89892-99-9Relevant academic research and scientific papers
Divergent selectivity in Mgl2-mediated ring expansions of methylenecyclopropyl amides and imides
Lautens, Mark,Han, Wooseok
, p. 6312 - 6316 (2007/10/03)
We report a novel approach to prepare five- and six-membered heterocyclic compounds via a ring expansion of monoactivated methylenecyclopropanes (MCPs) with aldimines and aldehydes in the presence of MgI2. Monoactivated MCPs behave as homo-Mich
Synthesis of phosphonate derivatives of methylenecyclopropane nucleoside analogues by alkylation-elimination method and unusual opening of cyclopropane ring
Guan, Hui-Ping,Qiu, Yao-Ling,Ksebati, Mohamad B.,Kern, Earl R.,Zemlicka, Jiri
, p. 6047 - 6059 (2007/10/03)
The synthesis of phosphonates of methylenecyclopropane nucleoside analogues 15a-18a, 15b-18b and 15c-18c by alkylation-elimination approach is described. In a foreshortened series, methanesulfonate 19 was transformed by Michaelis-Becker reaction with diethyl or diisopropyl phosphite to methylenecyclopropane phosphonates 20a or 20b. The latter were converted to vicinal dibromides 21a and 21b which were then used for alkylation-elimination of nucleic acid bases (adenine) or precursors (2-amino-6-chloropurine and N4-acetylcytosine). The intermediary Z+E-isomers 22a+23a and 22b+23b were dealkylated with bromo- of iodotrimethylsilane to free phosphonic acids 15a, 16a and phosphonate with an open cyclopropane ring 25 which were separated by ion exchange chromatography on Dowex 1. Phosphonate diesters 22c and 23c were separated by chromatography on silica gel, they were hydrolyzed to guanine derivatives 22d and 23d which were then dealkylated to give target analogues 15b, 16b and products of addition of hydrogen bromide or iodide across the double bond 26a or 26b. The E+Z-isomers 22e+23e were converted to cytosine phosphonates 15c+16c and cyclic phosphonate with an open cyclopropane ring 27a. In a homologous series of phosphonates, dibromocyclopropane 34 was converted to intermediate 31 by reaction with diisopropyl methyl phosphonate and subsequent β-elimination. Compound 31 was transformed to vicinal dibromide 36, a key component for alkylation-elimination of nucleic acid bases. The rest of the synthetic sequence followed the scheme described for the series of lower homologues to give the Z-isomeric phosphonates 17a, 17b, E-isomers 18a, 18b and E+Z-isomers 17c+18c as the final products. All methylenecyclopropane phosphonates were devoid of antiviral activity with the exception of guanine derivative 15b which inhibited the replication of varicella zoster virus (VZV) and it was non-cytotoxic.
The toxicity of methylenecyclopropylglycine: Studies of the inhibitory effects of (methylenecyclopropyl)formyl-CoA on enzymes involved in fatty acid metabolism and the molecular basis of its inactivation of enoyl-CoA hydratases
Li, Ding,Agnihotri, Gautam,Dakoji, Srikanth,Oh, Eugene,Lantz, Marily,Liu, Hung-Wen
, p. 9034 - 9042 (2007/10/03)
(Methylenecyclopropyl)formyl-CoA (MCPF-CoA), a toxic metabolite of methylenecyclopropy]glycine (MCPG), is known to have hypoglycemic activity due to its ability to interrupt the β-oxidation pathway of fatty acid metabolism. Earlier experiments have shown that acetoacetyl-CoA thiolase, 3- ketoacyl-CoA thiolase, acyl-CoA dehydrogenases, and enoyl-CoA hydratase (ECH) are cellular targets that can be inhibited by MCPFCoA and/or MCPG. To gain more insights with respect to the target specificity and the mode of action, we have carried out a detailed investigation of the effects of MCPF-CoA on a variety of enzymes involved in fatty acid metabolism. Our studies confirmed that MCPF-CoA is a potent inactivator for ECHs but shows little effect on other r-oxidation enzymes tested in this study. Our results also revealed that MCPF-CoA manifests distinct modes of inhibition among ECHs isolated from different sources, being a competitive inhibitor for rat liver ECH and an irreversible inactivator for the bovine liver as well as pig kidney ECH. Given the high sequence homology of the mammalian ECH genes studied so far, the structures of these proteins are expected to be similar. Thus, the effects of MCPF-CoA toward different ECHs must be governed in part by the interaction of MCPF-CoA with the active site of each ECH whose architecture may be subtly different. More importantly, the incubation results with bovine liver ECH established that MCPF-CoA inactivates this enzyme via a mechanism involving the covalent trapping of an active site nucleophile by the methylenecyclopropane ring. Since MCPF-CoA is a rare irreversible inhibitor for ECHs, it could serve as a new lead for designing more effective agents for modulating ECH activity so as to control and/or regulate fatty acid metabolism.
Mechanistic study on the inactivation of general Acyl-CoA dehydrogenase by a metabolite of hypoglycin A
Lai, Ming-Tain,Liu, Li-Da,Liu, Hung-Wen
, p. 7388 - 7397 (2007/10/02)
General acyl-CoA dehydrogenase (GAD) is a flavin-dependent (FAD) enzyme that catalyzes the oxidation of a fatty acyl-CoA to the corresponding α,β-enolyl-CoA. When GAD is exposed to (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), a metabolite of hypoglycin A
