Abstract
The Blue Biotechnology and Ecotoxicology Culture Collection (LEGE-CC) holds a vast number of cyanobacteria whose chemical richness is still largely unknown. To expedite its bioactivity screening we developed a natural products library. Sixty strains and four environmental samples were chromatographed, using a semiautomatic HPLC system, yielding 512 fractions that were tested for their cytotoxic activity against 2D and 3D models of human colon carcinoma (HCT 116), and non-cancerous cell line hCMEC/D3. Six fractions showed high cytotoxicity against 2D and 3D cell models (group A), and six other fractions were selected by their effects on 3D cells (group B). The metabolome of each group was organized and characterized using the MolNetEnhancer workflow, and its processing with MetaboAnalyst allowed discrimination of the mass features with the highest fold change, and thus the ones that might be bioactive. Of those, mass features without precedented identification were mostly found in group A, indicating seven possible novel bioactive molecules, alongside in silico putative annotation of five cytotoxic compounds. Manual dereplication of group B tentatively identified nine pheophytin and pheophorbide derivatives. Our approach enabled the selection of 7 out of 60 cyanobacterial strains for anticancer drug discovery, providing new data concerning the chemical composition of these cyanobacteria.
Highlights
Natural products continue to inspire many drug discovery programs; as such, more than sixty percent of the approved drugs comprise natural products, their synthetic derivatives, and their pharmacophore-inspired drugs [1]
In the last 10 years, LEGE-CC has had a significant increase in the number of deposited strains; its associated drug discovery has not been able to keep the same pace
As a possible solution for this problem, we designed a methodology for a cyanobacterial natural products library (LEGE-NPL)
Summary
Natural products continue to inspire many drug discovery programs; as such, more than sixty percent of the approved drugs comprise natural products, their synthetic derivatives, and their pharmacophore-inspired drugs [1]. Since the 1970s, more than 1630 unique cyanobacterial compounds have been described [3], mainly belonging to the classes of non-ribosomal peptides (NRPs), ribosomally synthesized and post translationally-modified peptides (RiPPs), polyketides (PKs), and the hybrid NRPs/PKs [3,4]. These hybrid molecules contribute to the diversity of structural motifs found in cyanobacterial compounds. Its synthetic derivatives monomethylauristatins yielded four approved antibody drug conjugates: Adcetris (2011) and Polivy (2019), used for the treatment of lymphoma; Padcev (2019), applied for the treatment of urinary tract cancers; and Blenrep (2020), for the treatment of relapsed and refractory multiple myeloma [6]
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