts, although in the case of 1,4-DMBcPh, the presence of the two methyl groups in one of the angular rings may also contribute to the decrease.
Times Cited: 1 English Article 386DN J AM CHEM SOC