Stereoisomeric separation and bioassay of a new organophosphorus compound, O,S-dimethyl-N-(2,2,2-trichloro-1-methoxyethyl)phosphoramidothioate: some implications for chiral switch.
The manufacture and use of single- or enriched-enantiomer pesticides are green-chemistry developments advocated in the 21st century, but predictive work for chiral switch of newly produced chiral active ingredients is limited. In the present study, the stereoselective separation, target activity, and nontarget toxicity of O,S-dimethyl-N-(2,2,2-trichloro-1-methoxyethyl)phosphoramidothioate (MCP), a new organophosphorus compound, were investigated. Because being highly active and safe is a prerequisite for marketing single-isomer products, the above studies were used to offer some implications for the chiral switch of racemic MCP. The results showed that all four stereoisomers of MCP were successfully separated with a Chiralpak AD column on HPLC. The resolved isomers and the pairs of enantiomers were further distinguished using a circular dichroism detector, designating the first and third eluted peaks as one pair of enantiomers and the second and fourth peaks as the other pair. Then, the insecticidal activities and acute and delayed toxicities of the resolved isomers of MCP were evaluated by their acute lethal efficacy against Daphina magna , their inhibitory potentials to acetylcholinesterase (AChE), and axon-like outgrowth of the SH-SY5Y cells, respectively. The inhibition potencies of the isomers against AChE in SH-SY5Y cells were low and slightly stereoselective. On the other hand, a significant difference was observed among the isomers in their activities and delayed neurotoxicities. The 48 h acute toxicities of isomers to D. magna followed the order peak 1 approximately pair 1 (i.e., equimolar mixture of peaks 1 and 3) > peak 4 approximately racemate > pair 2 (i.e., equimolar mixture of peaks 2 and 4) > peak 2 > peak 3, with 1.0-6.3-fold differences among them. In comparison, the inhibitory potentials of the isomers toward axon growth of SH-SY5Y cells decreased in the order peak 2 > pair 2 > peak 4 > racemate > peak 3 > pair 1 approximately peak 1, with at least a 60-fold difference between the strongest and weakest inhibitors. Those results imply that peak 1 has the optimal target selectivity and ecological profile among the four stereoisomers. It was calculated that two-thirds of the usual pesticide usage can be saved concomitantly with a substantial decrease in neuropathic risk if MCP is present only as peak 1 rather than the racemate. When considering the absence of the economically feasible synthetic methods and techniques to produce optically pure isomers of organophosphorus pesticides, pair 1 of MCP shows considerable worth for future applications on the basis of its biological predominance and cost effectiveness.
Zhou
Shanshan
S
Research Center of Green Chirality, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, People's Republic of China.
Wang
Lumei
L
Li
Ling
L
Liu
Weiping
W
D000818:Animals; D001681:Biological Assay; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity; D003621:Daphnia / Q000187:drug effects*; D006801:Humans; D007306:Insecticides / Q000737:chemistry* / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; C519624:chloramidophos