Synthesis and cytotoxic activities of goniothalamins and derivatives.

Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity. In our studies only (R)-configured goniothalamins showed antiproliferative activity, whereby (R)-configuration accords to natural goniothalamin (R)-1. Additionally, the δ-lactone needs to be unsaturated whereas our results show that the vinylic double bond is not mandatory for cytotoxicity. Furthermore, with a two-fold in vitro and in vivo strategy, we determined the inhibitory effect of the compounds to the yeast protein Pdr5. Here, we clearly demonstrate that the configuration seems to be of minor influence, only, while the nature of the substituent of the phenyl ring is of prime importance.

Translating observed household energy behavior to agent-based technology choices in an integrated modeling framework.

Decarbonizing the building sector depends on choices made at the household level, which are heterogeneous. Agent-based models are tools used to describe heterogeneous choices but require data-intensive calibration. This study analyzes a novel, cross-country European household-level survey, including sociodemographic characteristics, energy-saving habits, energy-saving investments, and metered household electricity consumption, to enhance the empirical grounding of an agent-based residential energy choice model. Applying cluster analysis to the data shows that energy consumption is not straightforwardly explained by sociodemographic classes, preferences, or attitudes, but some patterns emerge. Income consistently has the largest effect on demand, dwelling efficiency, and energy-saving investments, and the potential to improve a dwellings' energy use affects the efficiency investments made. Including the various sources of heterogeneity found to characterize the model agents affects the timing and speed of the transition. The results reinforce the need for grounding agent-based models in empirical data, to better understand energy transition dynamics.

Selective inhibition of P-gp transporter by goniothalamin derivatives sensitizes resistant cancer cells to chemotherapy.

Overexpression of efflux transporters of the ATP-binding cassette (ABC) transporter family, primarily P-glycoprotein (P-gp), is a frequent cause of multidrug resistance in cancer and leads to failure of current chemotherapies. Thus, identification of selective P-gp inhibitors might provide a basis for the development of novel anticancer drug candidates. The natural product goniothalamin and 21 derivatives were characterized regarding their ability to inhibit ABC transporter function. Among the goniothalamins, selective inhibitors of P-gp were discovered. The two most potent inhibitors (R)-3 and (S)-3 displayed the ability to increase intracellular accumulation of doxorubicin, thereby sensitizing P-gp-overexpressing tumor cells to chemotherapy by decreasing doxorubicin IC50 value up to 15-fold. Molecular docking studies indicated these compounds to inhibit P-gp by acting as transporter substrates. In conclusion, our findings revealed a novel role of goniothalamin derivatives in reversing P-gp-mediated chemotherapy resistance.

Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5.

Multidrug resistance (MDR) in tumors and pathogens remains a major problem in the efficacious treatment of patients by reduction of therapy options and subsequent treatment failure. Various mechanisms are described to be involved in the development of MDR with overexpression of ATP-binding cassette (ABC) transporters reflecting the most extensively studied. These membrane transporters translocate a wide variety of substrates utilizing energy from ATP hydrolysis leading to decreased intracellular drug accumulation and impaired drug efficacy. One treatment strategy might be inhibition of transporter-mediated efflux by small molecules. Isocoumarins and 3,4-dihydroisocoumarins are a large group of natural products derived from various sources with great structural and functional variety, but have so far not been in the focus as potential MDR reversing agents. Thus, three natural products and nine novel 3,4-dihydroisocoumarins were designed and analyzed regarding cytotoxicity induction and inhibition of human ABC transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) in a variety of human cancer cell lines as well as the yeast ABC transporter Pdr5 in Saccharomyces cerevisiae. Dual inhibitors of P-gp and BCRP and inhibitors of Pdr5 were identified, and distinct structure-activity relationships for transporter inhibition were revealed. The strongest inhibitor of P-gp and BCRP, which inhibited the transporters up to 80 to 90% compared to the respective positive controls, demonstrated the ability to reverse chemotherapy resistance in resistant cancer cell lines up to 5.6-fold. In the case of Pdr5, inhibitors were identified that prevented substrate transport and/or ATPase activity with IC50 values in the low micromolar range. However, cell toxicity was not observed. Molecular docking of the test compounds to P-gp revealed that differences in inhibition capacity were based on different binding affinities to the transporter. Thus, these small molecules provide novel lead structures for further optimization.

New Colchicine-Derived Triazoles and Their Influence on Cytotoxicity and Microtubule Morphology.

A series of new colchicinoids with a variable triazole unit at C-7 was synthesized through Cu(I)-catalyzed 1,3-dipolar cycloaddition (click-chemistry) of a colchicine-derived azide with various alkynes and the cytotoxicity against THP-1 and Jurkat cancer cell lines was used for structural optimization. Three particularly active compounds (IC50 ≤ 5 nM) were additionally investigated with respect to their efficacy against relevant solid tumor cell lines (HeLa, A549, and SK MES 1). Besides distorting the microtubule morphology by tubulin depolymerization, one compound also exhibited a pronounced centrosome declustering effect in triple negative breast cancer cells (MDA-MB-231) and nonsmall cell lung cancer cells (H1975).