Detail of "1118-89-4"

Reference

Methotrexate analogs

Methotrexate analogs. 10. Direct coupling of methotrexate and diethyl L-glutamate in the presence of peptide bond-forming reagents. Rosowsky, Andre; Yu, Cheng-Sein (Sidney Farber Cancer Inst., Harvard Med. Sch., Boston, Mass. 59-05-2 are also occured in this study., USA). J. Med. Chem., 21(2), 170-5 (English) 1978.Except for chemicals metioned above, 59-05-2 is also used. CODEN: JMCMAR. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) Section cross-reference(s): 28, 34 The reaction of methotrexate [59-05-2] with di-Et L-glutamate-HCl [1118-89-4] in the presence of peptide bond-forming reagents gave methotrexate g-L-glutamate di-Et ester (I) [65148-56-3], methotrexate a-L-glutamate di-Et ester (II) [65148-57-4], and methotrexate a,g-bis(L-glutamate tetra-Et ester) (III) [65148-60-9]. In the L1210 marine leukemia test, I and II increased median life span 40% and 10%, resp., while methotrexate gave a 60% increase. I was >10 times more active than II in vitro against lymphoblastic leukemia cells, while III was 2.4 times more active than its D,L,L diastereomer [65167-84-2]. ..

Benzoyl Ring Halogenated Classical 2-Amino-6-methyl-3,4-dihydro-4-oxo-5-substituted Thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine Antifolates as Inhibitors of Thymidylate Synthase and as Antitumor Agents

Benzoyl Ring Halogenated Classical 2-Amino-6-methyl-3,4-dihydro-4-oxo-5-substituted Thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine Antifolates as Inhibitors of Thymidylate Synthase and as Antitumor Agents. Gangjee, Aleem; Jain, Hiteshkumar D.; McGuire, John J.; Kisliuk, Roy L. (Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA). Journal of Medicinal Chemistry, 47(27), 6730-6739 (English) 2004 American Chemical Society. 1118-89-4 and 81542-91-8 are cas registry numbers. These chemicals are also mentioned in this article. CODEN: JMCMAR. ISSN: 0022-2623. DOCUMENT TYPE: Journal CA Section: 34 (Amino Acids, Peptides, and Proteins) Section cross-reference(s): 1, 7, 28 In an attempt to circumvent resistance to and toxicity of clin. used folate-based thymidylate synthase (TS) inhibitors that require folylpoly-g-glutamate synthetase (FPGS) for their antitumor activity, we designed and synthesized two classical 6-5 ring-fused analogs, N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5 -yl)thio]-2'-fluorobenzoyl]-L-glutamic acid (4) and N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5 -yl)thio]-2'-chlorobenzoyl]-L-glutamic acid (5), as TS inhibitors and antitumor agents. The key intermediates in the synthesis of these classical analogs were the mercaptans obtained from 2-halo-4-nitrobenzoic acids by redn. of the nitro groups followed by diazotization of the amines. The syntheses of analogs 4 and 5 were achieved via the oxidative addn. of the sodium salt of Et 2-halo-4-mercaptobenzoates to 2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine in the presence of iodine. The esters obtained from the reaction were deprotected and coupled with di-Et L-glutamate followed by sapon. Compds. 4 and 5 were both more potent inhibitors of human TS (IC50 values of 54 and 51 nM, resp.) than were PDDF and the clin. used ZD1694 and LY231514. Compds. 4 and 5 were not substrates for human FPGS up to 250 mM. In addn., 4 and 5 were growth inhibitory against CCRF-CEM cells as well as a no. of other tumor cell lines in culture, and protection studies established TS as the principal target of these analogs. .