SummaryInitially, the Atherton–Todd (AT) reaction was applied for the synthesis of phosphoramidates by reacting dialkyl phosphite with a primary amine in the presence of carbon tetrachloride. These reaction conditions were subsequently modified with the aim to optimize them and the reaction was extended to different nucleophiles. The mechanism of this reaction led to controversial reports over the past years and is adequately discussed. We also present the scope of the AT reaction. Finally, we investigate the AT reaction by means of exemplary applications, which mainly concern three topics. First, we discuss the activation of a phenol group as a phosphate which allows for subsequent transformations such as cross coupling and reduction. Next, we examine the AT reaction applied to produce fire retardant compounds. In the last section, we investigate the use of the AT reaction for the production of compounds employed for biological applications. The selected examples to illustrate the applications of the Atherton–Todd reaction mainly cover the past 15 years.

Edelfosine is an inhibitor of SK3 channel mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, (125)I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC(50) of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.

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