Design, synthesis, and in vitro evaluation of a carbamazepine derivative with antitumor potential in a model of Acute Lymphoblastic Leukemia
Cristian Álvarez-Gómez, Angela V. Fonseca-Benítez, James Guevara-Pulido
Abstract
Acute lymphoblastic leukemia (ALL) is a significant concern in both pediatric and adult demographics. Despite 156 approved cancer therapies based on small molecules, a mere five apply to all types of leukemia. Unfortunately, adherence to these treatments is low due to adverse side effects. Consequently, there is an urgent need to identify more effective treatment options for ALL. This study presents a potential solution. We have designed over fifty analogs of carbamazepine, utilizing a combination of ligand-based and structure-based drug design methodologies.
Introduction
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. It is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone [1]. The American Cancer Society estimates that in 2023, the United States will see over 6,500 new cases and almost 1,400 deaths from acute lymphoblastic leukemia (ALL). Sixty percent of cases occur in children, peaking at ages 2–5 and another after age 50 [2].
Materials and method
Computer-aided drug design
To design molecules rationally, we conducted a literature search in public databases such as ChEMBL, DrugBank, and PubChem to find molecules that have shown biological activity against ALL and beta-tubulin. Then, we used two strategies for the chosen molecules.
Results and discussion
We identified over 150 anticancer molecules, with eight approved for treating acute lymphoblastic leukemia (ALL). Of these, 5 are small molecules: nelarabine (1), vincristine (2), etoposide (3), teniposide (4), and dactinomycin (5) (see Table 1). Additionally, we found 30 molecules specifically targeting beta-tubulin, a promising target because leukemic cells, like those in ALL, divide more rapidly than normal cells. This rapid division can enhance beta-tubulin expression, making these cells more vulnerable to microtubule-interfering agents, such as vincas (vincristine) and taxanes.
Acknowledgments
I want to thank the INQA group and the pharmaceutical chemistry program for their support at Universidad El Bosque in Bogotá, Colombia.
Citation: Álvarez-Gómez C, Fonseca-Benítez AV, Guevara-Pulido J (2025) Design, synthesis, and in vitro evaluation of a carbamazepine derivative with antitumor potential in a model of Acute Lymphoblastic Leukemia. PLoS One 20(4): e0319415. https://doi.org/10.1371/journal.pone.0319415
Editor: Sapan Kamleshkumar Shah, Priyadarshini JL College of Pharmacy, INDIA
Received: September 6, 2024; Accepted: February 1, 2025; Published: April 28, 2025
Copyright: © 2025 Álvarez-Gómez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
