Organometallic-Erlotinib Conjugates Active against Lung Cancer Cells and as Emerging Virus Entry Inhibitors

Abstract

Conjugation of organometallic entities to drug molecules is a strategy that often results in products with new biological activity profiles compared to those of their progenitors. In this study, we utilized CuAAC and RuAAC reactions to synthesize a series of organometallic-erlotinib conjugates. Erlotinib is an important anti-non-small cell lung cancer drug with epidermal growth factor receptor tyrosine kinase (EGFR TK) inhibitory activity. Our studies show that ferrocenyl-erlotinib conjugates are more anticancer active than their ruthenocenyl and [Re2(μ-Cl)2(CO)6(μ-1,2-diazine)] counterparts against lung cancer A549 and Calu3 cells. Our most active conjugate, 3, demonstrates an IC50 value of 2.33 ± 0.94 μM against erlotinib-resistant A549 cells. Its mechanism of anticancer action involves a combination of EGFR TK inhibitory activity and the capability to generate reactive oxygen species in lung cancer cells. Interestingly, one of the anticancer-inactive ruthenocenyl-erlotinib conjugates showed inhibitory activity toward the replication of influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells. Furthermore, the same compound inhibits the entry of coronavirus SARS-CoV-1 and -2 into host human HEK293T cells expressing ACE-2 and TMPRSS2. We showed that this anticoronavirus activity results from the inhibition of ACE-2/TMPRSS2-driven spike protein proteolytic activation. The question of whether the discovered virus entry inhibition mechanism involves direct binding of the conjugate to ACE-2 or involves additional mediators, such as EGFR, remains open.