Background: Breast cancer is the most frequent cancer among women. Chemotherapy is
necessary for treating metastatic disease and represents an important therapeutic approach, although
antineoplastic drugs have high toxicity and may be limited by the development of drug resistance.
These problems impose an urgent need to discover new anticancer agents and, so, arylsulfonylhydrazone
analogues were designed, synthesized, and evaluated with regard to their cytotoxic activity
against breast cancer cells in order to identify novel potential antitumor agents.
Methods: Synthesis was performed as previously described by Fernandes and co-workers. Cytotoxicity
of sulfonylhydrazones against MDA-MB-231, MCF-7 and 3T3 cells was evaluated by MTT
method. Apoptotic effects was verified by Annexin-V/PI assay, Hoechst stain and propidium iodide
stain. Molecular modeling was executed using Spartan’10 version 1.1.0. Geometry optimization
was performed by the MMFF, PM6 and Hartree-Fock 3-31G* methods and electronic and lipophilic
properties were computed.
Results: Thirteen analogues were synthesized, which 3f and 4f were cytotoxic against evaluated
breast cancer cells. The most promising compound, 3f, showed IC50 values equal to 104.6 and
142.4 µM for MDA-MB-231 and MCF-7, respectively. 3f induced apoptosis, causing phosphatidylserine
externalization, pyknosis, and cell cycle arrest in the G0/G1 phase in MDA-MB-231 breast
cancer cells. Furthermore, 3f was selective for tumor cells when compared to 3T3 fibroblasts. Structure-
activity relationship suggests that introduction of a benzodioxol group increased cytotoxicity
and superior lipophilicity may be related to superior activity.
Conclusion: Sulfonylhydrazone analogues presented good activity against breast cancer cells by
inducing apoptosis and might be a promising scaffold to further molecular modifications persuing
more effective antitumoral agents.
Background:
Glioblastoma is one of the most aggressive types of tumors, which occurs in the central nervous system, and has a high fatality rate. Among the cellular changes observed in glioblastoma is the overexpression of certain anti-apoptotic proteins, such as Bcl-xL. Recently, the alkaloid sanguinarine (SAN) was identified as a potent inhibitor of this class of proteins.
Objective:
In this work, the antitumor activity of ten aryl-isoquinolines that were synthesized based on molecular simplification of SAN was investigated.
Methods:
The SAN derivatives were prepared by Suzuki reaction and bimolecular nucleophilic substitution. The compounds were tested against glioblastoma (U87MG) and melanoma (A375) tumor lines in the MTT and SRB assay. The cell death mechanism was evaluated by flow cytometry. The molecular modeling study was used to evaluate the interactions between the prepared compounds and the Bcl-xL protein.
Results:
Analogues presented IC50 values against glioblastoma lower than temozolomide. Evaluation against astrocytes and fibroblasts indicated that the analogues were significantly superior to SAN regarding selectivity. The most active compound, 2e, induced phosphatidylserine externalization and mitochondrial membrane depolarization, indicating apoptotic death by the intrinsic pathway. In addition, 2e provides cell cycle arrest at the G2/M phase. Molecular dynamics suggested that 2e interacts with Bcl-xL mainly by hydrophobic interactions.
Conclusion:
In our study, aryl-isoquinoline represents a relevant scaffold to be explored by medicinal chemists to develop potential anti-glioblastoma agents.
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