Savle P S, Medhekar R A, Kelley E L, May J G, Watkins S F, Fronczek F R, Quinn D M, Gandour R D
Department of Chemistry, Virginia Tech, Blacksburg 24061-0212, USA.
Chem Res Toxicol. 1998 Jan;11(1):19-25. doi: 10.1021/tx970019o.
A chiral, five-step synthesis of 2-(hydroxymethyl)-2,4-dimethylmorpholine (12) from (R)- and (S)-2-methylglycidols gives an overall yield of 63%. Morpholines (R)- and (S)-12 are converted into 2-(azidomethyl)-2,4-dimethylmorpholine (15) via 2,4-dimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholine (14). The tertiary morpholines 12, 14, and 15 are quaternarized to afford 2-(hydroxymethyl)-2,4,4-trimethylmorpholinum iodide (2), 2,4,4-trimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholinium iodide (3), and 2-(azidomethyl)-2,4,4-trimethylmorpholinium iodide (4), respectively, which all inhibit acetylcholinesterase (AChE). These morpholinium inhibitors are compared with conformationally constrained aryl hemicholinium AChE inhibitors. Enantiomers of 2 and 4 are reversible competitive inhibitors of AChE, with values of Ki = 360 +/- 30 microM for (S)-2, 650 +/- 90 microM for (R)-2, 450 +/- 70 microM for (S)-4, and 560 +/- 30 microM for (R)-4, respectively. Enantiomers of 3 are noncompetitive inhibitors of AChE with values of Ki = 19.0 +/- 0.9 microM for (S)-3 and 50 +/- 2 microM for (R)-3, respectively. AChE shows a 2-fold chiral discrimination in the case of inhibition by 2 and 3. Inhibition also changes from competitive to noncompetitive when (3-hydroxyphenyl)-N,N,N-trimethylammonium iodide (18) [Ki = 0.21 +/- 0.06 microM; Lee, B. H., Stelly, T. C., Colucci, W. J., Garcia, J. G., Gandour, R. D., and Quinn, D. M. (1992) Chem. Res. Toxicol. 5, 411-418] is converted into [3-[(4-nitrophenyl)sulfonoxy]phenyl]-N,N,N-trimethylammonium iodide (5), Ki = 6.0 +/- 0.5 microM. These results indicate that the 4-nitrobenzenesulfonyl group controls the mode of inhibition.
以（R）-和（S）-2-甲基缩水甘油为原料，通过五步手性合成法制备2-（羟甲基）-2,4-二甲基吗啉（12），总收率为63%。（R）-和（S）-12通过2,4-二甲基-2-[[（4-硝基苯基）磺酰氧基]甲基]吗啉（14）转化为2-（叠氮甲基）-2,4-二甲基吗啉（15）。叔吗啉12、14和15经季铵化分别得到2-（羟甲基）-2,4,4-三甲基吗啉碘化物（2）、2,4,4-三甲基-2-[[（4-硝基苯基）磺酰氧基]甲基]吗啉碘化物（3）和2-（叠氮甲基）-2,4,4-三甲基吗啉碘化物（4），它们均能抑制乙酰胆碱酯酶（AChE）。将这些吗啉鎓抑制剂与构象受限的芳基半胆碱鎓AChE抑制剂进行比较。2和4的对映体是AChE的可逆竞争性抑制剂，（S）-2的Ki值为360±30μM，（R）-2的Ki值为650±90μM，（S）-4的Ki值为450±70μM，（R）-4的Ki值为560±30μM。3的对映体是AChE的非竞争性抑制剂，（S）-3的Ki值为19.0±0.9μM，（R）-3的Ki值为50±2μM。在2和3的抑制作用中，AChE表现出2倍的手性识别。当（3-羟基苯基）-N,N,N-三甲基碘化铵（18）[Ki = 0.21±0.06μM；Lee, B. H., Stelly, T. C., Colucci, W. J., Garcia, J. G., Gandour, R. D., and Quinn, D. M. (1992) Chem. Res. Toxicol. 5, 411 - 418]转化为[3-[(4-硝基苯基)磺酰氧基]苯基]-N,N,N-三甲基碘化铵（5），Ki = 6.0±0.5μM时，抑制作用也从竞争性转变为非竞争性。这些结果表明4-硝基苯磺酰基控制着抑制模式。
