RESUMO
A number of mono- or diaminoalkylated indeno[1,2-c]isoquinolin-5,11-diones analogs of 1 were synthesized and evaluated for their DNA binding affinities, topoisomerase inhibition properties and antiproliferative activities against human cancer cell lines (HL60). Impact of the side chain connected to the aromatic D ring and to the N6 lactam position on the biological profile will be discussed.
Assuntos
DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo I/química , Isoquinolinas/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase II/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/toxicidade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/toxicidade , Temperatura de TransiçãoRESUMO
Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n=2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n=3 provided the highest DNA binding. Arginine derivative 32 (n=2, series II) and glycine derivative 34 (n=2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC(50) values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC(50) values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved.
Assuntos
Aminoácidos/química , Antineoplásicos/síntese química , Arginina/análogos & derivados , DNA Topoisomerases Tipo II/química , DNA/química , Indenos/química , Isoquinolinas/química , Inibidores da Topoisomerase II/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Arginina/síntese química , Arginina/química , Arginina/toxicidade , Linhagem Celular Tumoral , DNA/metabolismo , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Humanos , Isoquinolinas/síntese química , Isoquinolinas/toxicidade , Mutação , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/toxicidade , Temperatura de TransiçãoRESUMO
Indeno[2,1- c]quinolin-7-ones and 6 H-indeno[1,2- c]isoquinolin-5,11-diones, bearing two cationic aminoalkyl side chains, were synthesized and evaluated for DNA interaction, topoisomerases inhibition, and cytotoxicity against human cancer cell lines. They displayed strong interaction with DNA and one indeno[1,2- c]isoquinolin-5,11-dione bearing side chains at N-6 and C-8 positions ( 6a) was a potent human topoisomerase II inhibitor with high cytotoxicity toward HL60 cells. An increased topoisomerase II inhibition is found with (a) a cationic aminoalkyl side chain at the C-8 rather than at the C-9 position, (b) a dimethylaminoethoxy side chain at the C-8 position introduced on the N-6 monosubstituted derivative, going with suppression of topoisomerase I poisoning, and (c) a dimethylaminoethyl rather than a dimethylaminopropyl side chain at the N-6 position. The cytotoxicity was only partially reduced when using the topoisomerase II-mutated mitoxantrone-resistant HL60/MX2 cell line, suggesting that additional targets are involved in their mechanism of action. These indeno[1,2- c]isoquinolin-5,11-dione derivatives represent new DNA-topoisomerase II interfering anticancer molecules.
Assuntos
Antineoplásicos/síntese química , DNA/química , Indenos/síntese química , Isoquinolinas/síntese química , Quinolinas/síntese química , Inibidores da Topoisomerase II , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Humanos , Indenos/química , Indenos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Mitoxantrona/farmacologia , Desnaturação de Ácido Nucleico , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.
Assuntos
Antimaláricos/farmacologia , Príons/antagonistas & inibidores , Quinolinas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Linhagem Celular Tumoral , Cloroquina/análogos & derivados , Cloroquina/síntese química , Cloroquina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Camundongos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Three series of monoquinolines consisting of a 1,4-bis(3-aminopropyl)piperazine linker and a large variety of terminal groups were synthesized. Our aim was to prove that in related bisquinoline, it is the second quinoline moiety that is responsible for cytotoxicity and that it is not an absolute requirement for overcoming resistance to chloroquine (CQ). Eleven compounds displayed a higher selectivity index (ratio CC50/IC50 activity) than CQ, and one of them cured mice infected by Plasmodium berghei.
Assuntos
Antimaláricos/síntese química , Piperazinas/síntese química , Quinolinas/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cloroquina/farmacologia , Resistência a Medicamentos , Feminino , Humanos , Malária/tratamento farmacológico , Camundongos , Piperazinas/química , Piperazinas/farmacologia , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Synthesis and evaluation of the activity of new N(1)-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives against a chloroquine-resistant strain of Plasmodium falciparum are described. Selectivity indices were improved for two compounds versus the lead 1, the bis-cyclopropylmethyl derivative, thus increasing the therapeutic interest of our family. As our previous studies conducted on the mode of action of our compounds made us hypothesize the existence of original mechanisms and/or original targets, terminal amino derivatives can be considered as promising tools further mechanistical studies, as probes for affinity chromatography.
Assuntos
Antimaláricos/síntese química , Piperazinas/síntese química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Linhagem Celular , Cloroquina/farmacologia , Cromatografia de Afinidade , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piperazinas/farmacologiaRESUMO
Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antimaláricos/síntese química , Antimaláricos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Animais , Antimaláricos/química , Benzamidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Relação Estrutura-AtividadeRESUMO
Synthesis and evaluation of the activity of a new family of 1,4-bis(3-aminopropyl)piperazine derivatives against a chloroquine-resistant strain of Plasmodium falciparum, and as inhibitors of beta-hematin formation, are described. The highest antimalarial activities were obtained for compounds displaying the highest predicted vacuolar accumulation ratios and the best potencies as inhibitors of beta-hematin formation. The most potent compound displayed an activity 3-fold better than chloroquine for a comparable selectivity index upon MRC-5 cells. Therefore, in this series, the replacement of the 7-chloroquinoline group can constitute a strong rationale for further investigation.