Raltitrexed

Raltitrexed is an antimetabolite antineoplastic agent that acts as a specific thymidylate synthase inhibitor. As a quinazoline folate analogue, Raltitrexed inhibits DNA synthesis by blocking the conversion of deoxyuridine monophosphate to thymidine monophosphate. Raltitrexed is transported into cells via the reduced folate carrier (RFC) and is extensively polyglutamated intracellularly, enhancing its inhibitory potency and duration of action . This polyglutamation allows Raltitrexed to achieve long-lasting inhibition of thymidylate synthase even after plasma concentrations decline. Raltitrexed and its related impurities serve as critical reference standards for analytical method development, method validation (AMV), and quality control (QC) in ANDA filings.

Product Parameters

Application

Raltitrexed is a thymidylate synthase inhibitor. It has a relatively strong inhibitory effect on colon cancer cell lines, and is used as a single agent for the treatment of advanced colon and rectal cancer in patients who cannot receive combination chemotherapy and are unsuitable for fluorouracil (5-Fu)/calcium folinate.

Synthetic Route

2,6-Dimethyl-4(3H)-quinazolinone (I) undergoes N-alkylation with pivaloyloxymethyl chloride, followed by bromination with N-bromosuccinimide, to obtain 6-(bromomethyl)-2-methyl-3-[(pivaloyloxy)methyl]-4(3H)-Chemicalbook quinazolinone (III). (III) condenses with N-[5-methylaminothiophene-2-carbonyl]-L-glutamic acid diethyl ester (IV), the resulting product V is stirred and hydrolyzed with an aqueous ethanol solution of sodium hydroxide at room temperature, while the protective group is removed simultaneously, and then acidified to obtain the product.

Pharmacological Action

Raltitrexed is metabolized into various polyglutamates in cells to exert its anti-tumor effect, and its inhibitory effect on colon cancer cell lines is stronger than that of fluorouracil. The IC50 of raltitrexed is 1.3~3.9 nmol/L for long-term administration and 80 nmol/L for short-term administration, while the IC50 of the combination of fluorouracil and leucovorin is 330~5800 nmoL/ChemicalbookL for long-term administration and up to 150000 nmol/L for short-term administration. In vitro studies have observed that the combination of raltitrexed and fluorouracil has a synergistic effect, which depends on the administration regimens and dosages of the two drugs. In the treatment of HCT-8 colon cancer, administration of fluorouracil 4~24 h after raltitrexed administration produces a synergistic effect on day 7, while simultaneous administration of the two drugs or administration of fluorouracil prior to raltitrexed does not produce a synergistic effect.

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