The essential role of folates in nucleic acid precursor biosynthesis has made folate metabolism an attractive antitumor target for decades. We have reported several thieno[2,3-d]pyrimidine, pyrrolo[2,3-d]pyrimidine, furo[2,3-d]pyrimidine classical antifolates as selective tumor targeting agents. These agents are selectively transported by the folate receptor (FR) and/or proton-coupled folate transporter (PCFT) rather than the ubiquitous reduced folate carrier (RFC). These compounds inhibit FR and PCFT expressing tumor cells (KB and IGROV1) at picomolar to nanomolar IC50 values. It is suggested in the literature for classical antifolates that a heteroatom in the 7- position of pyrimidine-fused five member rings or the 8- position of pyrimidine-fused six member rings play a crucial role in drug uptake. Although the literature is surfeit with the synthesis of fused pyrimidine bicyclic and tricyclic analogs, a viable synthetic method for substituted cyclopenta[d]pyrimidine analogs is conspicuously absent. As part of our continuing efforts to synthesize molecules with targeted tumor-specific attributes, we report a novel synthetic methodology for 5- and 6-subsituted cyclopenta[d]pyrimidine nonclassical and classical antifolates.

Novel synthetic methodology for 5- and 6-subsituted cyclopenta[<i>d</i>]pyrimidine nonclassical and classical antifolates as TS and DHFR inhibitors

248th National Meeting (2014)

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Novel synthetic methodology for 5- and 6-subsituted cyclopenta[d]pyrimidine nonclassical and classical antifolates as TS and DHFR inhibitors