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1.
Curr Drug Deliv ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32384029

RESUMO

Polymer-drug conjugates are polymers with drug molecules chemically attached to polymer side chains through a weak covalent bond (degradable bond) or a dynamic covalent bond. These systems are known as prodrugs in the inactive form of the drug passing into the blood circulation system. When the prodrug reaches to the target organ, tissue or cell, the drug is activated by cleavage of the bond between the drug and polymer under certain conditions existing in the target organ. The advantages of polymer-drug conjugates compared to other controlledrelease carriers and conventional pharmaceutical formulations are the increased drug loading capacity, the prolonged in vivo circulation time, the enhanced intercellular uptake, the better controlled release, the improved therapeutic efficacy and the enhanced permeability and retention effect. The aim of the present review is the investigation of polymer-drug conjugates bearing anticancer drugs. The polymer through its side chains is linked to the anticancer drugs via dynamic covalent bonds such as hydrazone/imine bonds, disulfide bonds and boronate esters. These dynamic covalent bonds are cleaved in conditions existing only in cancer cells and not in healthy ones. Thus, ensures the selective release of the drug to the targeted tissue, reducing in this way the frequent side effects of chemotherapy, leading to a more targeted application, despite the nature of the applied polymer, possessing the ability to aim selectively tumors via incorporation of a relative ligand.

2.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861583

RESUMO

Inflammation and oxidative stress are involved in cardiovascular diseases. Nitrogen monoxide participates in the regulation of endothelial processes. Thus, derivatives of classic nonsteroidal anti-inflammatory drugs (NSAIDs), trolox or cinnamic acids esterified with 2-(nitrooxy)ethanol were designed and studied. It was found that the nitrogen monoxide (NO) releasing activity was comparable to that of S-nitroso-N-acetylpenicillamine. The nitrooxy derivatives decreased potently lipid indices in the plasma of hyperlipidaemic rats (30-85%). All compounds presented increased anti-inflammatory activity in vivo, inhibiting carrageenan-induced rat paw oedema as high as 76%, up to six times higher than that of the parent acids. Lipoxygenase inhibitory activity was significant for most of them, although the parent molecules exerted a minor effect (IC50 > 0.2 mM). Those compounds incorporating an antioxidant structure inhibited rat microsomal membrane lipid peroxidation strongly and possessed radical scavenging activity. These results indicated that the described compounds could act at different targets in multifactorial diseases, further limiting the possible adverse effects of drug combinations.


Assuntos
Anti-Inflamatórios/síntese química , Antioxidantes/síntese química , Cromanos/química , Cinamatos/química , Inflamação/tratamento farmacológico , Doadores de Óxido Nítrico/síntese química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/efeitos adversos , Modelos Animais de Doenças , Esterificação , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/genética , Estrutura Molecular , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Ratos
3.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
4.
Bioorg Med Chem Lett ; 27(21): 4800-4804, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29017787

RESUMO

Novel amide derivatives of trolox, 3,5-di-tert-butyl-4-hydroxybenzoic acid, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and cinnamic acid with cysteamine and l-cysteine ethyl ester were synthesised. In four cases, the disulfide derivatives were also isolated and tested. All compounds were examined for antioxidant activity, expressed as their ability to inhibit lipid peroxidation and to scavenge free radicals. They were found to demonstrate up to 17-fold better activity than that of the parent antioxidant acids. They could reduce acute inflammation up to 87%. The most active antioxidant compounds were further tested for their in vivo hypolipidemic effect, which ranged from 47% to 73%, and for their ability to protect the liver against oxidative toxicity caused by high paracetamol dose. The disulfide derivatives of 3,5-di-tert-butyl-4-hydroxybenzoic acid and cinnamic acid had no antioxidant activity and presented equal or lower anti-inflammatory effect than their thiol analogues, indicating that their molecular characteristics may not permit biological barrier penetration.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Substâncias Protetoras/química , Acetaminofen/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/síntese química , Antioxidantes/farmacologia , Butanos/química , Carragenina/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisteína/análogos & derivados , Cisteína/química , Edema/induzido quimicamente , Edema/prevenção & controle , Radicais Livres/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Parabenos/química , Substâncias Protetoras/síntese química , Substâncias Protetoras/farmacologia , Ratos
5.
Med Chem ; 13(5): 408-420, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28185540

RESUMO

BACKGROUND: Non-steroidal anti-inflammatory drugs are the oldest and most widely used medicines. However, their untoward effects, especially gastrointestinal toxicity, remain the main obstacle to their application. Because of their mechanism of action, cycloxygenase (COX) inhibition, in combination with the weekly acidic character of most of them, major protective mechanisms of the gastrointestinal system are suppressed and deregulated. OBJECTIVE: In this review, several compounds designed to retain anti-inflammatory activity, but devoid of gastrointestinal side effects, are presented. Thus, gastro-protective drugs, selective COX-2 inhibitors, nitric monoxide- and hydrogen sulphide-releasing agents, prodrugs, lipoxygenase (LOX) inhibitors and dual COX/LOX inhibitors are presented. Their mechanism of action, as well as their advantages and disadvantages are discussed. CONCLUSION: Efforts, aiming to the development of safe non-steroidal anti-inflammatory agents, are evolving, however there are still several problems concerning gastro-protection to be efficiently solved, thus, design of effective and safe agents for the treatment of inflammatory conditions still remains a major challenge.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Úlcera Péptica/prevenção & controle , Substâncias Protetoras/farmacologia , Animais , Química Farmacêutica , Colo/efeitos dos fármacos , Colo/patologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Gástrica/fisiologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Inibidores de Lipoxigenase/farmacologia , Óxido Nítrico/fisiologia , Doadores de Óxido Nítrico/farmacologia , Pró-Fármacos/farmacologia
6.
Med Chem ; 13(3): 214-225, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27823562

RESUMO

OBJECTIVES: A series of esters and amides, incorporating an antioxidant residue, such as trolox or caffeic acid, and various moieties with different biological activities, were synthesised. The obtained compounds demonstrated considerable anti-inflammatory, radical scavenging and antioxidant action. Thus, they could reduce carrageenan-induced rat paw oedema by 31-60% at 150 µmol/kg and inhibit rat microsomal membrane lipid peroxidation with IC50 values as low as 1.4 µM, which is much lower than that of trolox. Most of them could also inhibit soybean lipoxygenase. The thiomorpholine derivatives decreased significantly all lipidemic indices of Triton-induced hyperlipidemia in rats. The most active, the caffeic acid derivative (6), decreases triglycerides, total cholesterol and low density lipoprotein, in the plasma of hyperlipidemic rats, by 70%, 67%, and 73%, respectively, at 150 µmol/kg (i.p.). CONCLUSION: The synthesised compounds, designed to exhibit two or more pharmacological actions, may be considered useful in the study of agents addressed to conditions involving inflammation and oxidative stress.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Cromanos/farmacologia , Edema/tratamento farmacológico , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Carragenina , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Feminino , Hipolipemiantes/síntese química , Hipolipemiantes/química , Masculino , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 26(3): 910-913, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26750253

RESUMO

Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), α-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis.


Assuntos
Amidas/química , Anti-Inflamatórios não Esteroides/química , Hipolipemiantes/química , Morfolinas/química , Amidas/uso terapêutico , Animais , Colesterol/sangue , LDL-Colesterol/sangue , Edema/induzido quimicamente , Edema/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Hipolipemiantes/uso terapêutico , Ratos , Triglicerídeos/sangue
8.
Bioorg Med Chem Lett ; 25(22): 5028-31, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26494261

RESUMO

Novel esters of non steroidal anti-inflammatory drugs, α-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cinamatos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Propanóis/química , Propionatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/uso terapêutico , Carragenina , Cinamatos/síntese química , Cinamatos/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ésteres , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Ácidos Indolacéticos/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/uso terapêutico , Polietilenoglicóis , Propionatos/síntese química , Propionatos/uso terapêutico , Ratos , Soja , Ácido Tióctico/química
9.
Arch Pharm (Weinheim) ; 348(9): 629-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26191791

RESUMO

A number of thiomorpholine derivatives that are structurally similar to some substituted morpholines possessing antioxidant and hypocholesterolemic activity were synthesized. The new compounds incorporate an antioxidant moiety as the thiomorpholine N-substituent. The derivatives were found to inhibit the ferrous/ascorbate-induced lipid peroxidation of microsomal membrane lipids, with IC50 values as low as 7.5 µΜ. In addition, these compounds demonstrate hypocholesterolemic and hypolipidemic action. The most active compound (5) decreases the triglyceride, total cholesterol, and low-density lipoprotein levels in the plasma of Triton WR-1339-induced hyperlipidemic rats, by 80, 78, and 76%, respectively, at 56 mmol/kg (i.p.). They may also act as squalene synthase inhibitors. The above results indicate that the new molecules may be useful as leads for the design of novel compounds as potentially antiatherogenic factors.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Hiperlipidemias/tratamento farmacológico , Morfolinas/síntese química , Morfolinas/farmacologia , Animais , Biomarcadores/sangue , Colesterol/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Farnesil-Difosfato Farnesiltransferase/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/sangue , Estrutura Molecular , Polietilenoglicóis , Ratos , Relação Estrutura-Atividade , Triglicerídeos/sangue
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