Duke C C, Hambley T W, Holder G M, Navascues C O, Roberts-Thomson S, Ye Y R
Department of Pharmacy School of Chemistry, University of Sydney, NSW, Australia.
Chem Res Toxicol. 1991 Sep-Oct;4(5):546-55. doi: 10.1021/tx00023a010.
The major metabolites of the carcinogen 7-methylbenz[c]acridine (7MBAC), trans-5,6-dihydro-5,6-dihydroxy-7-methylbenz[c]acridine (7MBAC-5,6-DHD), and trans-8,9-dihydro-8,9-dihydroxy-7-methylbenz[c]acridine (7MBAC-8,9-DHD) were characterized as their enantiomers after separation of their bis-(+)-(1R,2S,4S)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5 -ene-2-carboxylic acid [(+)-HCA] esters and hydrolysis. The synthetic precursor, trans-3,4-dihydroxy-7-methyl-1,2,3,4-tetrahydrobenz[c]acridine (7MBAC-3,4-THD), was similarly separated into enantiomers, and the dihydrodiol trans-3(S),4(S)-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) was prepared from 7MBAC-3(S),4(S)-THD. Absolute configurations were assigned by the chiral exciton coupling of the bis-p-(dimethylamino)benzoate of 7MBAC-3(R),4(R)-THD, and by the semiempirical methods based on the biaryl chromophores of the enantiomers of 7MBAC-5,6-DHD and of the methanolysis products of the 5,6-oxide of 7MBAC which were resolved as their (+)-HCA esters. X-ray crystallography was used for 7MBAC-8(S),9(S)-DHD bis-(+)-HCA ester, and assignments were correlated with chiral exciton coupling of the bis-4-(dimethylamino)cinnamates of 7MBAC-5(R),6(R)-DHD and 7MBAC-8(S),9(S)-DHD. The stereochemical compositions of four metabolites (three dihydrodiols and 7MBAC-5,6-oxide) formed in incubations with rat liver microsomes from control and induced liver were determined by normal-phase separations of bis-(+)-HCA esters, and by chiral stationary-phase separation of the 5,6-oxide methanolysis products. The 3(R),4(R)-enantiomer of 7MBAC-3,4-dihydrodiol predominated, 74-98% enantiomeric purity, and purity for the oxide varied from about 71% 5(R),6(S)-oxide for control microsomes to about 28% 5(R),6(S)-oxide for liver microsomes obtained from 3-methylcholanthrene-pretreated rats.
致癌物7-甲基苯并[c]吖啶（7MBAC）的主要代谢产物反式-5,6-二氢-5,6-二羟基-7-甲基苯并[c]吖啶（7MBAC-5,6-DHD）和反式-8,9-二氢-8,9-二羟基-7-甲基苯并[c]吖啶（7MBAC-8,9-DHD）在分离其双-（+）-（1R,2S,4S）-内型-1,4,5,6,7,7-六氯双环[2.2.1]庚-5-烯-2-羧酸[（+）-HCA]酯并水解后，被表征为对映体。合成前体反式-3,4-二羟基-7-甲基-1,2,3,4-四氢苯并[c]吖啶（7MBAC-3,4-THD）同样被分离为对映体，并由7MBAC-3（S）,4（S）-THD制备了二氢二醇反式-3（S）,4（S）-二氢-3,4-二羟基-7-甲基苯并[c]吖啶（7MBAC-3,4-DHD）。通过7MBAC-3（R）,4（R）-THD的双对-（二甲基氨基）苯甲酸酯的手性激子耦合，以及基于7MBAC-5,6-DHD对映体和7MBAC的5,6-氧化物的甲醇解产物的联芳发色团的半经验方法，确定了绝对构型。对7MBAC-8（S）,9（S）-DHD双-（+）-HCA酯使用了X射线晶体学，并且将构型归属与7MBAC-5（R）,6（R）-DHD和7MBAC-8（S）,9（S）-DHD的双-4-（二甲基氨基）肉桂酸酯的手性激子耦合相关联。通过双-（+）-HCA酯的正相分离以及5,6-氧化物甲醇解产物的手性固定相分离，测定了在与对照和诱导肝的大鼠肝微粒体孵育中形成的四种代谢产物（三种二氢二醇和7MBAC-5,6-氧化物）的立体化学组成。7MBAC-3,4-二氢二醇的3（R）,4（R）-对映体占主导，对映体纯度为74 - 98%，氧化物的纯度范围从对照微粒体中约71%的5（R）,6（S）-氧化物到从3-甲基胆蒽预处理大鼠获得的肝微粒体中约28%的5（R）,6（S）-氧化物。
