Ligand/PTC-free intramolecular Heck reaction: synthesis of pyrroloquinoxalines and their evaluation against PDE4/luciferase/oral cancer cell growth in vitro and zebrafish in vivo

Abstract

A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been designed for the potential inhibition of PDE4 without inhibiting luciferase. A ligand/PTC (phase transfer catalyst) free intramolecular Heck cyclization strategy was used to prepare these compounds, some of which showed significant inhibition of PDE4B (IC50≈ 5-14 μM) and growth inhibition of oral cancer cells (CAL 27) but not inhibition of luciferase in vitro. They also showed acceptable safety profiles but no apoptosis in zebrafish embryos.

Ligand-free Pd-catalyzed C–N cross-coupling/cyclization strategy: An unprecedented access to 1-thienyl pyrroloquinoxalines for the new approach towards apoptosis

“…A number of methods have been reported for the synthesis of 1-aryl substituted pyrrolo [2,3-b]quinoxalines by our group [5,10] and others [11]. For example, this class of compounds has been synthesized by the action of primary aliphatic or aromatic amines on 2-chloro-3-alkynylquinoxalines prepared via Sonogashira coupling of 2,3-dichloroquinoxaline and terminal alkynes [11d].…”

“…In our earlier effort we have reported a series of 1,3-disubstituted pyrrolo [2,3-b]quinoxalines [5] (A, Fig. 2) as inhibitors of PDE4 without inhibiting the luciferase [6].…”

Design, synthesis, and molecular modeling of heterocyclic bioisostere as potent PDE4 inhibitors

“…While PDE4 has been the target of several inflammatory diseases including COPD and asthma, recent studies have indicated that inhibition of PDE4 isoforms raises the levels of intracellular cAMP, induces apoptosis, causes cell cycle arrest in a broad spectrum of tumor cells, and regulates the tumor microenvironment . For example, rolipram ( 1 ) and roflumilast ( 2 ) have been proven to have the ability to attenuate lung carcinogenesis in benzo(a)pyrene‐induced murine lung cancer model in mice .…”

Novel Quinazolin‐4(3H)‐one/Schiff Base Hybrids as Antiproliferative and Phosphodiesterase 4 Inhibitors: Design, Synthesis, and Docking Studies

“…PDE4 has also been shown to play a role in the proliferation, angiogenesis, and motility of multiple cancer types . Furthermore, inhibition of PDE4 has been proven to have chemotherapeutic potential against different forms of cancer, including oral , brain , and pancreatic cancer types. Thus, the discovery of novel selective PDE4B inhibitors possessing antineoplastic activity is of great interest .…”