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1.
Expert Opin Drug Discov ; 17(6): 581-601, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35321631

RESUMO

INTRODUCTION: Cancer has been identified as one of the leading causes of death worldwide. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds with antiproliferative effect and behaving as topoisomerase I inhibitors has become an active field of research. Depending on their mechanism of inhibition, they can be classified as catalytic inhibitors or poisons. AREAS COVERED: This review article summarizes the state of the art for the development of selective topoisomerase I inhibitors. Collected compounds showed inhibition of the enzyme, highlighting those approved for clinical use, the combination therapies developed, as well as related drawbacks and future focus. EXPERT OPINION: Research 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. Derivatives of CPT irinotecan, topotecan, and belotecan are the only clinically approved inhibitors. Currently, their limitations are being addressed by different stretegies. Future studies should focus not only on developing other active molecules but also on improving the bioavailability and pharmacokinetics of potent synthetic derivatives.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/uso terapêutico , Inibidores Enzimáticos/farmacologia , Humanos , Irinotecano/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/farmacocinética , Topotecan/uso terapêutico
2.
Bioorg Med Chem Lett ; 57: 128517, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34952177

RESUMO

This work describes the first synthesis of diethyl 6,6a,7,11b-tetrahydro-5H-indeno[2,1-c]quinolinylphosphonates 5, diethyl 7H-indeno[2,1-c]quinolinylphosphonates 6 and diethyl 7-oxo-7H-indeno[2,1-c]quinolinylphosphonates 7, which were prepared in good to high overall yields. The synthetic route involves a multicomponent reaction of 2-phosphonateaniline, aldehydes and indene as olefin and allows the selective generation of three stereogenic centres in a short, efficient and reliable manner. The selective dehydrogenation of 1,2,3,4-tetrahydroindenoquinolines leads to the formation of corresponding indenoquinolines, and subsequent oxidation of methylene group of the indenoquinolines allows the access to indenoquinolinones.


Assuntos
Antineoplásicos/farmacologia , Indenos/farmacologia , Ácidos Fosforosos/farmacologia , Quinolinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Indenos/síntese química , Ácidos Fosforosos/síntese química , Quinolinas/síntese química , Estereoisomerismo , Inibidores da Topoisomerase I/síntese química
3.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34451880

RESUMO

This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation. In the current report, a new series of dialkyl (2-arylquinolin-8-yl)phosphonates have been synthesized and their antiproliferative effect evaluated on different human cancer and embryonic cells, as well as on Leishmania infantum parasites, a eukaryotic protist responsible for visceral leishmaniasis. Thereby, the antitumor effect was assessed in human lung adenocarcinoma cells (A549), human ovarian carcinoma cells (SKOV3), and human embryonic kidney cells (HEK293) versus the non-cancerous lung fibroblasts cell line (MRC5). On the other hand, the antileishmanial activity was tested against both stages of L. infantum cell cycle, namely free-living promastigotes and intramacrophage amastigotes, using a primary culture of Balb/c splenocytes to calculate the selectivity index. Besides the antiproliferative and antileishmanial capacities, their behavior as topoisomerase 1B inhibitors has been evaluated as a possible mechanism of action.

4.
Pharmaceutics ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34452216

RESUMO

Background: Eukaryotic topoisomerase 1 is a potential target of anti-parasitic and anti-cancer drugs. Parasites require topoisomerase 1 activity for survival and, consequently, compounds that inhibit topoisomerase 1 activity may be of interest. All effective topoisomerase 1 drugs with anti-cancer activity act by inhibiting the ligation reaction of the enzyme. Screening for topoisomerase 1 targeting drugs, therefore, should involve the possibility of dissecting which step of topoisomerase 1 activity is affected. Methods: Here we present a novel DNA-based assay that allows for screening of the effect of small-molecule compounds targeting the binding/cleavage or the ligation steps of topoisomerase 1 catalysis. This novel assay is based on the detection of a rolling circle amplification product generated from a DNA circle resulting from topoisomerase 1 activity. Results: We show that the binding/cleavage and ligation reactions of topoisomerase 1 can be investigated separately in the presented assay termed REEAD (C|L) and demonstrate that the assay can be used to investigate, which of the individual steps of topoisomerase 1 catalysis are affected by small-molecule compounds. The assay is gel-free and the results can be detected by a simple colorimetric readout method using silver-on-gold precipitation rendering large equipment unnecessary. Conclusion: REEAD (C|L) allows for easy and quantitative investigations of topoisomerase 1 targeting compounds and can be performed in non-specialized laboratories.

5.
Expert Opin Ther Pat ; 31(6): 473-508, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33475439

RESUMO

INTRODUCTION: Topoisomerases are important targets for therapeutic improvement in the treatment of some diseases, including cancer. Inhibitors and poisons of topoisomerase I can limit the activity of this enzyme in its enzymatic cycle. This fact implies an anticancer effect of these drugs, since most cancer cells are characterized by both a higher activity of topoisomerase I and a higher replication rate compared to non-cancerous cells. Clinically approved inhibitors include camptothecin (CPT) and its derivatives. However, their limitations have encouraged different research groups to prepare new compounds, proof of which are the numerous research works and patents, some of them in the last five years. AREAS COVERED: This review covers patent literature on topoisomerase I inhibitors and their application published between 2016-present. EXPERT OPINION: The highest contribution toward patent development has been obtained from academics or small biotechnology companies. The most important fields of innovation include the preparation of prodrugs or inhibitors combined with other agents, as biocompatible polymers or antibodies. A promising development of topoisomerase I inhibitors is expected in the next years, directed to the treatment of diverse diseases, specifically toward different types of cancer and infectious diseases, among others.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Animais , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Desenvolvimento de Medicamentos , Humanos , Neoplasias/patologia , Patentes como Assunto
6.
Molecules ; 25(15)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32752070

RESUMO

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.


Assuntos
Naftiridinas/química , Alcaloides/biossíntese , Alcaloides/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Reação de Cicloadição , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Naftiridinas/síntese química , Naftiridinas/farmacologia , Oxirredução
7.
Molecules ; 25(14)2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32708796

RESUMO

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.


Assuntos
Química Farmacêutica , Complexos de Coordenação/síntese química , Naftiridinas/síntese química , Complexos de Coordenação/química , Indicadores e Reagentes/síntese química , Indicadores e Reagentes/química , Naftiridinas/química
8.
Eur J Med Chem ; 195: 112292, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32279049

RESUMO

The topoisomerase I enzymatic inhibition of hybrid quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridines and quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-ones was investigated. First, the synthesis of these fused compounds was performed by intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and unsaturated aldehydes affording corresponding hybrid 5-tosylhexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one compounds with good to high general yields. Subsequent dehydrogenation led to the corresponding more unsaturated dihydro (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one derivatives in quantitative yields. The new polycyclic products show excellent-good activity as topoisomerase I (TopI) inhibitors that lead to TopI induced nicking of plasmids. This is consistent with the compounds acting as TopI poisons resulting in the accumulation of trapped cleavage complexes in the DNA. The cytotoxic effect on cell lines A549, SKOV3 and on non-cancerous MRC5 was also screened. Tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one 9 resulted the most cytotoxic compound with IC50 values of 3.25 ± 0.91 µM and 2.08 ± 1.89 µM against the A549 cell line and the SKOV3 cell line, respectively. Also, hexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 8a and dihydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 10a showed good cytotoxicity against these cell lines. None of the compounds presented cytotoxic effects against non-malignant pulmonary fibroblasts (MRC-5).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Naftiridinas/química , Quinolinas/síntese química , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Quinolinas/química , Quinolinas/metabolismo , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia
9.
Eur J Med Chem ; 162: 18-31, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30408746

RESUMO

Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC50 value (0.61 ±â€¯0.18 µM) similar to the standard drug amphotericin B (0.32 ±â€¯0.05 µM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported.


Assuntos
Antiprotozoários/química , DNA Topoisomerases Tipo I/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Fósforo/química , Quinolinas/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/farmacologia , Quinolinas/uso terapêutico
10.
Eur J Med Chem ; 149: 225-237, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29501943

RESUMO

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 ±â€¯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 ±â€¯0.01 µM and 1,2,3,4-tetrahydroquinolinylphosphine sulfide derivative 10f with an IC50 value of 0.03 ±â€¯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.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fósforo/química , Quinolinas/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrogenação , Fosfinas , Relação Estrutura-Atividade
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