Duke C C, Holder G M, Rosario C A, Ryan A J
Department of Pharmacy, University of Sydney, NSW, Australia.
Chem Res Toxicol. 1988 Sep-Oct;1(5):294-303. doi: 10.1021/tx00005a007.
The major metabolites of the carcinogen dibenz[a,j]acridine formed in rodent liver microsomal preparations were trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine (DBAJAC-3,4-DHD) and dibenz[a,j]acridine 5,6-oxide (DBAJAC 5,6-oxide) [Gill et al. (1987) Carcinogenesis 8, 425-431]. The enantiomers of DBAJAC-3,4-DHD were prepared from the separable diastereoisomeric esters with (+)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxyl ic acid (HCA). The absolute configuration of trans-3(R),4(R)-dihydroxy-1,2,3,4-tetrahydrodibenz[a,j]acridine was assigned by conversion to the bis[p-(dimethylamino)benzoate] and examination of the exciton coupling in its circular dichroic (CD) spectrum. The 3(R),4(R)-tetrahydrodiol was converted to DBAJAC-3(R),4(R)-DHD. The enantiomers of DBAJAC 5,6-oxide were partially resolved by chiral stationary-phase chromatography, and subsequent methoxide attack afforded two enantiomerically enriched isomeric ethers from each fraction. The structures of the two ethers from each enantiomer were determined, and from their 1H NMR spin-spin coupling between the H5 and H6 signals and the CD spectra of the ethers, the absolute configuration of the ethers, and hence the 5,6-oxides, was determined. The enantiomeric composition of the 3,4-dihydrodiol and 5,6-oxide formed as microsomal metabolites of rat liver preparations was 69% 3R,4R and 81% 5R,6S, respectively. When rats were pretreated with 3-methylcholanthrene (MC), these percentages were 70% and 5%, indicating a reversed stereochemical preference for oxide formation in the MC-induced preparation. Results are also presented for phenobarbitone-induced rat liver and mouse liver preparations.
致癌物二苯并[a,j]吖啶在啮齿动物肝脏微粒体制剂中形成的主要代谢产物是反式-3,4-二羟基-3,4-二氢二苯并[a,j]吖啶（DBAJAC-3,4-DHD）和二苯并[a,j]吖啶5,6-氧化物（DBAJAC 5,6-氧化物）[吉尔等人（1987年），《癌变》8, 425 - 431]。DBAJAC-3,4-DHD的对映体由与(+)-内型-1,4,5,6,7,7-六氯双环[2.2.1]庚-5-烯-2-羧酸（HCA）可分离的非对映异构体酯制备而成。反式-3(R),4(R)-二羟基-1,2,3,4-四氢二苯并[a,j]吖啶的绝对构型通过转化为双[对-(二甲基氨基)苯甲酸酯]并检查其圆二色性（CD）光谱中的激子耦合来确定。3(R),4(R)-四氢二醇被转化为DBAJAC-3(R),4(R)-DHD。DBAJAC 5,6-氧化物的对映体通过手性固定相色谱法部分拆分，随后用甲醇钠进攻，从每个馏分中得到两种对映体富集的异构醚。确定了来自每个对映体的两种醚的结构，并根据它们的1H NMR中H5和H6信号之间的自旋 - 自旋耦合以及醚的CD光谱，确定了醚的绝对构型，从而确定了5,6-氧化物的绝对构型。作为大鼠肝脏制剂微粒体代谢产物形成的3,4-二氢二醇和5,6-氧化物的对映体组成分别为69% 3R,4R和81% 5R,6S。当用3-甲基胆蒽（MC）预处理大鼠时，这些百分比分别为70%和5%，表明在MC诱导的制剂中氧化物形成的立体化学偏好发生了逆转。还给出了苯巴比妥诱导的大鼠肝脏和小鼠肝脏制剂的结果。
