Synthesis and Evaluation of Several 3,4-Seco-Derivatives of Myricerone as Endothelin Receptor Antagonists

Cardiovascular diseases have been designated as a global health problem, with the number of reported cases increasing rapidly each year throughout the world in the populations of both developing and developed countries [1]. Endothelin-1 (ET-1) is a potent vasoconstrictor protein composed of 21 amino acids and was first isolated by Yanagisawa et al. [2] in 1988 from porcine aortic endothelial cells. ET-1 exhibits selective binding affinity for the ETA receptor, which has been shown to mediate vasoconstriction as well as the proliferation of vascular smooth muscle cells. One of the most important factors in the regulation of blood pressure is the vasoconstrictory action of vascular smooth muscle cells, which is caused by ETA receptor antagonists. Several research groups have been involved in the search for novel endothelin receptor antagonists from natural sources. Myricerone is an ETA receptor antagonist isolated from Myrica cerifera, and several synthetic analogues of this compound have been developed as potent and specific ETA receptor antagonists [3]. In this paper, we report our work on the modification of myricerone with the aim of developing novel ETA receptor antagonists with improved levels of activity. It was envisaged that a series of novel 3,4-seco-derivatives of myricerone (1) could be constructed according to the synthetic strategy shown in Scheme 1, with the Baeyer–Villiger oxidation reaction being used as the key step.