Zd 9331

O S^ Nolatrexed

Raltitrexed (TOM) was the first specific TS inhibitor to be approved for clinical use, and it is employed for advanced colorectal cancer. Its structure contains two classical bioisosteric modifications, namely replacement of the pteridine ring of folate by a quinazoline unit and replacement of the benzene ring of folate by a thiophene. This drug is transported into the cells by the reduced folate carrier (RFC), and its terminal glutamate residue is converted into a polyglutamate by folylpolyglutamate synthetase (FPGS). The polyglutamate form is more potent as an enzyme inhibitor and it is retained intracellularly, leading to a prolonged action (Fig. 2.26). A related TS inhibitor is pemetrexed (alimta, LY-231514), which also inhibits several other folate-related enzymes and will be discussed in Section 6.2.

ZD-9331 is also a potent inhibitor of TS that is under advanced clinical evaluation32 and differs from the previously mentioned compounds in several respects. One of them is the presence of a methyl group at C-7, which was designed from X-ray diffraction studies of TS that suggested that a 7-alkyl group would contribute to binding. Another difference is the 2'-fluorine substituent that also increased activity. One final interesting feature of ZD-9331 is the isosteric g-carboxyl-tetrazole replacement at the glutamic portion which prevents polyglutamation. Because this drug is active against TS in a non-polyglutamated form, it has the advantage over previously mentioned folate-based TS inhibitors of not being subject to resistance by FPGS downregulation.

Nolatrexed (thymitaq, AG-337) is the inhibitor structurally least related to folate. It crosses the cell membrane by passive diffusion rather than using the RFC and, since it is not retained inside the cells because it cannot be polygluta-mated, it requires a prolonged infusion (see Section 5.2). Phase II clinical trials

FIGURE 2.26 Active transport and polyglutamation of raltitrexed.

showed activity in patients with hepatocellular carcinoma, head and neck cancer,33 and adenocarcinoma of the pancreas.

The RFC is ubiquitous and is expressed in normal tissues, leading to increased toxicity of antifolate drugs. Another related membrane transporter is the a-isoform of the membrane folate receptor (MFR, a-FR), which has the advantage of being overexpressed in some tumors. For this reason, it is expected that TS inhibitors with MFR/RFC selectivity will be better tolerated.34 One of these compounds is CB-300638, which was designed on the basis of the crystal structures of inhibitors bound to TS35 and has shown promising preclin-ical data. This compound contains two glutamate units and cannot be further glutamated because of the unnatural R configuration at the a carbon of the second residue.36


Folic acid and its metabolites (collectively known as folates) are coenzymes of many essential biochemical transformations. Most importantly, they are involved in the previously mentioned transfer of one carbon unit in the de novo synthesis of thymidylic acid and purine nucleotides. Folate-dependent enzymes are obvious targets for cancer chemotherapy, but until 1980 only DHFR was exploited in this regard and in fact it was the first enzyme to be targeted for cancer chemotherapy.

In mammals, folic acid is taken with the diet and reduced to THF by dihydro-folic reductase in two stages, using NADPH as a cofactor. Further transformations of THF lead to 5,10-methylene-THF, 5,10-methenyl-THF, 5-formyl-THF, and 10-formyl-THF (Fig. 2.27), which are known as folinic acids and are involved in the transfer of one carbon units. DHFR inhibition leads to cell death due to the essential role of folinic acids in the synthesis of thymidylate and purine bases.

DHFR is a relatively small protein with a large active site in which DHF binds adjacent to the cofactor, NADPH, in a pocket buried deep within the enzyme.

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