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Graphical Abstract:

Modulation of PPAR-α by natural ligands is a novel strategy for the development of anticancer therapies. A series of 16 compounds based on the structure of 3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole (natural compound) with antitumour potential were designed and synthesised. The cytotoxicity and PPAR agonist activity of these synthetic 1,2,4-oxadiazoles were evaluated in the A-498 and DU 145 tumour cell lines. Preliminary biological evaluation showed that most of these synthetic 1,2,4-oxadiazoles are less cytotoxic (sulforhodamine B assay) than the positive control WY-14643. Regarding the PPAR-α modulation, compound 16was the most active, with EC50= 0.23–0.83 μM (PPAR-α). Additionally, compound 16had a similar activity to the natural compound (EC50= 0.18–0.77 μM) and was less toxic in the RPTEC and WPMY-1 cell lines (non-tumour cells) (CC50= 81.66–92.67 μM) than the natural compound. Looking at the link between chemical structure and activity, our study demonstrates that changes to the natural 1,2,4-oxadiazole at the level of the thiophenyl residue can lead to new agonists of PPAR-α with promising anti-tumour activity.

Graphical abstract:

Thirty-five macamide analogues were synthesised by modifying the initial molecular structure. The resulting structures were confirmed using NMR and MS. Cytotoxicity and the anti-inflammatory activity of these synthetic macamides were evaluated in the THP-1 cell line. Preliminary biological evaluation indicated that most of these synthetic macamides did not present cytotoxicity (MTT assay) in the tested cell line with respect to the control (actinomycin D). Regarding the anti-inflammatory activity, several analogues had a greater potential for inhibition of TNF-α than natural macamides. Synthetic macamide 4awas the most active (IC50= 0.009 ± 0.001 μM) compared to the C87 (control). Through looking at the link between the chemical structure and the activity, our study proves that changes made to natural macamides at the level of the alkyl chain, the benzyl position, the amide bond, and the addition of two methyl groups to the aromatic ring (metaposition) lead us to obtaining new macamides with greater anti-inflammatory activity.

Cybastacines A (1) and B (2) were discovered as a novel pentacyclic sesterterpenoid–alkaloid skeleton structure, with a guanidinium group. These molecules were isolated from a Nostocsp. cyanobacterium collected in the Canary Islands. Their structures were elucidated primarily by a combination of spectroscopic analyses and X-ray diffraction. These compounds showed antibiotic activities against several clinically relevant bacterial strains.