Novel 5‑Substituted
Pyrrolo[2,3‑<i>d</i>]pyrimidines as Dual Inhibitors
of Glycinamide Ribonucleotide
Formyltransferase and 5‑Aminoimidazole-4-carboxamide Ribonucleotide
Formyltransferase and as Potential Antitumor Agents
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Abstract
A new series of 5-substituted thiopheneyl
pyrrolo[2,3-<i>d</i>]pyrimidines <b>6</b>–<b>11</b> with varying chain
lengths (<i>n</i> = 1–6) were designed and synthesized
as hybrids of the clinically used anticancer drug pemetrexed (PMX)
and our 6-substituted thiopheneyl pyrrolo[2,3-<i>d</i>]pyrimidines <b>2c</b> and <b>2d</b> with folate receptor (FR) α and
proton-coupled folate transporter (PCFT) uptake specificity over the
reduced folate carrier (RFC) and inhibition of de novo purine nucleotide
biosynthesis at glycinamide ribonucleotide formyltransferase (GARFTase).
Compounds <b>6</b>–<b>11</b> inhibited KB human
tumor cells in the order <b>9</b> = <b>10</b> > <b>8</b> > <b>7</b> > <b>6</b> = <b>11</b>. Compounds <b>8</b>–<b>10</b> were variously
transported by FRα,
PCFT, and RFC and, unlike PMX, inhibited de novo purine nucleotide
rather than thymidylate biosynthesis. The antiproliferative effects
of <b>8</b> and <b>9</b> appeared to be due to their dual
inhibitions of both GARFTase and 5-aminoimidazole-4-carboxamide ribonucleotide
formyltransferase. Our studies identify a unique structure–activity
relationship for transport and dual target inhibition