title: 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.
authors: Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, 13563-120, São Carlos-SP, Brazil.
authors: Luma G
authors: LG
authors: Magalhaes
authors: Laboratório de Diversidade Molecular e Química Medicinal, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23897-000, Seropédica-RJ, Brazil.
authors: Fernando B
authors: FB
authors: Marques
authors: Laboratório de Diversidade Molecular e Química Medicinal, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23897-000, Seropédica-RJ, Brazil.
authors: Marina B
authors: MB
authors: da Fonseca
authors: Laboratório de Diversidade Molecular e Química Medicinal, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23897-000, Seropédica-RJ, Brazil.
authors: Kamilla R
authors: KR
authors: Rogério
authors: Laboratório de Diversidade Molecular e Química Medicinal, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23897-000, Seropédica-RJ, Brazil.
authors: Cedric S
authors: CS
authors: Graebin
authors: Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, 13563-120, São Carlos-SP, Brazil.
authors: Adriano D
authors: AD
authors: Andricopulo
mesh_terms: D000166:Acridines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000737:chemistry; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D014404:Tubulin; D050257:Tubulin Modulators; D011034:Podophyllotoxin; D003078:Colchicine