Synthesis and Reactivity of Oligo(ethylene glycol)-Tethered Morita–Baylis–Hillman Dimers in the Formation of Macrocyclic Structures Showing Remarkable Cytotoxicity

<b>Background/Objectives</b>: Crown ethers have received increasing interest owing to their ability to form stable complexes with cations. This molecular feature has been successfully exploited in the development of biologically relevant ionophores. <b>Methods</b>: In order to obtain innovative crown ethers derivatives, a Morita-Baylis-Hillman adduct (MBHA) acetate (<b>4</b>) bearing a phenylacetylene moiety was dimerized via the click-chemistry CuAAC reaction with oligo(ethylene glycol) diazide derivatives to build-up a small series of dimeric MBHA derivatives (<b>5a-d</b>). These dimeric MBHA derivatives were reacted with n-butylamine to afford tunable macrocyclic crown ether-paracyclophane hybrid architectures (<b>6a-d</b>). <b>Results</b>: Compounds (<i>E</i>,<i>Z</i>)-<b>6a</b>, (<i>E</i>,<i>E</i>)-<b>6a</b>, <b>6b-d</b> showed, in human breast cancer MDA-MB-231 and human melanoma A375 cells, IC₅₀ values comparable with those of reference anticancer agent Doxorubicin. <b>Conclusions</b>: This exploration approach provides original new macrocyclic architectures potentially useful as anticancer agents.