Molecular Modeling Studies and Synthesis of Novel Methyl 2-(2-(4-Oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)alkanoates with Potential Anti-cancer Activity as Inhibitors for Methionine Synthase

Abstract

Cobalamin-dependant cytosolic enzyme methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine (Hcy) to produce methionine and tetrahydrofolate (THF). MetS is over-expressed in the cytosol of certain breast and prostate tumour cells. Methionine used as a source of one carbon atom for the building of the DNA of the tumour cells, structural protein and enzymes. In this study, we designed, synthesized and evaluated the cytotoxic activity of a series of substituted methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)acetate and dipeptide that mimic the substructure of MTHF. Key words cobalamin: methionine; methionine synthase; quinozaline; thioamide; chemoselective reaction Methionine synthase (MetS) is one of the folic acid cycle enzymes that catalyses the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine to produce methionine and tetrahydrofolate. The catalysis occurred via the coenzyme cobalamin cofactor (CH 3 -Cb).1) This enzyme has been linked to the pathogenesis of anemias, neurodegenerative disorders and cancer.2) Using mammalian methionine synthase, X-ray studies show that it is constructed of 1227 amino acid residues and has a molecular mass of 136 kDa. 3)Cobalamin-dependent methionine synthase is made up of four modules 5-methyltetrahydrofolate and homocysteine binding regions from the C-terminal of the protein and cobalamin and the S-adenosylmethionine binding regions from N-terminal. 3)Methionine is an essential amino acid necessary for normal growth. Methionine is used as a methyl group donor, providing one carbon units for DNA synthesis.4) Methionine dependence is defined as the inability of cancer cells to grow in a methionine depleted medium even when replaced with the immediate precursor, homocysteine.5) Normal cells remain unaffected by methionine restrictions if supplemented with homocysteine, as they are able to synthesize methionine via methylation of homocysteine in sufficient quantities. Most metastatic tumours, such as those originating in prostate, lung and gastrointestinal tract, respond poorly to conventional chemotherapy. Novel treatment strategies for advanced cancer are therefore needed. Dietary restriction of the essential amino acid methionine offers promise as such a strategy, either alone or in combination with chemotherapy or other treatments. 6)Although there are many approaches for developing inhibitors for folic acid enzymes system collectively named antifolates.There are a limited number of reports concerning the inhibition of MetS. A series of inhibitors of substituted 2,4-diaminopyrimidine derivatives that could bind the substrate-binding pocket of dihydrofolate reductase was synthesized.7) 6-Substituted pyrrolo-and thieno[2,3-d]pyrimidine derivatives were identified as antifolates with selective membrane transport by proton-coupled folate transporter (PCFT) and folate receptors (FRs) over reduced folate carrier (RFC).8) A series of pyrido [2,3-d] pyrimidines was successful...

Synthesis of methyl [3-alkyl-2-(2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl)-acetamido] alkanoate

“…Recently we reported the molecular modeling studies and syntheses of methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido) alkanoates with potential anticancer activity as inhibitors for methionine synthase. 20 However a strong query still remains that is the development of simple, mild and efficient methods for preparation of quinazoline derivatives linked to amino acid residues by a spacer and the evaluation of their biological activities. In view of these facts and in continuation of our efforts in studing the chemoselective reactions of heterocyclic amides [21][22][23] and thioamides, 20,[24][25][26][27][28][29][30][31][32][33][34][35][36][37] we found interesting to synthesize a series of quinazoline derivatives linked to amino acids by a spacer.…”

Convenient Synthesis and Anticancer Activity of Methyl 2-[3-(3-Phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and N-Alkyl 3-((3-Phenyl-quinoxalin-2-yl)sulfanyl)propanamides

“…Earlier, we reported − the chemoselective S- and N-alkylation of the model compound 4-methyl-1-thioxo-1,2,4,5-tetrahydro­[1,2,4]­triazolo­[4,3- a ]­quinazolin-5-one with different electrophiles. These results were supported by quantum-chemical calculations. − We also applied these findings to the structure modification of a number of heterocyclic thioamides, quinazolines, tetrazoles, triazoloquinazolines, − , and triazoloquinoxalines . Nonproteinogenic amino acids are major components in a number of drugs including β-lactam antibiotics and antiviral drugs .…”

“…These results were supported by quantum-chemical calculations. 20−22 We also applied these findings to the structure modification of a number of heterocyclic thioamides, quinazolines, 23 tetrazoles, 24 triazoloquinazolines, 20−22,25 and triazoloquinoxalines. 26 Nonproteinogenic amino acids are major components in a number of drugs including β-lactam antibiotics 27 and antiviral drugs.…”

Synthesis and Cytotoxic Activity against K562 and MCF7 Cell Lines of SomeN-(5-Arylidene-4-oxo-2-thioxothiazolidin-3-yl)-2-((4-oxo-3-phenyl-3,4-dihydroquinazoline-2-yl)thio)acetamide Compounds

“…2-Mercapto-3-phenylquinazolin-4-one (2), ethyl 2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetate (3), and 2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetohydrazide (4) were prepared according to reported methods [1,3,7,14,15,18]. e similarity in both melting points and spectral characteristics of these compounds with the ones of the corresponding compounds in literature confirmed their formation.…”

“…Quinazolinones were considered to be a scaffold with potential biological activities. Besides possessing a variety of biological effects including antimicrobial [1][2][3][4][5][6], anticonvulsant [7,8], and antihistamine [9,10] activities, compounds containing quinazolin-4-one nucleus also showed promising anticancer potency [11][12][13][14][15][16][17][18][19][20]. Along with that, 5-arylidene-2thioxothiazolidine-4-one compounds are an important class of compounds with a wide range of pharmaceutical properties.…”