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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 25, Number 12
BKCSDE 25(12)
December 20, 2004 

Synthesis of Nonclassical Quinazolinone Antifolates as Thymidylate Synthase Inhibitors and Their Antitumor Activity In Vitro
Du-Jong Baek*, Tae-Beom Kang, Hyun Ju Kim
Quinazolinone, Nonclassical antifolates, Thymidylate synthase inhibitors, In vitro antitumor activity
Nonclassical quinazolinone analogs I, II, and III, in which the glutamic acid moiety of the classical antifolates is substituted by phenylglycine, phenylalanine or aminobenzoic acid and their methyl esters, were synthesized and evaluated as lipophilic inhibitors of thymidylate synthase (TS). The target compounds were generally potent inhibitors of L. casei and human TS with IC50 values within the narrow range of 0.2-10 μM and 0.003-0.03 μM, respectively. Further, most of the target compounds showed cytotoxicity against tumor cell lines of murine and human origin with IC50 values of as low as 0.050 μM. Substitution of another hydroxyl or carboxylic acid/ester group at the phenyl ring further increased the potency of TS inhibition and cell growth inhibition. Most effective were compounds If and Ic in which extra carboxylic acid/ester was present at the phenyl ring with nanomolar IC50 values of 0.0044 and 0.0093 μM against human TS and submicromolar cytotoxic growth inhibition against all four tumor cell lines.
1898 - 1906
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