Synthesis and Antiproliferative Activity Evaluation of the Disulfide-Containing Cyclic Peptide Thiochondrilline C and Derivatives

Abstract

Thiochondrilline C (4) was previously isolated from Verrucisispora sp. and reported to have moderate cytotoxicity against human lung adenocarcinoma cells. Herein, we report the synthesis of thiochondrilline C by N-terminal peptide extension, oxidative disulfide bond formation, and heterocycle installation as key steps. Antiproliferative activities for the prepared natural product and several derivatives against the NCI 60 cancer cell line panel are also described. Derivative 22 was identified as a moderately potent antiproliferative agent (50% growth inhibition (GI50) = 0.2-12.2 μM) with leukemia (average GI50 = 1.8 ± 0.1 μM) and colon (average GI50 = 2.4 ± 0.3 μM) cells being most sensitive.

Marine natural products

“…112 A number of successful synthetic and biosynthetic studies have been realised. These included peptide-based targets such as marthiapeptide, 113,114 the disulde-containing peptide thiochondrilline C, 115,116 bogorol A and the more thermodynamicallyfavoured (Z) isomer, 117,118 the siderophores amphibactin-T 119 and moanachelin ala-B. 120,121 The rst synthesis of fradcarbazole 122 was by semi-synthesis 123 from staurosporine.…”

Thiocoraline mediates drug resistance in MCF-7 cells via PI3K/Akt/BCRP signaling pathway

“…However, the Phase II trials were uniformly disappointing, with minimal to no activity against cervical squamous cell carcinoma (Dawson et al 2007). Both thiocoraline and echinomycin work by inhibiting the hypoxia inducible factor-1 (HIF-1) (Kong et al 2005;Vippila et al 2015), which bind to hypoxia response elements (HRE), resulting in the suppression of the growth of cancer cells (Wang et al 2011). Thiocoraline is now moving close to clinical development (Dawson et al 2007).…”

Divergent Approach for the Synthesis of Gombamide A and Derivatives

“…Our laboratory has become interested in synthesizing and evaluating disulfide-containing cyclic peptide natural products and derivatives as potential pharmacological probes. For example, we recently reported the synthesis and antiproliferative activity evaluation of thiochondrilline C and several derivatives …”

“…This material was treated with piperidine and then coupled with Fmoc-L-Pyr-OH using EDC and HOAt to generate 3 in 82% yield. The hexapeptide was then exposed to iodine to mediate oxidative disulfide bond formation that provided the cyclic peptide 11 in 83% yield. , Deprotection of the tert -butyl ester was carried out with trifluoroacetic acid to generate the corresponding carboxylic acid 2 in 79% yield.…”

“…For example, we recently reported the synthesis and antiproliferative activity evaluation of thiochondrilline C and several derivatives. 3 Gombamide A (1) is a disulfide-containing cyclic peptide recently isolated from the marine sponge Calthria gombawuiensis. 4 In addition, one of the cysteine residues that comprise the disulfide is linked to pyroglutamic acid while the other is attached to a styrylamide moiety, an uncommon functional group among isolated natural products.…”