Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites
Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites
复制标题
DOI：
10.1021/jo071145s
复制
发表时间：
2007-09-28
影响因子：
3.6
通讯作者：
Lakshman, Mahesh K.
中科院分区：
文献类型：
--
作者：
Bae, Suyeal;Mah, Heduck;Lakshman, Mahesh K.
1，4-二氟苯并[c]菲（1，4-DFBcPh）及其推定的代谢产物，二氢二醇和二醇环氧化物，已被合成和结构表征，并已被评估的代谢产物的DNA结合的程度。以适量的萘苯乙烯为原料，经光化学环化反应合成了1，4-DFBcPh和1，4-二氟-10-甲氧基苯并[c]菲。以1，4-二氟-10-甲氧基苯并[c]菲为原料合成了二氢二醇，并以二氢二醇为原料非对映选择性地合成了二醇环氧化物。有趣的差异，注意到在H-1 NMR谱的系列I（顺式）二醇环氧化物的苯并[c]菲（BcPh）和1，4-DFBcPh的BcPh二醇环氧化物显示准双赤道取向的羟基，但在1，4-DFBcPh的情况下，这些是双轴设置。这种差异可能源于1，4-DFBcPh中峡湾区氟原子的存在。还观察到1，4-DFBcPh及其衍生物的通过空间、峡湾区的H-F耦合。BcPh和1，4-DFBcPh及其二氢二醇的比较X射线晶体学分析表明，引入氟使分子畸变增加约6-7度。作为一个指南，估计分子的扭曲和它的影响，并在已知的情况下，与X-射线结构的比较，优化结构的BcPh，1，4-DFBcPh，和1，4-DMBcPh（二甲基类似物），以及它们的二氢二醇和二醇环氧化物进行了计算。这些化合物的相对芳香性进行了评估核独立的化学位移计算，和C-13 NMR化学位移计算规范诱导原子轨道计算。对1，4-DFBcPh及其二氢二醇进行代谢，并评估人乳腺癌MCF-7细胞中的DNA结合量。然后将DNA结合的程度与BcPh及其二氢二醇和强致癌物苯并[a]芘进行比较。1，4-DFBcPh系列2（反）二醇环氧化衍生的DNA加合物也进行了比较，从细胞内氧化的二氢二醇与随后的DNA结合。这些实验表明，分子畸变增加降低了对末端代谢物的代谢活化，但形成的二醇环氧化物代谢物是DNA损伤物质。
1,4-Difluorobenzo[c]phenanthrene (1,4-DFBcPh) and its putative metabolites, the dihydrodiol and diol epoxides, have been synthesized and structurally characterized, and the extent of DNA binding by the metabolites has been assessed. 1,4-DFBcPh and 1,4-difluoro-10-methoxybenzo[c]phenanthrene were prepared by photochemical cyclization of appropriate naphthylphenylethylenes. The dihydrodiol was synthesized from 1,4-difluoro-10-methoxybenzo[c]phenanthrene, and the diol epoxides were diastereoselectively synthesized from the dihydrodiol. Interesting differences were noted in H-1 NMR spectra of the series I (syn) diol epoxides of benzo[c]phenanthrene (BcPh) and 1,4-DFBcPh; the BcPh diol epoxide displays a quasi-diequatorial orientation of the hydroxyl groups, but in the 1,4-DFBcPh case these are diaxially disposed. This difference probably stems from the presence of the fjord-region fluorine atom in 1,4-DFBcPh. A through-space, fjord-region H-F coupling has also been observed for 1,4-DFBcPh and its derivatives. Comparative X-ray crystallographic analyses of BcPh and 1,4-DFBcPh and their dihydrodiols show that introduction of fluorine increases the molecular distortion by about 6-7 degrees. As a guide to estimating the molecular distortion and its effects, and for comparison with the X-ray structures in known cases, optimized structures of BcPh, 1,4-DFBcPh, and 1,4-DMBcPh (the dimethyl analogue) as well as their dihydrodiols and diol epoxides were computed. Relative aromaticities of these compounds were assessed by nucleus-independent chemical shift calculations, and C-13 NMR chemical shifts were computed by gauge-inducing atomic orbital calculations. 1,4-DFBcPh and its dihydrodiol were subjected to metabolism, and the amount of DNA binding in human breast cancer MCF-7 cells was assessed. The extent of DNA binding was then compared with that for BcPh and its dihydrodiol and the potent carcinogen benzo[a]pyrene. The 1,4-DFBcPh series 2 (anti) diol epoxide-derived DNA adducts were also compared with those arising from intracellular oxidation of the dihydrodiol with subsequent DNA binding. These experiments showed that increased molecular distortion decreased metabolic activation to the terminal metabolites but that diol epoxide metabolites that are formed are the DNA-damaging species.