Thymidylate synthase inhibitor

Fig. 8. Thymidylate synthase inhibitors designed to fit into the A/, AJ -methylenetetrahydrofolate binding site. The best inhibitors from each class are the classical antifolate TS inhibitor (31), the naphthostyril-based lead compound (32), and the tetrahydroquinoline-based lead compound (33), iC values (in nAI)...

Fig. 9. Thymidylate synthase inhibitors found after analysis with the computet program DOCK (see Table 2).

Rustum YM, Harstrick A, Cao S, Van-hoefer U, Yin MB, Wilke H et al. Thymidylate synthase inhibitors in cancer therapy direct and indirect inhibitors. 

Wang W, Marsh S, Cassidy J et al. Pharmacogenomic dissection of resistance to thymidylate synthase inhibitors. Cancer Res 2001 61 5505-5510. 

Wang W, Cassidy J (2003) Constitutive nuclear factor-kappa B mRNA, protein overexpression and enhanced DNA-binding activity in thymidylate synthase inhibitor-resistant tumour cells. Br J Cancer 88(4) 624-629... 

Phenanthroindolizidine and phenanthroquinolizidine alkaloids involve a phenanthrene (Phe ] Phe Phe (angular)) fused with an indolizidine or quinolizidine, respectively. The phenanthroindolizidines tylophorine (phenanthrene G5N G4N ) and tylocrebrine (phenanthrene G5N C4N ) and the phenanthroquinolizidine crypto-pleurine (phenanthrene G5N C5N ) are toxic, cytotoxic protein synthesis inhibitors. The phenanthroindolizidines tylophorine and pergularinine are thymidylate synthase inhibitors. 

Thymidylate synthase inhibitors (129), using DOCK to identify the starting lead. 

Takemura Y, Jackman AL (1997) Eolate-based thymidylate synthase inhibitors in cancer chemotherapy. Anti-Cancer Drugs 8 3-16... 

Fig. 7. Thymidylate synthase inhibitors designed to bind in the cofactor-binding site using crystal structure of coli enzyme complexed with 5-fluoro-2 -deoxyuridylate (35).

Jiang, L., Lee, P. C., White, J., and Rathod, P. K. (2000). Potent and selective activity of a combination of thymidine and 1843U89, a folate-based thymidylate synthase inhibitor, against Plasmodium falciparum. Antimicrob. Agents Chemother. 44,1047-1050. 

Fig. 26.17 Structure-based design of thymidylate synthase inhibitors, (a) The coenzyme 5,10-methylenete-trahydrofotate. (b) The classical antifolate CB3717. (c) Interactions of the pteridine moiety of CB3717 with active site residues Asp169 and Ala263 and with wat430, a bound water molecule. For explanation, see text. (Adapted, with permission, from Reich, S.H. and Webber, S.E. (1993) Perspect. Drug Dis. Des. 1 371-390. 1993 Escom Science Publishers B.V.)...

Fig. 26.18 Structure-based design of thymidylate synthase inhibitors, (a) Drug lead 2-methyl-2-desamino-/ / °-propargyl-5,8-dideazafolic acid, (b) Derivative lacking the CO-L-glutamate mpiety. (c) Designed diphenylsulfone derivative, (d) AG85, a designed A7-sulfonylindole derivative selected for clinical evaluation.

Fig, 26.19 Structure-based design of thymidylate synthase inhibitors de novo design of a novel lead structure. See text for explanation. 

Flucytosine is a powerful antifungal agent used in the treatment of serious systemic fungal infections, such as Cryptococcus neoformans and Candida spp (Table 40.2). Flucytosine itself is not cytotoxic but, rather, is a pro-drug that is taken up by fungi and metabolized to 5-fluorouracil (5-FU) by fungal cytidine deaminase (Fig. 40.11) (51). Then, 5-FU is converted to 5-fluorodeoxyuridine, which as a thymidylate synthase inhibitor interferes with both protein and RNA biosynthesis. 5-Fluorouracil is cytotoxic and is employed in cancer chemotherapy (see Chapter 42). Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism. Resistance rapidly develops to flucytosine when used alone, so it is almost always used in conjunction with amphotericin B. Use of flucytosine has declined since the discovery of fluconazole. 

N. L. Lehman, Future potential of thymidylate synthase inhibitors in cancer therapy, Exp. Opin. Invest. Drugs., 11 (2002) 1775-1787. 

Many quinazolinone-based compounds function as thymidylate synthase inhibitors by directly binding to the active site of thymidylate synthase. This results in the inhibition of DNA replication as well as DNA damage, S-phase cell arrest, and caspase-dependent apoptosis. Many compounds of this class have been successfully employed as anti-cancer pharmaceutics. Two examples, nolatrexed, a compound used to treat unresectable hepatocellular carcinoma (HCC), and raltitrexed, a first-line treatment against advanced colorectal cancer, are highlighted below. 

Historical approaches to treatment of liver metastases have included administration of the thymidylate synthase inhibitors in an attempt to delay... 

Fluorouracil Pyrimidine Colorectal, pancreatic, breast Thymidylate synthase inhibitor Acral erythema maculopap. rash inj. site reaction CD St Anaph diarrhea myelosuppression GI mucositis Palmar-plantar dermatitis risk factor. Diag.—IDT and patch (with care) IgE-mediated Direct cytotoxic effect... 

Rafi I, Taylor GA, Calvefe JA, Boddy AV, Balmanno K, Bailey N, Lind M, Calvert AH, Webber S, Jackson RC, Johnston A, Clendeninn N, Newell DR (1995) Clinical pharmacokinetic and pharmacodynamic studies with the nonclassical antifolate thymidylate synthase inhibitor 3,4- dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazolone dihydrochloride(AG337) given by 24-hour continuous intravenous infusion. Chn Cancer Res 1 1275-1284... 

Figure 12 Design paradigm used in the structure-based discovery of thymidylate synthase inhibitors. ...

---