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.