ChemInform Abstract: Design and Synthesis of Cyclopenta[g]quinazoline‐Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents.

Abstract

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Development and Binding Mode Assessment of N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic Acid (BGC 945), a Novel Thymidylate Synthase Inhibitor That Targets Tumor Cells

“…35,36 Among other improvements, this route did not require the cobalt catalyst system used in earlier routes. 31,32 A molar yield of 13.3% with respect to the tricyclic acid starting material was achieved in very good quality. The purity results were 99.5% of area percent basis (a/a) by achiral HPLC, 99.6% enantiomeric excess (ee) 6S chiral purity, and 99.8% L,D diastereomeric purity (see Experimental Section).…”

“…The inhibitor 1 (Figure and Scheme A) belongs to a series of cyclopenta([ g ]quinazoline-based antifolates for which synthesis and development have been described previously. , These compounds were synthesized by stepwise addition of a p -aminobenzoate moiety, an N10-substituent, and a dipeptide moiety to a cyclopenta[ g ]quinazoline ring. Importantly, an l -Glu-γ- d -Glu dipeptide moiety replaces the glutamate moiety present in other antifolates. , Further intracellular polyglutamylation of TS antifolate inhibitors by folate polyglutamate synthase increases their affinity for TS. , The l -Glu-γ- d -Glu dipeptide moiety of 1 serves the same purpose as the polyglutamate tail, increasing affinity for TS through electrostatic interactions with the positively charged polyglutamate-binding groove on the enzyme.…”

“…The d -Glu protects 1 from peptide hydrolases in the cell. As mentioned above, several routes of synthesis of 1 are reported. , For preparation of the sample for X-ray crystallography as well as the initial phase I clinical study drug substance, an innovative four-stage synthetic route was evolved and conducted under Good Manufacturing Practices at Regis Technologies, Inc. (Morton Grove, IL) (Scheme ). , Among other improvements, this route did not require the cobalt catalyst system used in earlier routes. , A molar yield of 13.3% with respect to the tricyclic acid starting material was achieved in very good quality. The purity results were 99.5% of area percent basis (a/a) by achiral HPLC, 99.6% enantiomeric excess (ee) 6 S chiral purity, and 99.8% l , d diastereomeric purity (see Experimental Section).…”

“…The inhibitor 1 (Figure 1 and Scheme 1A) belongs to a series of cyclopenta([g]quinazoline-based antifolates for which synthesis and development have been described previously. 31,32 These compounds were synthesized by stepwise addition of a p-aminobenzoate moiety, an N10-substituent, and a dipeptide moiety to a cyclopenta[g]quinazoline ring. Importantly, an L-Glu-γ-D-Glu dipeptide moiety replaces the glutamate moiety present in other antifolates.…”

“…As mentioned above, several routes of synthesis of 1 are reported. 31,32 For preparation of the sample for X-ray crystallography as well as the initial phase I clinical study drug substance, an innovative four-stage synthetic route was evolved and conducted under Good Manufacturing Practices at Regis Technologies, Inc. (Morton Grove, IL) (Scheme 1). 35,36 Among other improvements, this route did not require the cobalt catalyst system used in earlier routes.…”