Reacciones de cicloadición [4+2] inter-e intramolecular para la síntesis de quinolinas fosforadas y naftiridinas como inhibidores enzimáticos

364 p.En esta tesis doctoral, se han estudiado diferentes metodologías para la síntesis de quinolinas fosforadas y naftiridinas fusionadas con otros heterociclos mediante la reacción de Povarov. Además, se ha utilizado la reacción de Povarov en su forma intermolecular e intramolecular dando lugar a una amplia gama de heterociclos nitrogenados. Además, se ha evaluado la actividad biológica de los compuestos.Por un lado, se estudió el comportamiento de los aductos sintetizados como inhibidores de topoisomerasa I humana y topoisomerasa I de leishmania.Por otro lado, se ha evaluado la actividad antiproliferativa de los compuestos sintetizados en diferentes líneas celulares cancerosas de pulmón (A549), ovario (SKOV3), riñón (HEK3) y mama (BT20), así como en una línea de células de pulmón no cancerosas (MRC5)

Reacciones de cicloadición [4+2] inter-e intramolecular para la síntesis de quinolinas fosforadas y naftiridinas como inhibidores enzimáticos

364 p.En esta tesis doctoral, se han estudiado diferentes metodologías para la síntesis de quinolinas fosforadas y naftiridinas fusionadas con otros heterociclos mediante la reacción de Povarov. Además, se ha utilizado la reacción de Povarov en su forma intermolecular e intramolecular dando lugar a una amplia gama de heterociclos nitrogenados. Además, se ha evaluado la actividad biológica de los compuestos.Por un lado, se estudió el comportamiento de los aductos sintetizados como inhibidores de topoisomerasa I humana y topoisomerasa I de leishmania.Por otro lado, se ha evaluado la actividad antiproliferativa de los compuestos sintetizados en diferentes líneas celulares cancerosas de pulmón (A549), ovario (SKOV3), riñón (HEK3) y mama (BT20), así como en una línea de células de pulmón no cancerosas (MRC5)

Synthesis of Heterocyclic Fused [1,5]naphthyridines by Intramolecular HDA Reactions

Povarov reaction [1] can be considered as an example of HDA reactions and represents an excellent method for the preparation of nitrogen-containing heterocyclic compounds [2]. When aldimines, derived from aromatic amines and unsaturated functionalized aldehydes, are treated with a Lewis acid, the Povarov reaction takes place intramolecularly [3]. In this work, the synthesis of new families of heterocyclic fused [1,5]naphthyridines is reported. In this way, via an efficient and straightforward intramolecular Povarov reaction catalyzed by boron trifluoride etherate, tetrahydro-6H-chromeno[4,3-b][1,5]naphthyridines and tetrahydro-6Hquinolino[ 4,3-b][1,5]naphthyridines are obtained. Dehydrogenation of tetrahydroderivatives with DDQ gives compounds 6H-chromeno[4,3-b][1,5]naphthyridine and 6H-quinolino[4,3-b][1,5]naphthyridine. This methodology allows access to novel compounds with biological activity. Based on the success of camptothecin (CPT) and its derivatives as inhibitors of Topoisomerase I (TopI) [4], as well as our results obtained with naphthyridine derivatives [5], we report here that these novel heterocyclic compounds are possible candidates, some of them showing excellent activity as TopI inhibitors. The cytotoxic effect on several cancer and noncancer cell lines was also screened

Kanptotezina eta haren deribatuak minbiziaren aurkako borrokan: Topoisomerasa I inhibitzaileak

ABSTRACT: Cancer has been identified as one of the leading causes of death worldwide, claiming almost 10 million lives by 2020, according to the WHO. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds that may behave as topoisomerase I inhibitors with antiproliferative effect has become an active field of research. Investigation related to topoisomerase I inhibitors in cancer therapy started with camptothecin (CPT). This compound was first selected as a good anticancer agent and then topoisomerase I was identified as its therapeutic target. CPT and its derivatives (irinotecan, topotecan and belotecan) are the only clinically approved inhibitors. Currently, their limitations are being addressed by means of the use of combination therapies with different drugs, drugs combined with antibodies, adoption of protocols to increase the bioavailability, such as administration of nanoparticles, emulsions, liposomes. Future studies should focus not only on developing other active molecules, but also on improving the bioavailability and pharmacokinetics of potent synthetic derivatives.; Minbizia heriotza-eragile nagusienen artean azaltzen da mundu mailan; 2020an, esaterako, 10 milioi heriotza inguru eragin zituen, WHO (World Health Organization) erakundearen arabera. Minbiziaren aurkako tratamendu farmakologikoari dagokionez, agente kimioterapiko eraginkorrenen artean balidatuta dago topoisomerasa I (TOP1, DNAren metabolismoan era zuzenean parte hartzen duen entzima) aparteko itu terapeutiko gisa. Era honetan, molekula antiproliferatibo berrien garapenerako interes handiko ikerketa arloa bilakatu da TOP1 inhibitzeko gai diren konposatu kimiko berrien sintesia. Historiari begiratuz, kanptotezina (KPT) izan zen aurkitu zen lehen giza topoisomerasa I (TOP1)-en inhibitzailea, 70eko hamarkadan. Harrezkero, KPTren eratorri sintetiko seguruagoak garatu dira (irinotekan, topotekan eta belotekan besteak beste), gaur egun erabilera klinikorako onarpena jaso duten TOP1 inhibitzaile bakarrak, alegia. Hala eta guztiz ere, bigarren belaunaldiko KPTren eratorri sintetiko hauek eragozpen kimiko anitz erakusten dituzte, haien erabilera klinikoa erabat mugatzen dutenak. Gaur egungo erreferentziazko ikerketen norabidea da, molekula aktibo berrien sintesiaz gain, KPTren eratorrien eta bestelako hautagai terapeutiko potentzialen eraginkortasuna eta aktibitate biologikoa hobetzea, hala nola farmako konbinazio sinergikoak bilatuz eta konposatu kimikoen farmakozinetika modulatuz

Hydrogen sulphide-triggered theranostic prodrugs based on the dynamic chemistry of tetrazines

[EN] Dynamic nucleophilic aromatic substitution of tetrazines (S(N)Tz) has been employed to build theranostic prodrugs that are activated by hydrogen sulfide. H2S is typically found in high concentrations in some kinds of cancer cells and it is able to trigger the disassembly of tetrazine prodrugs. In such a way, a dual release of drugs and/or fluorescent compounds can be selectively triggered.This work was financially supported by Ministerio de Ciencia e Innovación (PGC2018-094503-B-C21). J.S. thanks Cabildo de Tenerife for the Agustín de Betancourt programme. M.D.P thanks the ACIISI and the European Social Fund (ESF) for a predoctoral grant

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined.This research was funded by the Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI), Fondo Europeo de Desarrollo Regional (FEDER; RTI2018-101818-B-I00, UE) and by Gobierno Vasco, Universidad del País Vasco (GV, IT 992-16; UPV)

Fused 1,5-Naphthyridines: Synthetic Tools and Applications

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.Financial support from the Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI), Fondo Europeo de Desarrollo Regional (FEDER; RTI2018-101818-B-I00, UE), and by Gobierno Vasco, Universidad del País Vasco (GV, IT 992-16; UPV) is gratefully acknowledged

A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.This research was funded by Agnes og Poul Friis Fond (81008-003), Købmand Sven Hansen og Hustru Ina Hansens Fond, Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) y Fondo Europeo de Desarrollo Regional (FEDER; RTI2018-101818-B-I00, UE), and by Gobierno Vasco, Universidad del País Vasco (GV, IT 992-16; UPV)

Novel topoisomerase I inhibitors. Syntheses and biological evaluation of phosphorus substituted quinoline derivates with antiproliferative activity

This work describes the synthesis of 1,2,3,4-tetrahydroquinolinylphosphine oxides, phosphanes and phosphine sulfides as well as that of quinolinylphosphine oxides and phosphine sulfides, which were synthesized in good to high overall yield. The synthetic route involves a multicomponent reaction of (2-phosphine-oxide)-, 2-phosphine- or (2-phosphine-sulfide)-aniline, aldehydes and olefins and allows the selective generation of two stereogenic centres in a short, efficient and reliable synthesis. The selective dehydrogenation of 1,2,3,4-tetrahydroquinolinylphosphine oxides and phosphine sulfides leads to the formation of corresponding phosphorus substituted quinolines. Some of the products which were prepared showed excellent activity as topoisomerase I (Top1) inhibitors. In addition, prolonged effect of the most potent compounds is maintained with the same intensity even after 3 min of the beginning of the enzymatic reaction. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV03) and human embryonic kidney (HEK293) was also screened. 1,2,3,4-Tetrahydroquinolinylphosphine oxide 6g with an IC50 value of 0.25 ± 0.03 μM showed excellent activity against the A549 cell line in vitro, while 1,2,3,4-tetrahydroquinolinylphosphane 9c with an IC50 value of 0.08 ± 0.01 μM and 1,2,3,4-tetrahydroquinolinylphosphine sulfide derivative 10f with an IC50 value of 0.03 ± 0.04 μM are more active against the A549 cell line. Moreover, selectivity towards cancer cell (A549) over non-malignant cells (MRC5) has been observed. According to their structure, they may be excellent antiproliferative candidates.Financial support from the Ministerio de Economía y Competitividad (MINECO, CTQ2015-67871-R) and by Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. Technical and human support provided by IZO-SGI, SGIker (UPV/EHU, MICINN, GV/EJ, ERDF and ESF) is gratefully acknowledged

Novel phosphine sulphide gold(i) complexes: topoisomerase I inhibitors and antiproliferative agents

Producción CientíficaThis work describes the synthesis of the gold(I) complexes of phosphine sulphides. The formation of these new derivatives has been confirmed by X-ray crystallography. The coordination of gold(I) with the sulphur atom of the phosphine sulphides favors the inhibition of topoisomerase I as well as a high cytotoxicity of the gold(I)-complexed compounds against the cancer line A549 with IC50 values in the nanomolar range and IC50 values below 5 μM against the SKOV3 cell line. It should be noted that the cytotoxicities observed for the new gold(I) complexes are higher than those observed for phosphine sulphide ligands before binding to gold. Furthermore, the results also indicate that the presence of a nitrogenated heterocycle, such as tetrahydroquinoline or quinoline, is also necessary for the TopI inhibition to be maintained. In addition, no toxicity was observed when the non-cancerous lung fibroblast cell line (MRC5) was treated with the new phosphine sulphide gold(I) complexes prepared.Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación - Fondo Europeo de Desarrollo Regional (grant RTI2018-101818-B-I00)Ministerio de Economía, Industria y Competitividad (grant CTQ2017-89217P)Gobierno Vasco - Universidad del País Vasco (grant IT 992-16