RESUMO
The synthesis of aminopropoxy derivatives of betulin, erythrodiol, uvaol and oleantriol via cyanoethylation of triterpenoids hydroxyl groups and subsequent reduction of cyanoethyl fragments is described. High and specific in vitro antitumor activity (cytotoxicity) of 3beta,28-di-O-[3-(aminopropoxy)]lupa-20(29)-ene and 3beta-O-hydroxy-28-O-[3-(aminopropoxy)]olean-12-ene towards a wide range of human tumor cell lines is discovered. The aminopropoxy group is shown to be a new perspective pharmacophor group for design of anticancer agents on the basis of triterpenoids.
Assuntos
Antineoplásicos/síntese química , Ácido Oleanólico/análogos & derivados , Triterpenos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Triterpenos/química , Triterpenos/farmacologiaRESUMO
The synthesis of a new group of triterpenoid acylates on the basis of oleanolic, glycyrrhetic and ursolic acids and betulin is described. In studying the activity of the synthesized compounds in relation to reproduction of virus pathogens of respiratory infections 28-O-methoxycynnamoylbetulin shows high activity against influenza type A (H1N1) the selectivity index SI > 100. The high activity of 3,28-dinicotinoylbetulin against papilloma virus (strain HPV-11) was detected, the selectivity index SI was 35.
Assuntos
Antivirais/síntese química , Vírus da Influenza A Subtipo H1N1/fisiologia , Papillomaviridae/fisiologia , Triterpenos/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Avaliação de Medicamentos , Humanos , Influenza Humana/dietoterapia , Infecções por Papillomavirus/tratamento farmacológico , Triterpenos/química , Triterpenos/farmacologiaRESUMO
The synthesis of a new group of triterpenoid acylates has been conducted on the basis of oleanolic, glycyrrhetic, and ursolic acids and betulin. 28-ortho-Methoxycynnamoylbetulin has been demonstrated to possess high activity against the influenza type A (H1N1) virus with the selectivity index SI > 100 while studying the activity of the synthesized compounds in relation to the reproduction of viral pathogens of respiratory infections. The high activity of 3,28-dinicotinoylbetulin against the papilloma virus (strain HPV-11) was detected with the selectivity index SI 35.
RESUMO
One of the main problems of present-day oncology is the ability of neoplastic cells to develop different mechanisms of resistance to chemotherapeutic agent. A natural compound oleanolic acid (OA) was found to be active against many types of neoplastic cells. This paper examines the influence of eight semisynthetic oleanolic acid derivatives on drug-sensitive human acute promyelocytic leukemia cell line HL-60 and its multidrug resistant subline ABCC1 overexpressing HL-60/AR. Viability inhibition, proapoptotic activity, as well as influence on the ABCC1 gene expression level, ability to inhibit the transport function of multidrug resistance associated protein 1 (ABCC1) and to alter its level by the tested compounds, were evaluated. The most potent compounds were DIOXOL (methyl 3,11-dioxoolean-12-en-28-oate) and HIMOXOL (methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate). DIOXOL was most efficient in inducing apoptosis of HL-60 cells. It activated both intrinsic and extrinsic pathways of apoptotic cell death. Proapoptotic properties of DIOXOL were probably related to the significant decrease of p65 NFκB level and inhibition of its translocation to the nucleus. In turn, HIMOXOL was the most potent compound against resistant HL-60/AR cells. It inhibited ABCC1 transport function (short time response) and decreased the level of ABCC1 protein (long time response) as a result of reduction of ABCC1 expression.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Fragmentação do DNA/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Células HL-60/efeitos dos fármacos , Células HL-60/enzimologia , Humanos , Leucemia Promielocítica Aguda/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ácido Oleanólico/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
The synthesis of hemisuccinates of some derivatives of oleanolic acid is reported, their inhibitory response to experimentally induced gastric ulcers in rats is examined. The hemisuccinates 13a (sodium salt of 13), 14 and 17 are more effective inhibitors than carbenoxolon-sodium.
Assuntos
Antiulcerosos , Ácido Oleanólico , Sapogeninas , Animais , Antiulcerosos/síntese química , Antiulcerosos/farmacologia , Masculino , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/síntese química , Ácido Oleanólico/farmacologia , Ratos , Reserpina/farmacologia , Sapogeninas/síntese química , Sapogeninas/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Relação Estrutura-AtividadeRESUMO
Nitroimidazole derivatives 3a-3g, 4a-4g and 5-8 were synthesized by treating 4,5-dinitro- and 2-methyl-4,5-dinitroimidazole (1,2) with phenacyl bromide, its p-substituted derivatives or epichlorohydrin. 1-(3-Chloro-2-hydroxypropyl)-4,5-dinitroimidazole (5) and its 2-methyl derivative 6 have been converted to imidazo-oxazoles 7 and 8 or amino imidazole derivatives 9-14 by the action of potassium carbonate or cyclic amines (pyrrolidine, piperidine, morpholine and N-methylpiperazine). Some of the newly synthesized nitroimidazole derivatives show antibacterial and fungicidal activity. The electron affinity of the nitroimidazole derivatives 1-24 is discussed on the basis of their half-wave potentials and in the connection with their eventual radiosensitizing properties.
Assuntos
Anti-Infecciosos/síntese química , Antifúngicos/síntese química , Azóis/síntese química , Nitroimidazóis/síntese química , Antibacterianos , Azóis/farmacologia , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Elétrons , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nitroimidazóis/farmacologiaRESUMO
Nitroimidazole derivatives 4a-4c, 5a-5c, 8a-8c and 9a-9c were synthesized by treating 4,5-dinitro- and 2-methyl-4,5-dinitroimidazole (1,2) or their silver salts [1.Ag,, 2.Ag) with chlorosubtituted phenacyl bromides 3a-3c, diethyl sulphate or ethyl iodide, allyl iodide and ethyl chloro-, azo- or bromoacetate. 2,4(5)-dinitroimidazole (10) has been converted to the 2,4-dinitroimidazole derivative 10a by the action of ethyl bromoacetate in the presence of sodium ethylate. A modified method for the synthesis of 6a and 6b has been described. 7a and 7b have been obtained by a known method. Some of the newly synthesized nitroimidazole derivatives show antibacterial and fungicidal activity.
Assuntos
Anti-Infecciosos/síntese química , Azóis/síntese química , Fungicidas Industriais/síntese química , Nitroimidazóis/síntese química , Antibacterianos , Anti-Infecciosos/farmacologia , Azóis/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Testes de Sensibilidade Microbiana , Nitroimidazóis/farmacologiaRESUMO
The authors report on the synthesis of 3-acetyloleanol acid-28-amids 10, 12-16, 19, 20, 22 and 24. The amids 16 (30%) and 24 (37%) were of most favourable inhibiting effect on the formation of gastric ulcera following pylorus ligature. The ulcer formation caused by p. o. administration of indometacin (Metindol) was in the main reduced by the amids 15 (60%), 16 (34%), and 24 (46%). With both the methods the effect of carbenoxolon sodium amounts to 40 or 50%. In ulcera induced by indometacin, the 11- and 3-oxooleanol acid derivates 12 and 18 revealed stimulating characteristics.