Synthesis and Biological Evaluation of Reniochalistatins A–E and a Reniochalistatin E Analogue

Graphical Sponging up SAR data : The marine sponge Reniochalina stalagmitis is the source of a set of cyclic peptides known as reniochalistatins. Herein we report the total synthesis of reniochalistatins A–E, along with evaluations of their anticancer and antitubercular activities. Our results pave the way for further investigations into the structure–activity relationships of this class of cyclic peptide. The total synthesis of reniochalistatins A–E, along with a reniochalistatin E analogue (inverso-E) was successfully achieved through Fmoc-based solid-phase peptide synthesis and subsequent macrolactamization with PyBOP and DIEA. The biological activities of these reniochalistatins and a key linear peptide intermediate were systematically evaluated. Among these seven synthesized compounds, linear reniochalistatin B was found to have potent activity against several cancer cell lines not shown by the cyclic reniochalistatin B counterpart. In addition, linear reniochalistatin B was found to have antitubercular activity (IC 50 =1.4 μ m ). Inverso-E possesses increasing cytotoxicity against the HeLa and LNCaP cell lines after simple alternation of the sequence of amino acids in reniochalistatin E. The results of these studies provide a feasible method to further investigate the structure–activity relationships (SARs) of reniochalistatins A–E.