Structure-Based Bioisosterism Design, Synthesis, Antitumor and Toxicity Assessment of Novel Aplysinopsin Analogs

Eight new LQFM's Aplysinopsin analogs (12a-h) were synthesized and were evaluated for their anticancer profile on MCF-7 (breast cancer), SiHA and HeLa (cervical cancer). The compounds were obtained through the rational drug design strategy, bioisosterism, by changing the indole scaffold of Aplysinopsin by phenylpyrazole, a subunit extensively explored for designing potent and selective anticancer agents. The synthesis was performed in three simple steps, followed by structural elucidation through nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry, and global yield ranged from 10% to 93%. Regarding the biological assay, the best result was achieved with 12g, which showed antiproliferative activity against all cell lines evaluated, with IC₅₀ 59.22, 58.33, and 55.32 μM for MCF-7, SiHA and HeLa, respectively. The safety profile, in the Zebrafish-based model, showed the mortality rate for 12g in concentration-time-dependent, from 87 μM, over 120 h. All Aplysinopsin analogs demonstrated drug-likeness in agreement to Lipinski and Veber rules. Although the moderate antiproliferative activity displayed by 12g, our results include new Aplysinopsin analogs that may be promising lead compounds for further studies, since chemical structures related to this marine compound have provided satisfactory results as anticancer agents against a variety of human tumor cell lines.