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.
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