Assessment of in vitro and in silico Antiproliferative Effects of p-Cymene and Its Naturally Occurring 7-Oxygenated Derivatives on Human Cancer Cell Lines.

To evaluate the in vitro and silico antiproliferation of p-cymene, cumin aldehyde, cuminic acid, and cuminol against human cancer cell lines (HCCLs). The sodium salt of the organic acid was included after synthesis. The quality of the compounds was verified using analytical methods. A primary screening of the compounds at 100 µM was conducted (n=6) on nine HCCLs (SK-MEL-28, K562, Lucena, Jurkat, Caco-2, MDA-MB-231, THP-1, U87-MG, and Calu-3) and HEK-293 through the MTT method after 48h-incubation. The viability curve and apoptotic and necrotic cell populations of cumin aldehyde-treated Calu-3 cells were determined. The statistical significance relative to the vehicle was evaluated using ANOVA and Dunnett. The possibility of being active (Pa) on HCCLs and biological targets was assessed in silico using CLC-Pred. Moreover, the ADMET properties were predicted using three servers. Only cumin aldehyde induced a low and significant (31±5%, p<0.001) in vitro antiproliferation, and even then, only on the Calu-3 line (IC50 650 µM). Only necrosis was significant (p<0.01) with 300 µM after 24h. The absence (p>0.05) of in vitro activity on the other HCCLs corroborated the low in silico probability of being active (Pa≤0.33), except for cumin aldehyde on the MDA-MB-231 line (Pa=0.47). P-cymene was proven to be the most toxic compound to human health. Excepting cumin aldehyde, the lack of the antiproliferation potential of these p-cymene derivatives was extensively demonstrated for the first time. Cuminaldehyde induced toxicity in a lung adenocarcinoma line, corroborating the literature. Six selective and three specific cell lines were proposed to evaluate the anticancer activity of the compounds in addressed studies, mainly involving those with Pa≥0.50. The inhibition of five targets seems to play a role in inducing HCCL antiproliferation. The ADMET estimated that cumin aldehyde, cuminol, and sodium cuminate are the safest compounds for human use.