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1.
ACS Med Chem Lett ; 4(11): 1059-63, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24900605

ABSTRACT

A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.

2.
Bioorg Med Chem Lett ; 17(8): 2241-5, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17306533

ABSTRACT

DNA microarray analysis comparing human tumor tissues with normal tissues including hematopoietic progenitor cells resulted in identification of membrane dipeptidase as a prodrug activation enzyme. Novel prodrugs of 2'-deoxy-2'-methylidenecytidine (DMDC) including compound 23 that are activated by membrane dipeptidase (MDP) preferentially in tumor tissue were designed and synthesized to generate the active drug, DMDC, after hydrolysis of the dipeptide bond followed by spontaneous cyclization of the promoiety.


Subject(s)
Antineoplastic Agents/chemical synthesis , Deoxycytidine/analogs & derivatives , Dipeptidases/metabolism , Drug Design , Gene Expression Regulation, Neoplastic , Prodrugs/chemical synthesis , Prodrugs/metabolism , Antineoplastic Agents/pharmacokinetics , Deoxycytidine/chemistry , Deoxycytidine/metabolism , Deoxycytidine/pharmacokinetics , Dipeptidases/genetics , Humans , Hydrolysis , Membrane Proteins , Neoplasm Proteins/metabolism , Oligonucleotide Array Sequence Analysis , Structure-Activity Relationship , Tumor Cells, Cultured
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