Discovering and validating effective drugs to manage arthropod-borne diseases (ABD) is a timely and important research challenge with major impacts on real-world control programs at the time of quick resistance development in the targeted pathogens. This editorial highlights major research advances in the development of drugs for the control of vector-borne diseases, with a significant focus on malaria, Chagas disease, dengue, human African trypanosomiasis, leishmaniasis, and Zika. Broad reviews providing new insights on ABD recently published in Molecules have also been covered in “The Editors’ pick” section.

https://www.mdpi.com/1420-3049/25/21/5175/pdf

Arthropod-Borne Disease Control at a Glance: What's New on Drug Development?

A world tour in the name of natural products.

The Aurora kinases, including Aurora A, B and C, play critical roles in cell division. They have been found overexpressed in a number of types of cancer and may thus be potential targets in cancer therapy. Several Aurora kinase inhibitors have been identified and developed. Some of these have been used in clinical trials and have exhibited certain efficacy in cancer treatment. However, none of these has yet been applied clinically due to the poor outcomes. Oxostephanine is an aporphine alkaloid isolated from several plants of the genus Stephania. This compound has been reported to inhibit Aurora kinase activity in kinase assays and in cancer cells. The present study aimed to investigate the real-time effects of oxostephanine extracted from Stephania dielsiana Y.C. Wu leaves on the growth of an ovarian cancer cell line (OVCAR-8, human ovarian carcinoma); these effects were compared to those of the well-known Aurora kinase inhibitor, VX-680. The effects of oxostephanine on stromal cells, as well as endothelial cells were also examined. The results demonstrated that oxostephanine was an Aurora kinase inhibitor through the prevention of histone H3 phosphorylation at serine 10, the mislocalization of Aurora B and the induction of aneuploidy. Moreover, this substance was selectively cytotoxic to human umbilical vein endothelial cells (hUVECs), whereas it was less cytotoxic to human fibroblasts and umbilical cord-derived mesenchymal stem cells. In addition, this compound significantly attenuated the migration and tube formation ability of hUVECs. Taken together, the present study demonstrates that oxostephanine plays dual roles in inhibiting Aurora kinase activity and angiogenesis. Thus, it may have potential for use as a drug in cancer treatment.

Dual roles of oxostephanine as an Aurora kinase inhibitor and angiogenesis suppressor

https://figshare.com/articles/journal_contribution/Two_new_monoterpene_esters_from_i_Illigera_paviflora_i_Dunn_roots/21401709/1/files/37998084.pdf

Two new monoterpene esters from <i>Illigera paviflora</i> Dunn roots

Chalcones have a three-carbon α,β-unsaturated carbonyl system composed of two phenolic rings. Many chalcones have shown broad spectrum of biological activities with clinical potentials against various diseases. They are usually abundant in seeds, fruit skin, bark and flowers of most edible plants. Among them, chalcones bearing 2-hydroxy-3-methyl-3-butenyl (HMB) group have been reported several times in the past few decades due to their novel scaffolds and numerous interesting biological activities. In this paper, we reviewed the isolation of twelve natural chalcones and a natural chalcone-type compound bearing 2-hydroxy-3-methyl-3-butenyl group discovered so far, and reviewed their synthesis methods and biological activities reported in the literature. We anticipate that this review will inspire further research of natural chalcones.

Progress of isolation, chemical synthesis and biological activities of natural chalcones bearing 2-hydroxy-3-methyl-3-butenyl group

Natural products remain a viable source of novel therapeutics, and as detection and extraction techniques improve, we can identify more molecules from a broader set of plant tissues. The aim of this study was an investigation of the cytotoxic and anti-plasmodial activities of the methanol extract from Stephania dielsiana Y.C. Wu leaves and its isolated compounds. Our study led to the isolation of seven alkaloids, among which oxostephanine (1) is the most active against several cancer cell lines including HeLa, MDA-MB231, MDA-MB-468, MCF-7, and non-cancer cell lines, such as 184B5 and MCF10A, with IC50 values ranging from 1.66 to 4.35 μM. Morever, oxostephanine (1) is on average two-fold more active against cancer cells than stephanine (3), having a similar chemical structure. Cells treated with oxostephanine (1) are arrested at G2/M cell cycle, followed by the formation of aneuploidy and apoptotic cell death. The G2/M arrest appears to be due, at least in part, to the inactivation of Aurora kinases, which is implicated in the onset and progression of many forms of human cancer. An in-silico molecular modeling study suggests that oxostephanine (1) binds to the ATP binding pocket of Aurora kinases to inactivate their activities. Unlike oxostephanine (1), thailandine (2) is highly effective against only the triple-negative MDA-MB-468 breast cancer cells. However, it showed excellent selectivity against the cancer cell line when compared to its effects on non-cancer cells. Furthermore, thailandine (2) showed excellent anti-plasmodial activity against both chloroquine-susceptible 3D7 and chloroquine-resistant W2 Plasmodium falciparum strains. The structure-activity relationship of isolated compound was also discussed in this study. The results of this study support the traditional use of Stephania dielsiana Y.C. Wu and the lead molecules identified can be further optimized for the development of highly effective and safe anti-cancer and anti-plasmodial drugs.

Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds.

Many agents targeting the colchicine binding site in tubulin have been developed as potential anticancer agents. However, none has successfully made it to the clinic, due mainly to dose limiting toxicities and the emergence of multi-drug resistance. Chalcones targeting tubulin have been proposed as a safe and effective alternative. We have shown previously that quinolone chalcones target tubulin and maintain potent anti-proliferative activity vis-a-vis colchicine, while also having high tolerability and low toxicity in mouse models of cancer and refractivity to multi-drug resistance mechanisms. To identify the most effective anticancer chalcone compound, we synthesized 17 quinolone-chalcone derivatives based on our previously published CTR-17 and CTR-20, and then carried out a structure-activity relationship study. We identified two compounds, CTR-21 [((E)-8-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] and CTR-32 [((E)-3-(3-(2-ethoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] as potential leads, which contain independent moieties that play a significant role in their enhanced activities. At the nM range, CTR-21 and CTR-32 effectively kill a panel of different cancer cells originated from a variety of different tissues including breast and skin. Both compounds also effectively kill multi-drug resistant cancer cells. Most importantly, CTR-21 and CTR-32 show a high degree of selectivity against cancer cells. In silico, both of them dock near the colchicine-binding site with similar energies. Whereas both CTR-21 and CTR-32 effectively prevents tubulin polymerization, leading to the cell cycle arrest at G2/M, CTR-21 has more favorable metabolic properties. Perhaps not surprisingly, the combination of CTR-21 and ABT-737, a Bcl-2 inhibitor, showed synergistic effect in killing cancer cells, since we previously found the "parental" CTR-20 also exhibited synergism. Taken together, CTR-21 can potentially be a highly effective and relatively safe anticancer drug.

/pdf/lead-optimization-of-novel-quinolone-chalcone-compounds-by-a-23m0l8cnz9.pdf

James Knockleby

Papers

Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds.

Lead optimization of novel quinolone chalcone compounds by a structure-activity relationship (SAR) study to increase efficacy and metabolic stability.