Synthesis and Anticancer Evaluation of Pyrrolo2,3-dpyrimidine-Based Derivatives

Pyrrolo2,3-dpyrimidine is a privileged fused heterocyclic scaffold that has attracted considerable attention in medicinal chemistry due to its diverse biological activities. Herein, we report an efficient synthesis strategy for the preparation of the pyrrolo2,3-dpyrimidine-based natural toyocamycin aglycone and pyrrolo2,3-dpyrimidine derivatives. The synthesis of toyocamycin aglycone features a key benzylamine nucleophilic substitution followed by a palladium-catalyzed cyanation reaction. From a key intermediate derived from this route, nineteen new pyrrolo2,3-dpyrimidine derivatives were rapidly synthesized via key Suzuki–Miyaura coupling and amine nucleophilic substitution reactions. Their cytotoxic activities were evaluated against Huh-7 and HepG liver cancer cell lines. Most derivatives were inactive after 24 h. However, 28a–28c, 28e and 28f exhibited moderate cytotoxicity with IC50 values ranging from 5.7 to 62.6 μM. Among them, compound 28e displayed the highest potency against HepG cells, with IC50 values of 5.7 μM. Compared with normal HEK293 cells, it showed a selectivity index (SI) of 3.60 against HepG cells. Preliminary structure-activity relationship analysis suggested that incorporation of a cyclopropyl group further improves antitumor activity.