Cancer Cells Show\nHigher Sensitivity to Melatonin-Tamoxifen\nDrug Conjugates than to Combination of Melatonin and Tamoxifen

Drug conjugates of tamoxifen and melatonin linked through\nthe amide\nside chain of melatonin (<b>4a</b>,<b>4b</b>) were reported\nas promising agents for future treatment of breast cancer, possibly\nreversing the adverse effects of tamoxifen. Here, we report the synthesis\nand pharmacological evaluation of a novel series of anticancer drug\nconjugates linking melatonin with tamoxifen through polymethylene\nspacers through the ether oxygen of melatonin (<b>16a</b>–<b>c</b>, <b>19a</b>–<b>c</b>, <b>21</b>) and compare them to the previously reported amide-linked analogues <b>4a</b> and <b>4b</b>. All hybrid ligands are antagonists\nof estrogen receptor alpha and agonists of the melatonin MT<sub>1</sub> receptor with variable potencies. Several drug conjugates including\nthe (CH<sub>2</sub>)<sub>4</sub>-linked analogues <b>4a</b> and <b>16a</b> and the (CH<sub>2</sub>)<sub>6</sub>-linked compound <b>16c</b> showed higher potency to inhibit cell viability than the\ncombination of melatonin and tamoxifen on at least one cancer cell\nline including MCF-7, MDA-MB-231, and HT-1080.