Thymectacin

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Thymectacin
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Chemical and physical data
Formula C21H25BrN3O9P
Molar mass 574.321 g·mol−1
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Thymectacin (NB-1011, NB-101, N-[[5-[(E)-2-Bromovinyl]-2'-deoxyuridin-5'-O-yl]](phenoxy)phosphoryl]-L-alanine methyl ester) is an anticancer prodrug of brivudine monophosphate. It developed by New Biotics and it has entered in phase I clinical trials for colon cancer. [1]

Description of Thymectacin: Thymectacin, also known as NB-1011, is a small molecule phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine with potential antineoplastic activity. Selectively active against tumor cells expressing high levels of thymidylate synthase (TS), BVdU pronucleotide analogue NB1011 is converted intracellularly by TS to bromovinyldeoxyuridine monophosphate (BVdUMP) which competes with the natural substrate, deoxyuridine monophosphate, for binding to TS. Unlike TS inhibitors, this agent is a reversible substrate for TS catalysis. Thus, TS retains activity and converts BVdUMP into cytotoxic metabolites.

Related Research Articles

Nucleotide Biological molecules that form the building blocks of nucleic acids

Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are composed of three subunit molecules: a nitrogenous base, a five-carbon sugar, and a phosphate group consisting of one to three phosphates. The four nitrogenous bases in DNA are guanine, adenine, cytosine and thymine; in RNA, uracil is used in place of thymine.

Uridine monophosphate synthetase protein-coding gene in the species Homo sapiens

Uridine monophosphate synthase (UMPS) is the enzyme that catalyses the formation of uridine monophosphate (UMP), an energy-carrying molecule in many important biosynthetic pathways. In humans, the gene that codes for this enzyme is located on the long arm of chromosome 3 (3q13).

A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.

Thymidine kinase InterPro Family

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

Nucleic acid metabolism

Nucleic acid metabolism is the process by which nucleic acids are synthesized and degraded. Nucleic acids are polymers of nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Destruction of nucleic acid is a catabolic reaction. Additionally, parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

Pyrimidine biosynthesis occurs both in the body and through organic synthesis.

Thymidylate synthase mammalian protein found in Homo sapiens

Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

Orotate phosphoribosyltransferase class of enzymes

Orotate phosphoribosyltransferase (OPRTase) or orotic acid phosphoribosyltransferase is an enzyme involved in pyrimidine biosynthesis. It catalyzes the formation of orotidine 5'-monophosphate (OMP) from orotate and phosphoribosyl pyrophosphate. In yeast and bacteria, orotate phosphoribosyltransferase is an independent enzyme with a unique gene coding for the protein, whereas in mammals and other multicellular organisms, the catalytic function is carried out by a domain of the bifunctional enzyme UMP synthase (UMPS).

Deoxycytidine kinase protein-coding gene in the species Homo sapiens

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

5,10-Methylenetetrahydrofolate chemical compound

5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer [6R]-5,10-methylene-THF.

Deoxyuridine monophosphate chemical compound

Deoxyuridine monophosphate (dUMP), also known as deoxyuridylic acid or deoxyuridylate in its conjugate acid and conjugate base forms, respectively, is a deoxynucleotide.

dCMP deaminase protein-coding gene in the species Homo sapiens

dCMP deaminase is an enzyme which converts deoxycytidylic acid to deoxyuridylic acid.

dUTP diphosphatase InterPro Family

In enzymology, a dUTP diphosphatase (EC 3.6.1.23) is an enzyme that catalyzes the chemical reaction

DUT (gene) protein-coding gene in the species Homo sapiens

DUTP pyrophosphatase, also known as DUT, is an enzyme which in humans is encoded by the DUT gene on chromosome 15.

UCK2 protein-coding gene in the species Homo sapiens

Uridine-cytidine kinase 2 (UCK2) is an enzyme that in humans is encoded by the UCK2 gene.

CMPK protein-coding gene in the species Homo sapiens

UMP-CMP kinase is an enzyme that in humans is encoded by the CMPK1 gene.

Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy. This inhibition prevents the methylation of C5 of deoxyuridine monophosphate (dUMP) thereby inhibiting the synthesis of deoxythymidine monophosphate (dTMP). The downstream effect is promotion of cell death because cells would not be able to properly undergo DNA synthesis if they are lacking dTMP, a necessary precursor to dTTP . Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L.

Trifluridine/tipiracil chemical compound

Trifluridine/tipiracil is a combination drug that is used as a third- or fourth-line treatment of metastatic colorectal cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21 that catalyzes the reaction:

Fluorodeoxyuridylate chemical compound

Fluorodeoxyuridylate, also known as FdUMP, 5-Fluoro-2'-deoxyuridylate, or 5-Fluoro-2'-deoxyuridine 5'-monophosphate sodium salt, is a molecule formed in vivo from 5-fluorouracil or 5-fluorodeoxyuridin.

References

  1. Wilson RH (October 2006). "Novel therapeutic developments other than EGFR and VEGF inhibition in colorectal cancer". The Oncologist. 11 (9): 1018–24. doi:10.1634/theoncologist.11-9-1018. PMID   17030644.