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

Abstract

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 =1.4 μm). 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.

Recent Progress in Solid‐Phase Total Synthesis of Naturally Occurring Small Peptides

“…[67] With a free hydroxyl group of Ser5, it led to low efficiency of the esterification between Thr3 and Ile13, and severe epimerization in the following stepwise elongation, resulted in 1:1 epimer ratio. When a pseudoproline dipeptide of d-Orn4À Ser5 (85) was used as a protecting and turninducing group, the efficiency was improved, and epimerization was minimized to give paenibacterin A1 (88) in an overall 15% yield and paenibacterin A2 (89) in an overall 21% yield (Scheme 12).…”

“…So proline has a restricted ϕ angle and often acts as a turn inducer in peptide synthesis. In recent years, a series of naturally occurring peptides containing the Pro unit has been simply prepared by standard SPPS, such as cherimolacyclopeptide E, [86] carteritins A and B, [87] hymenamides C and D, [87] trichormamide A, [88] reniochalistatin AÀ E, [89] phakellistatin 13, [87] 17 and 18 [90] from the 2-CT-resin, whereas stylissatin A [91] from a 4-sulfamylbutyryl AM resin.…”