New derivatives bearing alkyl phosphonic acid moieties as a promising scaffold against drug-resistant H69AR small cell lung cancer models

Abstract

Small cell lung cancer (SCLC), although less common than non-small cell lung cancer (NSCLC), is an aggressive and lethal form of lung cancer. Even if it was diagnosed and started being treated early, it still contributes to poor survival rates. Standard therapies, including platinum-based chemotherapy and immune checkpoint inhibitors, offer limited and short-lived benefits due to the rapid disease relapse and widespread metastasis. One of the promising strategies for the new drug against SCLC development is the rational design of 9H-carbazole or other structurally similar chromophores with an alkyl phosphonic acid moiety, expecting dual-targeting ability, potentially targeting both nuclear and cytoplasmic effectors involved in SCLC progression and resistance. The aim of this work was to synthesise phenothiazine, phenoxazine, anthraquinone and substituted carbazole derivatives, containing an alkyl phosphonic acid moiety and to evaluate their in vitro antiproliferative activity using the well-established anthracycline-resistant H69AR small cell lung cancer (SCLC) cell model. The results demonstrate that 9H-carbazole derivatives bearing alkyl phosphonic acid groups could be explored as a promising scaffold class for the further development of compounds against drug-resistant SCLC.