Identification of effective anticancer g-quadruplex-targeting chemotypes through the exploration of a high diversity library of natural compounds

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand individual natural products was investigated. The combination of molecular docking-based virtual screening and the G4-CPG experimental screening assay proved to be useful to quickly and effectively identify—out of many natural compounds—five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Indeed, the selected ligands proved to specifically interact with G4 structures due to peculiar interaction patterns, while they were unable to firmly bind to a DNA duplex. From biological assays, Chelidonine and Rotenone emerged as the most active compounds of the series against cancer cells, also showing good selectivity over normal cells. Notably, the anticancer activity correlated well with the ability of the two compounds to target telomeric G4s

The triprenylated anthranoid Ferruginin A, a promising scaffold for the development of novel antibiotics against Gram-positive bacteria

In today’s post-antibiotic era, the search for new antimicrobial compounds is of major importance and nature represents one of the primary sources of bioactive molecules. In this work, through a cheminformatics approach, we clustered an in-house library of natural products and their derivatives based on a combination of fingerprints and substructure search. We identified the preny-lated emodine-type anthranoid ferruginin A as a novel antimicrobial compound. We tested its ability to inhibit and kill a panel of Gram-positive and Gram-negative bacteria, and compared its activity with that of two analogues, vismione B and ferruanthrone. Furthermore, the capability of these three anthranoids to disrupt staphylococcal biofilm was investigated, as well as their effect on the viability of human keratinocytes. Ferruginin A showed a potent activity against both the planktonic and biofilm forms of Gram-positive bacteria (i.e., Staphylococcus aureus and S. epidermidis) and had the best therapeutic index compared to vismione B and ferruanthrone. In conclusion, ferruginin A represents a promising scaffold for the further development of valuable antimicrobial agents

A unique high-diversity natural product collection as a reservoir of new therapeutic leads

Plants represent a rich source of structurally diverse secondary metabolites, which can be exploited in the development of new clinically important compounds. Indeed, due to their biodiversity, medicinal plants represent the largest library of compounds that has ever existed. To date less than 1% of this vast biodiversity has been exploited in drug discovery, due to several factors, including the lack of an appropriate multidisciplinary perspective. Here we review the successful application of computer-aided methods in screening a unique and high-diversity in house collection library composed of around 1000 individual natural products, isolated mainly from indigenous plants collected in biodiversity-rich countries, especially of the tropics and subtropics, and enlarged with their semi-synthetic and synthetic derivatives, as well as plant material extracts, up to around 2000 components. During the last ten years, the in house library has provided several lead compounds that have been developed, and in some cases patented, as anticancer and antimicrobial agents. The main classes of the library are described, including (but not limited to) alkaloids, terpenoids, Diels-Alder-type adducts, isoflavones, chalcones, and cannabinoids. The main focus is on the chemical characteristics and biological activity of these identified compounds, with particular attention being given to those currently under patent or in the preclinical phase. We also assess the use of computer-aided methods in screening this unique and diverse in house collection of natural products that, over the last ten years, has provided some lead compounds that have been developed, and in some cases patented, as anticancer and antimicrobial agents. Finally, this review highlights the potential use of plant food extracts as a source of nutraceuticals and functional foods. The multidisciplinary approach described herein may further motivate research groups involved in natural product chemistry to potentially benefit from a limitless source of novel bioactive compounds

Chalcones and Chalcone-mimetic Derivatives as Notch blocking agents in T-cell acute lymphoblastic leukemia

The Notch signaling pathway is an inter-cellular communication system driving many biological processes in different tissues and in a wide spectrum of organisms. Indeed, it is considered a rationale target in the therapy of cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL).[1] Although the currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side effects, limiting their widespread therapeutic use. Since natural products have long been used as medicines for human diseases and are considered a relevant resource of lead compounds for drug discovery, an in house library of natural products and their derivatives was used as a potential source of inhibitors of the Notch signaling in T-ALL.[2] Eight representative molecules of the library were selected through a cheminformatics approach and tested in vitro. The chalcone scaffold emerged as a promising tool to inhibit Notch signalling; indeed, the synthesis of several chalcones combined with their biological evaluation highlighted the 2′,4-dihydroxy-4′-methoxychalcone (named chalcone 8) as the most potent Notch inhibitor of the series, suggesting the synergistic activity of 2′- and 4-hydroxyl groups.[2] Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were further designed and synthesized and their antiproliferative activity in KOPTK1 cells was evaluated.[3] Among them, 2’,4-dihydroxy-3-methyl-4’-methoxychalcone (compound 1) and 2,4-dimethoxyphenil-7-methoxy-1,2,3,4-tetrahydronaphtalen-2-yl-methanone (compound 18) proved to be new promising Notch-blocking agents, exhibiting cell growth reduction and inhibitory effects comparable to that of compound 8

Ent-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors

Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent-beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent-beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent-beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors