Synthesis and structure–activity relationships studies of brartemicin analogs as anti-invasive agents

Abstract

Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to find more potent anti-invasive agents and study the structure-activity relationships, a series of 19 brartemicin analogs were prepared via two synthetic routes from α,α-D-trehalose and evaluated for their anti-invasive activities. Compound 4f, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, was more potent than the natural brartemicin. It inhibited the invasion of murine colon 26-L5, colon carcinoma SW620, melanoma B16-BL6 and breast MDA-MB-231 cells with IC50 values of 0.15, 2.35, 4.12 and 2.61 μM, respectively. Analog 4p, 6,6'-bis(3,4-dimethoxycinnamoyl)-α,α-D-trehalose, was as potent as brartemicin against invasion of murine colon 26-L5 carcinoma cells in vitro. The structure-activity relationships of these novel trehalose-based compounds were summarized.

The secondary metabolites of rare actinomycetes: chemistry and bioactivity

“…One analog was as potent as brartemicin against the invasion of murine colon 26-L5 carcinoma cells in vitro. 105 As potent antibacterial agents, actinomadurol (65) (for Staphylococcus aureus, Proteus hauseri and Kocuria rhizophila; MIC values ¼ 0.39-0.78 mg mL À1 ) 23 and nocardithiocin (207) (towards rifampicin-resistant and -sensitive Mycobacterium tuberculosis strains, most of which were inhibited at concentrations of 0.025-1.56 mg mL À1 ) 66 have shown excellent antimicrobial activities. As for potent antifungal agents, the new compounds A4 (177) and A5 (178) have displayed signicant inhibition towards the fungi M. ramannianus, A. carbonarius and P. expansum.…”

Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

“…The natural product brartemicin is a TDE with two substituted benzoates esterified to the 6- and 6′-positions ( 8a , Figure 4 ). Brartemicin ( 8a ) was recently isolated from the culture broth of an actinomycete of the genus Nonomuraea and the natural product, along with synthetic analogs ( 66 ), were found to have an inhibitory effect on cancer cell invasion ( 67 ). Given the structural resemblance of brartemicin to other trehalose-based Mincle ligands, there has been much interest in determining whether brartemicin and/or analogs can bind and activate Mincle.…”

The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle

“…As a side note, both these compounds were reported to have anti-invasive activity on cancer cells in the same range as brartemicin. 7 Structurally, these two analogs provide preliminary information about the importance of the substitution pattern on the aromatic rings for mediating binding to the mincle CRD. In order to investigate the importance of the dimeric structure, we prepared monoester derivative 4 starting from the monoacetate of protected α,α-trehalose using a mitsunobu esterification protocol.…”

“…However, the direct binding targets of these compounds and the molecular mechanisms by which they work remain obscure. 7 …”