The chemistry and pharmacology of privileged pyrroloquinazolines

Abstract

The advent of next-generation sequencing (NGS) technology has plummeted the cost of whole genome sequencing, which has provided a long list of putative drug targets for a variety of diseases ranging from infectious diseases to cancers. The majority of these drug targets are still awaiting high-quality small molecule ligands to validate their therapeutic potential and track their druggability. Screening compound libraries based on privileged scaffolds is an efficient strategy to identify potential ligands to distinct biological targets. 7H-Pyrrolo[3,2-f]quinazoline (PQZ) is a potential privileged heterocyclic scaffold with diverse pharmacological properties. A number of biological targets have been identified for different derivatives of PQZ. This review summarized the synthetic strategies to access the chemical space associated with PQZ and discussed their unique biological profiles.

Design, synthesis and evaluation of antitumor acylated monoaminopyrroloquinazolines

“…1 These structures are great starting points to discover small molecule ligands to different classes of biomolecules including proteins and nucleic acids. 1,2 Perhaps the most prominent member among the privileged scaffolds is benzodiazepine which has been shown to present numerous biological activities including γ-aminobutyric acid (GABA) receptor modulation, 3,4 cholecystokinin (CCK) receptor modulation 5-7 and apoptosis-inducing activity. 8,9 In medicinal chemistry, structure-activity relationship (SAR) studies on privileged structures are generally highly productive with clearly discernible SAR patterns.…”

“…2,10 7 H -Pyrrolo[3,2- f ]quinazoline-1,3-diamine ( 1 , Figure 1) was originally synthesized as a dihydrofolate reductase (DHFR) inhibitor in the 1970s. 11 Over the ensuing four decades, derivatives of 1 have been shown to display additional biological activities by inhibiting diverse targets including G-protein coupled protease-activated receptors (PARs), 12 protein tyrosine phosphatase 1B (PTP1B) 13 and serum paraoxonase (PON).…”

“…11 Over the ensuing four decades, derivatives of 1 have been shown to display additional biological activities by inhibiting diverse targets including G-protein coupled protease-activated receptors (PARs), 12 protein tyrosine phosphatase 1B (PTP1B) 13 and serum paraoxonase (PON). 2,14 During this period, the chemical space associated with 1 was heavily investigated, most of which focused on different alkyl groups of varying hydrophobicity at N -7. 2 Recently, we further expanded the chemical space associated with 1 through developing a unique suite of methods to regioselectively mono- N -acylate the three nucleophilic nitrogens in 1 (i.e.…”

“…2,14 During this period, the chemical space associated with 1 was heavily investigated, most of which focused on different alkyl groups of varying hydrophobicity at N -7. 2 Recently, we further expanded the chemical space associated with 1 through developing a unique suite of methods to regioselectively mono- N -acylate the three nucleophilic nitrogens in 1 (i.e. N- 1, N- 3 and N- 7) (Figure 1).…”

“…10 It is obvious that both the sterics and electronics around position 1 of the pyrroloquinazoline nucleus are significantly different between 2b and 4b (Figure 2), suggesting that this structural change will further enhance the diversity of the chemical space belonging to pyrroloquinazoline. 2 In this report, we describe the synthesis and anticancer potential of a series of such compounds 4 .…”