- Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen
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A series of Glutaryl-Hyp-Ala-Ser-Chg-Gln-4-aminobenzyl phosphoramide mustard conjugates (1a-e) was designed and synthesized as potential prodrugs for site-specific activation by PSA in prostate cancer cells. All conjugates were found to be substrates of PSA with cleavage occurring between Gln and the para-aminobenzyl (PAB) linker. Structure-activity relationship studies on these conjugates indicated that introduction of electron-withdrawing fluorine(s) on the phenyl ring in the PAB linker uniformly improved the chemical stability of the conjugates while the position of substitution affected differently the self-immolative process of conjugates upon proteolysis. Introduction of a fluorine at ortho position to benzylic phosphoramide as in 1b results in better stability of the conjugate prior to activation while maintaining its antiproliferative activity upon activation by PSA. The conjugate 1b with 2-fluoro substitution was identified as a promising lead for further evaluation and optimization in the development of prostate cancer-targeted prodrugs.
- Wu, Xinghua,Hu, Longqin
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p. 2697 - 2706
(2016/06/08)
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- HYDRAZONE COMPOUNDS AND THEIR USE
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The present invention relates to hydrazone compounds of Formula I: (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R1, R2, R3, R4, L1, and L2 are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I as inhibitors of TRPM5 protein.
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Page/Page column 133
(2010/12/17)
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- BENZAMIDE DERIVATIVES
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The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds in the treatment of pain.
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Page/Page column 68
(2010/04/27)
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- 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
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In an attempt to circumvent resistance to and toxicity of clinically used folate-based thymidylate synthase (TS) inhibitors that require folylpoly-γ-glutamate synthetase (FPGS) for their antitumor activity, we designed and synthesized two classical 6-5 ring-fused analogues, 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 analogues were the mercaptans 10 and 11, which were obtained from the corresponding nitro compounds 6 and 7 respectively, by reduction of the nitro groups followed by diazotization of the amines. The syntheses of analogues 4 and 5 were achieved via the oxidative addition of the sodium salt of ethyl 2-halo-substituted-4-mercaptobenzoate (16 or 17) to 2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyirolo[2,3-d]pyrimidine (18) in the presence of iodine. The esters obtained from the reaction were deprotected and coupled with diethyl-L-glutamate followed by saponification. Compounds 4 and 5 were both more potent inhibitors of human TS (IC50 values of 54 and 51 nM, respectively) than were PDDF and the clinically used ZD1694 and LY231514. Compounds 4 and 5 were not substrates for human FPGS up to 250 μM. In addition, 4 and 5 were growth inhibitory against CCRF-CEM cells as well as a number of other tumor cell lines in culture, and protection studies established TS as the principal target of these analogues.
- Gangjee, Aleem,Jain, Hiteshkumar D.,McGuire, John J.,Kisliuk, Roy L.
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p. 6730 - 6739
(2007/10/03)
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- Anti-cancer compounds
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Quinazolines of the formula: STR1 wherein R1 -R8 are defined as in the specification, or a pharmaceutically acceptable salt, ester or amide thereof areof therapeutic value, particularly in the treatment of cancer.
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