Phenotypic screening has played a fundamental role in drug discovery by providing new molecular entities. In order to sustain further discoveries by phenotypic screening, we are in great need to access novel chemical space. Privileged chemical scaffolds are potential ligands to a diverse array of receptors and thus novel chemical space resulting from privileged chemical scaffolds can provide the basis to discover novel bioactive compounds with drug-like properties. Pyrroloquinazoline-1,3-diamine  is a privileged chemical scaffold with significant biological activities. However, the currently accessible chemical space is rather limited. In particular, the regioselectively mono-N-acylated chemical space has been untapped likely due to the significant challenges in rapidly preparing these compounds. However, such compounds are expected to significantly modulate the electrostatics of the structure core and are the potential chemical space to discover novel biologically active leads. In this presentation, we will describe our efficient methodology to rapidly synthesize mono-N-acylated products at N1, N3 and N7 of pyrroloquinazoline-1,3-diamine. This methodology effectively exploits the distinct differences in nucleophilicity and pKa of the three ionizable nitrogen atoms. To demonstrate the biological utility of this expanded chemical space, a phenotypic anti-breast cancer screen was performed against the newly synthesized library. Distinct structure-activity relationship patterns were observed with these regioisomers. A potent and nontoxic anti-breast cancer agent with N3-(2-naphthoyl) group was identified with a unique mechanism of action.

Discovery of a potent anti-breast cancer agent from expanded chemical space of pyrrolo[3,2-<i>f</i>]quinazoline-1,3-diamines

246th National Meeting (2013)

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Discovery of a potent anti-breast cancer agent from expanded chemical space of pyrrolo[3,2-f]quinazoline-1,3-diamines