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Review

Inhibitors of dihydroorotate dehydrogenase

Pages 41-54 | Published online: 25 Feb 2005

Bibliography

  • ALLISON AC, EUGUI EM: Inhibitors of de novo purine and pyrimidine synthesis as immunosuppressive drugs. Transplant. Proc. (1993) 25(3 Suppl. 2):8–18.
  • FAIRBANKS LD, BOFILL M, RUCKEMANN K, SIMMONDS HA: Importance of ribonucleotide availability to pro-liferating T-lymphocytes from healthy humans. Dis-proportionate expansion of pyrimidine pools and contrasting effects in de novo synthesis inhibitors. J. Biol. Chem. (1995) 270(5029682–29689.
  • WEIL C: Cyclosporin A: review of results in organ and bone-marrow transplantation in man. Med. Res. Rev. (1984) 4(2):221–265.
  • MORE, YUSSIM A, CHODOFF L, SCHWARTZ ME: New im-munosuppressive agents for maintenance therapy in organ transplantation. BioDrugs (1997) 8(6)469–488.
  • DELL CP: Antiproliferative naphthopyrans: biological activity, mechanistic studies and therapeutic poten-tial. Curr. Med. Chem. (1998) 5:179–194.
  • KENSLER TW, COONEY DA: Chemotherapeutic inhibi-tors of the enzymes of the de novo pyrimidine path-way. Adv. Pharmacol. Chemother. (1981) 18:273–350.
  • GERO AM, O'SULLIVAN WJ: Purines and pyrimidines in malarial parasites. Blood Cells (1990) 16(2-3):467–484.
  • DEFREES SA, SAWICK DP, CUNNINGHAM B et al.: Structure-activity relationships of pyrimidines as di-hydroorotate dehydrogenase inhibitors. Biochem. Pharmacol. (1988) 37 (20):3807–3816.
  • BUNTAIN IG, SUCKLING CJ, WOOD HCS: Latent inhibi-tors Part 4. Irreversible inhibition of dihydroorotate dehydrogenase by hydantoins derived from amino ac-ids. J. Chem. Soc. Perkin Trans. 1(1988) 3175–3182.
  • FRASER W, SUCKLING CJ, WOOD HCS: Latent inhibitors Part 7. Inhibition of dihydroorotate dehydrogenase by spirocyclopropanobarbiturates. J. Chem. Soc. Perkin Trans. 1(1990) 3137–3144.
  • BENNETT LL, SMITHERS D, ROSE LM, ADAMSON DJ, THO-MAS HJ: Inhibition of synthesis of pyrimidine nucleo-tides by 2-hydroxy-3-(3,3-dichloroally1)-1,4-naphthoquinone. Cancer Res. (1979) 39:4868–4874.
  • HAMMOND DJ, BURCHELL JR, PUDNEY M: Inhibition of pyrimidine biosynthesis de novo in Plasmodium falci-parum by 2- (44-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol. Biochem. Parasitol. (1985) 14(0:97–109.
  • ITTARAT I, ASAWAMAHASAKDA W, MESHNICK SR: The effects of antimalarials on the Plasmodium fakipa-rum dihydroorotate dehydrogenase. Exp. Parasitol. (1994) 79(1):50–56.
  • DEXTER DL, HESSON DP, ARDECKY RJ et al: Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-y0-3-methyl-4-q uinolinecarboxylic acid sodium salt], against experimental tumors. Cancer Res. (1985) 45(11, Pt. 1):5563–5568.
  • CHEN S-F, RUBEN RL, DEXTER DL: Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro--1,1'-bipheny1-4-y1)-3-methyl-4-quinolinecarboxylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis. Cancer Res. (1986) 46:5014–5019.
  • ••This paper was the first report of inhibition of a mammalianDHODase by a compound which was not a substrate or co-factor analogue.
  • CHEN S-F, PERRELLA FW, BEHRENS DL, PAPP LM: Inhibi-tion of dihydroorotate dehydrogenase activity by bre-quinar sodium. Cancer Res. (1992) 52:3521–3527.
  • MAROUN J, RUCKDESCHEL J, NATALE R et al.: Multicen-ter Phase II study of brequinar sodium in patients with advanced lung cancer. Cancer Chemother. Pharmacol (1993) 32:64–66.
  • JAFFEE BD, JONES EA, LOVELESS SE, CHEN SF: Unique immunosuppressive activity of brequinar sodium. Transplant. Proc. (1993) 25(3, Suppl. 2):19–22.
  • MAKOWKA L, CHAPMAN F, CRAMER DV: Historical de-velopment of brequinar sodium as a new immunosup-pressive drug for transplantation. Transplant. Proc. (1993) 25(3, Suppl. 2):2–7.
  • MAKOWKA L, SHER LS, CRAMER DV: The development of brequinar as an immunosuppressive drug for trans-plantation. Immunol. Rev. (1993) (136):51–70.
  • •This paper is an in-depth review of BQR for organ transplan-tation, with much background information also included.
  • CRAMER DV: Brequinar sodium. Transplant. Proc. (1996) 28(2)960–963.
  • •This is a more up-to-date review of BQR.
  • XU X, WILLIAMS JW, SHEN J et al.: In vitro and in vivo mechanisms of action of the antiproliferative and im-munosuppressive agent, brequinar sodium. J. Imrnu-nol. (1998) 160:846–853.
  • CHEN S-F, PAPP LM, ARDECKY RJ eta].: Structure-activity relationships of quinoline carboxylic acids. A new class of inhibitors of dihydroorotate dehydrogenase. Biochem. Pharmacol. (1990) 40(4):709–714.
  • ••This report is a very thorough SAR summary of BQRanalogues.
  • REN S, WU SK, LIEN EJ: Dihydroorotate dehydrogenase inhibitors: quantitative structure-activity relationship analysis. Pharm. Res. (1998) 15(2):286–295.
  • BATT DG, COPELAND RA, DOWLING RL et al.: Immuno-suppressive structure-activity relationships of bre-quinar and related cinchoninic acid derivatives. Bioorg. Med. Chem. Lett. (1995) 5(14):1549–1554.
  • •This paper updates the SAR of BQR analogues with respect to immunosuppressive activity.
  • SLOBODA AE, POWELL D, POLETTO JF et al.: Antiinflam- matory and antiarthritic properties of a substituted quinoline carboxylic acid: CL 306,293. J. Rheumatol (1991) 18:855–860.
  • SCOTT JVV, DEJOY SQ, JEYASEELAN R et al: Studies on the effect of CL 306,293, a substituted quinoline car-boxylic acid, on the clinical disease induced in mice with LP-BM5 virus. Antiviral Res. (1993) 20:71–81.
  • ITO T, KAMILKE W, OHKAWA A et al: Immunosuppres-sive effect on alloimmune responses of new immuno-suppressant, KF20444. Organ Biol. (1997) 4(2):43–48.
  • NAKAJIMA H, NUKUI E, NAKASATO Y et al.: Immunosup-pressive effect of new immunosuppressant, KF20444. Organ Biol. (1997) 4(2):49–57.
  • PITTS WJ, JETTER JVV, PINTO DJ et al.: Structure-activity relationships of some tetracyclic heterocycles related to the immunosuppressive agent brequinar sodium. Bioorg. Med. Chem. Lett. (1998) 8:307–312.
  • •This paper provides a discussion of the SAR of bridged ana-logues of BQR.
  • JACOBSON IC, REDDY PG, PITTS WJ, MAGOLDA RL: Chemistry related to the synthesis of the aza-fused analog of brequinar sodium. 216th ACS Meeting Boston, USA (1998). ORGN132.
  • BATT DG, PETRAITIS JJ, SHERK SR et al: Heteroatom- and carbon-linked biphenyl analogs of brequinar as im-munosuppressive agents. Bioorg. Med. Chem. Lett. (1998) 8(13):1745–1750.
  • ••This paper describes the SAR of BQR variants with more di-verse 2-substituents, discussing shape requirements of the lipophilic binding pocket.
  • PALLY C, SMITH D, JAFFEE B et al: Side effects of bre-quinar and brequinar analogs, in combination with cyclosporine, in the rat. Toxicology (1998) 127 (1-3) 207–222.
  • SCHUURMAN HJ, TANNER M, PALLY C, JAFFEE BD: Bre-quinar and brequinar analogues in rat allo- and xeno-transplantation. Transplant. Proc. (1998) 30:2240–2243.
  • BARTLETT RR, CAMPION G, MUSIKIC P et al.: Leflu-nomide: a novel immunomodulating drug. In: Nonster-oidal Anti-inflammatory Drugs. AJ Lewis, DE Furst (Eds.), Marcel Dekker, Inc., New York (1994):349–366.
  • ••This review summarises the interesting in vitro and in vivoprofiles of LFM.
  • BARTLETT RR, BRENDEL S, ZIELINSKI T, SCHORLEMMER HU: Leflunomide, an immunorestoring drug for the therapy of autoimmune disorders, especially rheuma-toid arthritis. Transplant. Proc. (1996) 28(6)3074–3078.
  • •This is a briefer but more recent review of LFM, including clinical data. 37.First approval for leflunomide. Scrip (1998) 2370:22.
  • ROZMAN B: Clinical experience with leflunomide in rheumatoid arthritis. J. Rheumatol. (1998) 25 (Suppl. 53):27–32.
  • GREENE S, WATANABE K, BRAATZ-TRULSON J, LOU L: In-hibition of dihydroorotate dehydrogenase by the im-munosuppressive agent leflunomide. Biochem. Pharmacol. (1995) 50 (6) :861–867.
  • CHERWINSKI HM, COHN RG, CHEUNG P et al. The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J. Pharmacol. Exp. Ther. (1995) 275(2):1043–1049.
  • WILLIAMSON RA, YEA CM, ROBSON PA et al.: Dihydro-°rotate dehydrogenase is a high affinity binding pro-tein for A771726 and mediator of a range of biological effects of the immunomodulatory compound. J. Biol. Chem. (1995) 270(38):22467–22472.
  • KNECHT W, BERGJOHANN U, GONSKI S, KIRSCHBAUM B, LOEFFLER M: Functional expression of a fragment of human dihydroorotate dehydrogenase by means of the baculovirus expression vector system, and kinetic investigation of the purified recombinant enzyme. Eur. j Biochem. (1996) 240:292–301.
  • DAVIS JP, CAIN GA, PITTS WJ, MAGOLDA RL, COPELAND RA: The immunosuppressive metabolite of leflu-nomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry (1996) 35:1270–1273.
  • FOX RI: Mechanism of action of leflunomide in rheu-matoid arthritis. J. Rheumatol. (1998) 25 (Suppl. 53):20–26.
  • ReCKEMANN K, FAIRBANKS LD, CARREY EA et al.: Leflu-nomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy hu-mans. J. Biol. Chem. (1998) 273(34):21682–21691.
  • •This paper summarises the mechanistic controversy around LFM, with many references, and provides evidence for DHODase inhibition as the major mechanism.
  • XU X, BLINDER L, SHEN J et al.: In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MIII/Mpj-lprilpr mice. J. Im-munol. (1997) 159:167–174.
  • SIEMASKO K, CHONG ASF, JACK H-M et al.: Inhibition of JAK3 and STAT6 tyrosine phorsphorylation by the im-munosuppressive drug leflunomide leads to a block in IgGi production. J. Immunol. (1998) 160:1581–1588.
  • SHAWVER LK, SCHWARTZ DP, MANN E et al.: Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by Is144- (trifluoro-methyl) -phenyl] 5-methylisoxazole-4-carboxamide. Clin. Cancer Res. (1997) 3:1167–1177.
  • KUO EA, HAMBLETON PT, KAY DP et al.: Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibi-tors: 2-cyano-3-cyclopropy1-3-hydroxy-N43'-methyl--4'-trifluoromethylphenyl]propenamide and related compounds. J. Med. Chem. (1996) 39:4608–4621.
  • ••This is a very thorough discussion of the SAR of LFM and me-tabolite analogues against both DHODase and immune models.
  • ALBERT R, KNECHT H, ANDERSEN E et al.: Isoxazolyl-thioamides as potential immunosuppressants. A com-binatorial chemistry approach. Bioorg. Med. Chem. Lett. (1998) 8:2203–2208.
  • BERTOLINI G, AQUINO M, BIFFI M et al.: New rational hypothesis for the pharmacophore of the active me-tabolite of leflunomide, a potent immunosuppressive drug. J. Med. Chem. (1997) 40:2011–2016.
  • PAPAGEORGIOU C, ZURINI M, WEBER H-P, BORERR X: Leflunomide's bioactive metabolite has the minimal structural requirements for the efficient inhibition of human dihydroorotate dehydrogenase. Bioorg. Chem. (1997) 25:233–238.
  • PAPAGEORGIOU C, ALBERT R, FLOERSHEIM P et al.: Pyrazole bioisosteres of leflunomide as B-cell immunosup-pressants for xenotransplantation and chronic rejections: scope and limitations. J. Med. Chem. (1998) 41:3530–3538.
  • •This paper describes interesting compounds related to the metabolite of LFM which show a divergence between immu-nosuppression and DHODase inhibition.
  • CLEAVELAND ES, MONKS A, VAIGRO-WOLFF A et al.: Site of action of two novel pyrimidine biosynthesis inhibi-tors accurately predicted by the COMPARE program. Biochem. Pharmacol. (1995) 49(7)947–954.
  • CLEAVELAND ES, ZAHAREVITZ DW, KELLEY JA et al.: Identification of a novel inhibitor (NSC 665564) of di-hydroorotate dehydrogenase with a potency equiva-lent to brequinar. Biochem. Biophys. Res. Commun. (1996) 223:654–659.
  • GUSTAFSON G, DAVIS G, WALDRON C, SMITH A, HENRY M: Identification of a new antifungal target site through a dual biochemical and molecular genetics approach. Curr. Genet. (1996) 30 (2) :159–165.
  • •This report suggests antifungal therapy as a target for DHODase inhibition.
  • BALKOVEC JM: Non-azole antifungal agents. Ann. Rep. Merl. Chem. (1998) 33:173–182.
  • MURRAY MC, PERKINS ME: Chemotherapy of malaria. Ann. Rep. Med. Chem. (1996) 31:141–150.
  • CHU DTW: Recent developments in antibacterial re-search. Ann. Rep. Med. Chem. (1998) 33:141–150.
  • WACHSMAN M, HAMZEH FM, ASSADI NB, LIETMAN PS: Antiviral activity of inhibitors of pyrimidine de novo biosynthesis. Antiviral Chem. Chemother. (1996) 7(1):7–13.
  • •This paper suggests that DHODase inhibition may be useful for some forms of antiviral therapy.
  • DAVIS JP, COPELAND RA: Histidine to alanine mutants of human dihydroorotate dehydrogenase. Identifica-tion of a brequinar-resistant mutant enzyme. Biochem. Pharmacol. (1997) 54(4):459–465.
  • BJOERNBERG O, ROWLAND P, LARSEN S, JENSEN KF: Ac-tive site of dihydroorotate dehydrogenase A from Lac-tococcus lactis investigated by chemical modification and mutagenesis. Biochemistry (1997) 36 (51) : 16197–16205.
  • ROWLAND P, NIELSEN FS, JENSEN KF, LARSEN S: The crystal structure of the flavin containing enzyme dihy-droorotate dehydrogenase A from Lactococcus lactis. Structure (London) (1997) 5(2):239–252.
  • ••This publication is the first report of detailed structural infor-mation for a DHODase.

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