Two newly synthesized 5-methyltetrahydrofolate-like compounds inhibit methionine synthase activity accompanied by cell cycle arrest in G1/S phase and apoptosis in vitro.

Abstract

Cobalamin-dependent methionine synthase, with a cofactor of vitamin B12, catalyzes the reaction of 5-methyltetrahydrofolate and homocysteine to form methionine and tetrahydrofolate, which takes a core position in folate cycle, one-carbon-unit transfer, and sulfur amino acid pathways. The 'methyl folate trap' hypothesis suggests that methionine synthase is a potential target for anticancer drug development. ZL031 and ZL033 are 5-methyltetrahydrofolate-like compounds that have been newly synthesized as potential inhibitors of the enzyme. To identify the effect of these two compounds on methionine synthase activity, a spectrophotometric assay was used and the results proved that ZL031 and ZL033 inactivated methionine synthase in HL-60 cells with an IC50 dose of 10.0 and 1.4 mumol/l, respectively. Moreover, obvious inhibitory effect on proliferation of HL-60 cells was observed, leading to our further investigation of the underlying anticancer mechanism. Under the circumstances of methionine synthase deficiency and subsequent folate depletion, cell cycle was arrested in G1/S phase and apoptosis was also observed. Analysis of cell cycle regulatory proteins demonstrated that cyclin E and cyclin-dependent kinase 2 were both increased. Furthermore, reduction of caspase-3, poly (ADP-ribose) polymerase, caspase-8, and caspase-9 protein levels were observed. In all the biological experiments we have performed, ZL033 has shown a better efficacy compared with ZL031. These results suggest that ZL031 and ZL033, as novel methionine synthase inhibitors, caused G1/S phase delay and apoptosis and eventually inhibit the proliferation of HL-60 cells in vitro. ZL033, with a carboxylic acid substituent, might have a better potential for drug development than ZL031 with an ester substituent.

• Authors: Cai Tang, Zhili Zhang, Bo Xu, Min Li, Junyi Liu, Jingrong Cui
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 19 Issue 7 Pg. 697-704 (Aug 2008) ISSN: 0959-4973 [Print] England
• PMID: 18594211 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclin E
• Enzyme Inhibitors
• Glutamates
• N-(4-((2-(2,4-diamino-5-(2,3-dibromopropyl)-5,6,7,8-tetrahydropyrido(3,2-d)pyrimidin-6-yl)methyl)amino)-3-bromobenzoyl)glutamic acid
• Pyrimidines
• Tetrahydrofolates
• diethyl N-(4-((2-(2,4-diamino-5-(2,3-dibromopropyl)-5,6,7,8-tetrahydropyrido(3,2-d)pyrimidin-6-yl)methyl)amino)-3-bromobenzoyl)glutamate
• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
• CDK2 protein, human
• Cyclin-Dependent Kinase 2
• 5-methyltetrahydrofolate

Topics

• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cyclin E (biosynthesis)
• Cyclin-Dependent Kinase 2 (biosynthesis)
• Enzyme Inhibitors (pharmacology)
• G1 Phase (drug effects)
• Glutamates (pharmacology)
• HL-60 Cells
• Humans
• Pyrimidines (pharmacology)
• S Phase (drug effects)
• Tetrahydrofolates (pharmacology)