Discovery of a Series of Acridinones as Mechanism-Based Tubulin Assembly Inhibitors with Anticancer Activity

Abstract

Microtubules play critical roles in vital cell processes, including cell growth, division, and migration. Microtubule-targeting small molecules are chemotherapeutic agents that are widely used in the treatment of cancer. Many of these compounds are structurally complex natural products (e.g., paclitaxel, vinblastine, and vincristine) with multiple stereogenic centers. Because of the scarcity of their natural sources and the difficulty of their partial or total synthesis, as well as problems related to their bioavailability, toxicity, and resistance, there is an urgent need for novel microtubule binding agents that are effective for treating cancer but do not have these disadvantages. In the present work, our lead discovery effort toward less structurally complex synthetic compounds led to the discovery of a series of acridinones inspired by the structure of podophyllotoxin, a natural product with important microtubule assembly inhibitory activity, as novel mechanism-based tubulin assembly inhibitors with potent anticancer properties and low toxicity. The compounds were evaluated in vitro by wound healing assays employing the metastatic and triple negative breast cancer cell line MDA-MB-231. Four compounds with IC50 values between 0.294 and 1.7 μM were identified. These compounds showed selective cytotoxicity against MDA-MB-231 and DU-145 cancer cell lines and promoted cell cycle arrest in G2/M phase and apoptosis. Consistent with molecular modeling results, the acridinones inhibited tubulin assembly in in vitro polymerization assays with IC50 values between 0.9 and 13 μM. Their binding to the colchicine-binding site of tubulin was confirmed through competitive assays.

Centrosome – a promising anti-cancer target

“…This target has been demonstrated to be successful due to the effects of taxanes (paclitaxel and docetaxel) and vinca alkaloids (vinblastine, vincristine, and vinorelbine) 112. Paclitaxel, vinblastine, and vincristine are well-known compounds clinically used for targeting tubulin as their mechanisms of action 113,114.…”

From Medicinal Chemistry to Human Health: Current Approaches to Drug Discovery for Cancer and Neglected Tropical Diseases

“…2). With the goal of identifying structurally non-complex molecules resembling the binding properties of podophyllotoxin, this approach led to the characterization of a series of acridinones as novel microtubule destabilizers (Magalhaes et al 2016). Following this strategy, a series of azaanalogues of podophyllotoxin that contain only one chiral center was synthesized using a one-step multicomponent reaction.…”

Planejamento e caracterização de moduladores da proteína tubulina candidatos a fármacos para o tratamento do câncer

“…As acridinonas 1-4 foram identificadas durante o desenvolvimento de um trabalho de mestrado em nosso grupo, a partir de uma série de 16 compostos. 51,78 Estes…”

“…86 Verificou Os resultados de inibição da polimerização da tubulina corroboram os estudos de docagem molecular que realizamos anteriormente. 78 As poses geradas para os isômeros S em geral apresentaram energias de ligação mais favoráveis. Além disso, a inspeção visual dos resultados também nos levou a concluir que este seria o isômero com maior probabilidade de interagir com o sítio da colchicina.…”