Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents

[EN] The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondriadirected vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 mM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon coadministration with a pump-efflux inhibitor.We thank Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033, and Junta de Andalucia (FQM134) for financial support. A.P. and J.M.P. thank the Spanish Government (PGC2018-094503-B-C22, MCIU/AEI/FEDER, UE) and the Canary Islands Government (ProID2020010101, ACIISI/FEDER, UE) for financial support. A.P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS2020010055. J.D. and M.P thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (451-03-9/2021e14/200007). This work was performed within the framework of COST Action CA17104 STRATAGEM -"New diagnostic and therapeutic tools against multidrug resistant tumors". We would also like to thank the Servicio de Resonancia Magn~etica Nuclear, CITIUS (University of Seville) for the performance of NMR experiments.Hicke-García, FJ.; Puerta, A.; Dinic, J.; Pesic, M.; Padrón, JM.; López, Ó.; Fernández-Bolaños, JG. (2022). Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents. European Journal of Medicinal Chemistry. 228:1-16. https://doi.org/10.1016/j.ejmech.2021.11398011622

Applied mathematics and nonlinear sciences in the war on cancer

Cancer is a major health problem in the industrialized world being the second leading cause of death in the USA and EU after heart disease. A huge quantity of resources is spent every year on cancer research, resulting in a small, yet sustained, reduction in cancer death rates (in the last ten years this was about 1 − 2% per year in the US) [1]. However, there is a widespread concern about the slow pace at which these discoveries in fundamental biology are translated into safe and effective clinical interventions. Statistics is already considered to be a basic ingredient of medical education and routinely used in research, specifically in clinical studies. This is so even when many physicians have a limited understanding of statistics and risk analysis [2]. However, the potential of other mathematical tools such as differential equations, advanced numerical methods, optimization, etc, have not been broadly incorporated into medical research on clinical care. This is so in spite of the fact that these methods are part of the standard toolbox of the applied mathematician that have proven useful in many other fields of science and engineering.VMP-G is partially supported by Ministerio de Economía y Competitividad/FEDER (MINECO), Spain [grant numbers: MTM2012-31073 and MTM2015-71200-R], Consejería de Educación Cultura y Deporte from Junta de Comunidades de Castilla-La Mancha (Spain) [grant number PEII-2014-031-P] and James S. Mc. Don-nell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (Special Initiative Collaborative - Planning Grant 220020420 and Collaborative award 220020450). PSG is supported by MINECO under grants RD12/0036/0027 and SAF2015-65175-R. We would like to acknowledge MôLAB members (Universidad de Castilla-La Mancha, Spain) Juan Belmonte-Beitia, Gabriel F. Calvo and Alicia Martínez-González for a critical reading of the manuscript.S

Anticancer properties of the abietane diterpene 6, 7-dehydroroyleanone obtained by optimized extraction

Aim: 6,7-dehydroroyleanone (DHR) is a cytotoxic abietane present in the essential oil of Plectranthus madagascariensis. Methods/results: Different extraction parameters were tested, and its extraction optimization was accomplished with a Clevenger apparatus-based hydrodistillation. After isolation, its effect on microtubules, P-glycoprotein and caspases was assessed on several cell lines and the compound was coupled with hybrid nanoparticles. The results show that DHR does not interfere with microtubule formation, but evades the resistance mechanisms of P-glycoprotein. Strong activation of caspases-3 and -9 indicates that DHR is able to induce apoptosis by triggering the intrinsic cell death pathway. Moreover, the assembly of DHR with hybrid nanoparticles was able to potentiate the effect of DHR in cancer cells. Conclusion: DHR seems to be a promising starting material with anticancer properties to further be explored.This work was supported by PADDIC 2016 and 2017 (ALIES-COFAC) as part of the PhD Program in Health Sciences from Universidad de Alcalá de Henares and Universidade Lusófona de Humanidades e Tecnologias. The authors would like to thank Diogo Ladeiras for the collaboration in the HPLC work. The authors would also like to thank to Fundação para a Ciência e Tecnologia for the financial support under the reference UID/DTP/04567/2016 – CBIOS/PRUID/BI1/2017, and the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant number III41031). This work was performed within the framework of COST Action CM1407 (challenging organic syntheses inspired by nature – from natural products chemistry to drug discovery)

Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors

Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in Plectranthus spp. The cytotoxic diterpene 6,7-dehydroroyleanone (1) is the main component of the P. madagascariensis (Pers.) Benth. essential oil, while 7α-acetoxy-6β-hydroxyroyleanone (2) can be isolated from acetonic extracts of P. grandidentatus Gürke. The reactivity of the natural royleanones 1 and 2 was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-O-tert-butyl-carbonate-royleanone (20), 6,7-dehydro-12-O-methylroyleanone (21), 6,7-dehydro-12-O-benzoylroyleanone (22), and 7α-acetoxy-6β-hydroxy-12-O-benzoylroyleanone (23) were obtained as pure with overall modest to excellent yields (21–97%). P-gp inhibition potential of the derivatives 20–23 was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6β-benzoyloxy-12-O-(4-chloro)benzoylroyleanone (4), has also been tested. The P-gp inhibiting effects of compounds 1–4 were also assessed through a Rhodamine 123 accumulation assay. Derivatives 4 and 23 have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound 4 presented higher anti-P-gp potential than the natural diterpenes 1, 2, and 3, with comparable inhibitory potential to Dexverapamil. Moreover, derivative 4 showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin