Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase.

Phenethyl-based edelfosine-analogs with saturated, monounsaturated, or polyunsaturated alkoxy substituents on phenyl ring were designed as novel antitumor lipids modulating p38 MAPK. Evaluation of the synthesised compounds against nine panels of diverse cancer cells presented saturated and monounsaturated alkoxy-substituted derivatives as the most active than other derivatives. In addition, ortho-substituted compounds were more active than meta- or ortho-substituted compounds. They were potential anticancer agents against blood, lung, colon, CNS, ovary, renal, and prostate cancers but not against skin nor breast cancers. Compounds, 1b and 1a emerged as the most potential anticancer agents. Assessment of compound 1b impact on p38 MAPK and AKT confirmed it as an inhibitor of p38 MAPK but not AKT. In silico study suggested compounds 1b and 1a as possible binders to the lipid binding pocket of p38 MAPK. Overall, compounds 1b and 1a as novel broad spectrum antitumor lipids modulating activity of p38 MAPK for further development.

Synthesis and biological evaluation of cyclopentane-linked alkyl phosphocholines as potential anticancer agents that act by inhibiting Akt phosphorylation.

Three new series of novel alkylphosphocholine (APC) derivatives containing a cyclopentane ring near the phosphocholine head group were synthesized. In the first set of analogues, the phosphocholine head group was attached to the secondary alcohol of trans-2-(hydroxymethyl)cyclopentanol, whereas in the second and third sets of analogues, the phosphocholine head group was linked to the primary alcohol of trans- and cis-2-(hydroxymethyl)cyclopentanol, respectively. Of the compounds synthesized, compound 6d most potently inhibited Akt phosphorylation with an IC(50) value of 3.6 µM, its potency was greater than the reference compounds miltefosine, perifosine, and erufosine. Compounds 6b and 6d exhibited the most potent growth-inhibitory effects on A549, MCF-7, and KATO-III human cancer cell lines. These compounds also showed more active anti-proliferative effects than the reference compounds. Importantly, the cytotoxic effects of these compounds on A549 cell line were proportional to their abilities to inhibit Akt phosphorylation, which supports that these synthesized APC compounds are novel inhibitors of the Akt cell survival pathway.