Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Med Chem ; 243: 114777, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36174412

RESUMO

A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC50 ≈ 1 µM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC50 0.026-0.043 µM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Pró-Fármacos , Triterpenos , Humanos , Pró-Fármacos/farmacologia , Pirazinas/farmacologia , Potencial da Membrana Mitocondrial , Antineoplásicos Fitogênicos/farmacologia , Células HeLa , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Triterpenos/farmacologia , Antineoplásicos/farmacologia , Piridinas/farmacologia
2.
Eur J Med Chem ; 224: 113706, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34311159

RESUMO

A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC50 below 5 µmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC50 and almost complete inhibition at 5 × IC50. Interestingly, compound 4.39 at 5 × IC50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug.


Assuntos
Alcadienos/farmacologia , Antineoplásicos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Alcadienos/síntese química , Alcadienos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Ácido Betulínico
3.
J Mater Chem B ; 8(3): 484-491, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31834347

RESUMO

Cancer is a global disease of great importance, and the need for novel cytotoxic drugs is still eminent. A series of spermine amides of several selected triterpene acids (betulonic, heterobetulonic, oleanolic, ursolic and platanic acid) have been synthesized to search for new cytotoxic and antimicrobial agents. The compounds have also been subjected to the investigation of their physico-chemical characteristics (ability to self-assemble), and to an in silico comparative calculation of their physico-chemical and ADME parameters. In the in vitro screening tests with several target compounds (8a-8c and 11c), their cytotoxicity changed with prolonged time, which appeared to be a result of formation of dynamic supramolecular networks. This phenomenon is important in investigation of the effect of self-assembly on biological activity. The most important compounds in this series were spermine derivatives of heterobetulonic acid (3b) and ursolic acid (8b), showing cytotoxicity <5 µM and <10 µM, respectively, on all tested cancer cell lines. Comparable cytotoxicity was also displayed by 13b, formerly a model compound prepared for testing of the synthetic procedures, the 1,2-diaminoethane derivative. The target compounds 3b and 8b displayed antimicrobial activity on Staphylococcus aureus, Streptococcus mutans and Listeria monocytogenes at a concentration 6.25 µM. Supramolecular characteristics of several compounds were documented by the TEM and SEM micrographs showing fibrous, partially helical, networks, and UV measurements showing changes in the intensity of UV signals, also indicating formation of supramolecular systems.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Espermina/farmacologia , Triterpenos/farmacologia , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Enterococcus faecalis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Teste de Materiais , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Espermina/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Triterpenos/química
4.
Bioconjug Chem ; 30(11): 2844-2858, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31553559

RESUMO

A set of 41 glycosidic conjugates of pentacyclic triterpenes was synthesized in order to improve the solubility of highly cytotoxic parent compounds. Their in vitro cytotoxic activity was evaluated in 25 cancer cell lines and 2 noncancer fibroblasts. Fifteen compounds had high cytotoxicity on the T-lymphoblastic leukemia cell line CCRF-CEM and 6 of them were active in multiple cell lines of various histogenic origin and not toxic in fibroblasts. Compound 11a had IC50 of 0.64 µM in CCRF-CEM cells, 0.60 µM in K-562 cells, and 0.37 µM in PC-3 cells; compound 12a had IC50 of 0.64 µM in CCRF-CEM cells and 0.71 µM in SW620 cells; compound 17b had IC50 of 0.86 µM in HCT116 cells and 0.92 µM in PC-3 cells. Compounds 11b and 12b were slightly less active than the previously mentioned derivatives; however, their solubility was significantly better, and therefore they were selected for the in vivo evaluation of the pharmacokinetic profile in mice. In both compounds, the maximum concentration in plasma was achieved very rapidly-the highest level in plasma was found 1 h after administration (22.2, respectively, 6.4 µM). For compound 12b, the resorption was followed with fast elimination, and 12 h after administration, the compound was not detected in plasma. In contrast, compound 11b was eliminated more slowly; it was still present in plasma after 12 h, but its concentration dropped below the detection limit after 24 h. The elimination half-time determined for compound 11b was 2.4 h and for compound 12b just about 1.4 h. These values are reasonable for further drug development.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células , Desoxiaçúcares/química , Glicosídeos/química , Neoplasias/metabolismo , Neoplasias/patologia , Triterpenos/farmacologia , Animais , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Distribuição Tecidual , Triterpenos/química , Triterpenos/farmacocinética , Células Tumorais Cultivadas
5.
Eur J Med Chem ; 140: 403-420, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-28987603

RESUMO

To improve the properties of cytotoxic triterpenoid acids 1-5, a large set of hydrophilic esters was synthesized. We choose betulinic acid (1), dihydrobetulinic acid (2), 21-oxoacid 3 along with highly active des-E lupane acids 4 and 5 as a model set of compounds for esterification of which the properties needed to be improved. As ester moieties were used - methoxyethanol and 2-(2-methoxyethoxy)ethanol and glycolic unit (type a-d), pyrrolidinoethanol, piperidinoethanol and morpholinoethanol (type f-h), and monosaccharide groups (type i-l). As a result, 56 triterpenic esters (49 new compounds) were obtained and their cytotoxicity on four cancer cell lines and normal human fibroblasts was tested. All new compounds were fully soluble at all tested concentrations, which used to be a problem of the parent compounds 1 and 2. 16 compounds had IC50 < 10 µM on at least one cancer cell line, 12 compounds had cytotoxicity of <10 µM against at least three of four tested cancer cell lines. The highest activity was found for compound 3c (1.8 µM on MCF7, 2.8 µM on HeLa, and 1.6 µM on G-361 cells) which also had no toxicity on non-cancerous BJ fibroblasts at the highest tested concentration (50 µM). High selective cytotoxicity was also found in compounds 1k, 2k, 3c, and 3i that are ideal candidates for drug development. Therefore, more studies to identify the mechanism of action were performed in case of 1k, 3c, and 3g such as effects on cell cycle and apoptosis. It was found that compounds 3c and 3g can induce apoptosis via caspase-3 activation and modulation of protein Bcl-2 in G-361 cells. In conclusion, compounds 1k, 3c, and 3g show high and selective cytotoxicity, therefore they are significantly better candidates for anti-cancer drug development than the parent acids 1-5.


Assuntos
Proliferação de Células/efeitos dos fármacos , Triterpenos/síntese química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/química , Humanos , Análise Espectral/métodos , Triterpenos/química
6.
ChemMedChem ; 12(5): 390-398, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28084676

RESUMO

A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC50 values less than 10 µm against CCRF-CEM cells (e.g., 3 b: IC50 =2.9 µm) as well as 2'-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50 =9.7 µm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 k, IC50 =11.4 µm). Compound 5 c leads to the accumulation of cells in the G2 phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1×IC50 . The G2 /M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5 c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3 b) and methyl 2-thiocyanometulonate (3 c) were found to inhibit nucleic acid synthesis only at 5×IC50 . We assume that in 3 b and 3 c (unlike in 5 c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1×IC50 or lower concentration.


Assuntos
Antineoplásicos/síntese química , Ácido Oleanólico/análogos & derivados , Tiazóis/química , Triterpenos/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Ácido Oleanólico/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/toxicidade
7.
Steroids ; 112: 88-94, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27192427

RESUMO

7-Oxygenated metabolites of dehydroepiandrosterone (DHEA) are known for their neuroprotective and immunomodulatory properties. These neuroactive steroids are currently predominately analysed by mass spectrometry, for which the use of internal deuterated standards is necessary. The aim of this study was to synthesize the deuterated derivatives of 7α-hydroxy-DHEA and 7-oxo-DHEA and test them in liquid chromatography-tandem mass spectrometry (LC-MS/MS) in order to enhance the performance characteristics of this method. Here we report the synthesis of 3α deuterium-labelled 7α-hydroxy-DHEA and 7-oxo-DHEA. Deuterium was introduced into the 3α position by reduction of the corresponding 3-ketone with a protected 17-carbonyl group using NaBD4. Our new procedure allows the easier synthesis of deuterated steroid labelled compounds. The use of these deuterated steroids enabled us to improve the human plasma LC-MS/MS analysis of 7α-hydroxy-DHEA and 7-oxo-DHEA in terms of sensitivity, precision and recovery.


Assuntos
Cromatografia Líquida , Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/síntese química , Deutério/química , Espectrometria de Massas em Tandem , Desidroepiandrosterona/química , Estrutura Molecular
8.
Eur J Med Chem ; 121: 120-131, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27236068

RESUMO

Lupane derivatives containing an electronegative substituent in the position 2 of the skeleton are often cytotoxic, however, the most active compounds are not selective enough. To further study the influence of a substituent in the position 2 in lupane and 18α-oleanane derivatives on their biological properties, we prepared a set of 38 triterpenoid compounds, 19 of them new, most of them substituted in the position 2. From betulin, we obtained 2-bromo dihydrobetulonic acid and 2-bromo allobetulon and their substitutions yielded derivatives with various substituents in the position 2 such as amines, amides, thiols, and thioethers. Nitration of allobetulon and dihydrobetulonic acid gave 2-nitro and 2,2-dinitro derivatives. Fifteen derivatives had IC50 < 50 µM on a chemosensitive CCRF-CEM (acute lymphoblastic leukemia) cell line and were tested on another seven cancer cell lines including resistant and two non-cancer lines. 2-Amino allobetulin had IC50 4.6 µM and caused significant block of the tumor cells in S and slightly in G2/M transition and caused strong inhibition of DNA and RNA synthesis at 5 × IC50. 2-Amino allobetulin is the most active derivative of 18α-oleanane skeletal type prepared in our research group to date.


Assuntos
Antineoplásicos/química , Ácido Oleanólico/análogos & derivados , Triterpenos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Ácidos Nucleicos/antagonistas & inibidores , Ácidos Nucleicos/biossíntese , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Triterpenos/farmacologia
9.
Bioconjug Chem ; 26(12): 2563-70, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26537839

RESUMO

To better understand the mechanism of action of antitumor triterpenes, we are developing methods to identify their molecular targets. A promising method is based on combination of quantitative proteomics with SILAC and uses active compounds anchored to magnetic beads via biotin-streptavidin interaction. We developed a simple and fast solid-phase synthetic technique to connect terpenes to biotin through a linker. Betulinic acid was biotinylated from three different conjugation sites for use as a standard validation tool since many molecular targets of this triterpene are already known. Then, a set of four other cytotoxic triterpenoids was biotinylated. Biotinylated terpenes were similarly cytotoxic to their nonbiotinylated parents, which suggests that the target identification should not be influenced by linker or biotin. The developed solid-phase synthetic approach is the first attempt to use solid-phase synthesis to connect active triterpenes to biotin and is applicable as a general procedure for routine conjugation of triterpenes with other molecules of choice.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Biotina/química , Biotina/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Antineoplásicos/síntese química , Biotina/síntese química , Biotinilação , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Técnicas de Síntese em Fase Sólida , Triterpenos/síntese química
10.
Nat Prod Rep ; 32(9): 1303-30, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26030604

RESUMO

Triterpenoids are natural compounds with a variety of biological activities and are usually produced by plants as secondary metabolites. In recent decades, scientists focused on the properties of triterpenoids have discovered many activities, such as antitumor, antiviral, antimicrobial, anti-inflammatory and others. Thousands of new triterpenoids with various skeletal modifications have now been synthesized. One of the most important modifications is the formation of a new heterocyclic ring. The simple fact that the vast majority of currently used drugs are heterocyclic compounds has encouraged a lot of researches to synthesize analogous triterpenoid derivatives in order to find new molecules with higher activities and consequently optimize their pharmacological profile. The biological properties of triterpenoid heterocycles are very promising and many of them have been studied, especially as antitumor agents. This review is mainly focused on the synthesis of various types of nitrogen and occasionally sulfur-containing heterocyclic triterpenoids for their potential use as future drugs in medicine and in addition discusses their overall biological activities.


Assuntos
Compostos Heterocíclicos , Nitrogênio/química , Enxofre/química , Triterpenos , Anti-Infecciosos , Anti-Inflamatórios , Antineoplásicos , Antivirais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Estrutura Molecular , Triterpenos/síntese química , Triterpenos/química , Triterpenos/farmacologia
11.
Eur J Med Chem ; 96: 482-90, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25942059

RESUMO

In this article, we describe the preparation and cytotoxic properties of a small focused library of lupane and 18α-oleanane triterpenoids that contain a combination of two structural motifs known to enhance the biological activities. First, we introduced two fluorine atoms to position 2 of the skeleton. Second, we synthesized a set of hemiester prodrugs, which were intended to increase the solubility and activity. Starting from betulin, we obtained two hydroxyketones (derivatives of dihydrobetulinic acid and allobetulin) and their fluorination using DAST provided 2,2-difluoro-3-oxo-compounds as the main products. Then the 3-oxo group in each derivative was reduced by NaBH4 to obtain 3ß-hydroxy compounds suitable for modifying by various hemiesters. We prepared 21 compounds, 11 of them new, their cytotoxicity was tested on T lymphoblastic leukemia CCRF-CEM cells first and the most active derivatives were selected for screening on another six tumor and two non-tumor cell lines. All of them showed selectivity against cancer lines with therapeutic index between 2 and 8. All hemiesters had activity in the same range as the free hydroxyl derivatives and they would be suitable prodrugs for future in vivo experiments. Interestingly, all hemiesters of 2,2-difluorodihydrobetulonic acid had higher activity against p53 knock-out p53-/- cancer cell line than against the non-mutated analog. In active derivatives, the cell cycle was analyzed by flow cytometry and several compounds slowed down cell cycle progression through G0/G1 or S-phase.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Triterpenos/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Conformação Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Bioorg Med Chem ; 20(11): 3666-74, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22551630

RESUMO

The aim of this work was to synthesize a set of heterocyclic derivatives of lupane, lup-20(29)-ene, and 18α-oleanane, and to investigate their cytotoxic activities. Some of those heterocycles were previously known in the oleanane (allobetulin) group; however, to our knowledge the syntheses and biological activities of lupane heterocycles have not been reported before. Starting from betulin (1) and betulinic acid (2), we prepared 3-oxo compounds and 2-bromo-3-oxo compounds 3-10, 2-hydroxymethylene-3-oxo compounds 11-13 and ß-oxo esters 14-16. Condensation of these intermediates with hydrazine, phenylhydrazine, hydroxylamine, or thiourea yielded the pyrazole and phenylpyrazole derivatives 17-22, pyrazolones 23-25, isoxazoles 26 and 27, and thiazoles 28-31. Fifteen compounds (14-16, 18-25, and 29-32) have not been reported before. The cytotoxicity was measured using panel of seven cancer cell lines with/without MDR phenotype and non tumor MRC-5 and BJ fibroblasts. The preferential cytotoxicity to cancer cell lines, particularly to hematological tumors was observed, the bromo acids 5, 6 showed highest activity and selectivity against tumor cells.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Triterpenos Pentacíclicos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Ácido Betulínico
13.
J Nat Prod ; 70(4): 526-32, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17371067

RESUMO

Twelve lupane, 18alpha-oleanane, and des-E-lupane derivatives (1a-5b) were either extracted from natural sources or synthesized from betulinic acid (1a) and betulin (2). Compounds 1b, 1c, 3b, 3c, 4b, 4c, 5a, and 5b were then used as starting materials for further synthesis of a series of pyrazines and benzopyrazines (6a-18); 20 of them are new (6a-6e, 7a-7d, and 10a-18). Activity of pyrazine 6a against the T-lymphoblastic leukemia cell line CEM encouraged us to synthesize several new esters (6b-6d) to study structure-activity relationships with respect to substitution of the carboxyl group at position 28. The synthesized compounds were tested for cytotoxicity against a variety of cancer cell lines of different histogenetic origin, and the results were compared with cytotoxicity of the known starting compounds. Significant cytotoxic activity against A 549, K 562, and multidrug-resistant K 562-tax cell lines was found in pyrazines 6a, 6d, and 6e.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Pirazinas/farmacologia , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia de Células T , Estrutura Molecular , Triterpenos Pentacíclicos , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação , Células Tumorais Cultivadas , Ácido Betulínico
15.
Bioorg Med Chem ; 13(19): 5527-35, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16087342

RESUMO

The aim of this work was to find an optimal ester group for preparation of lupane derivatives connecting high cytotoxicity with good chemical and pharmacological properties. Activities of methyl-, pivaloyloxymethyl- (Pom-), and acetoxymethyl- (Acm-) esters were compared with the activity of free acids. Although the methyl- and Pom-esters were generally less active than free acids, some Acm-esters had cytotoxicity similar to or even better than the starting compounds. Cytotoxic activity was measured in five cancer cell lines.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Triterpenos/síntese química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Esterificação , Humanos , Conformação Molecular , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 15(19): 4196-200, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16051489

RESUMO

This research is based on intention to prepare and test 3beta-hydroxy and 3beta,28-dihydroxy analogues of new pro-apoptotic derivatives (betulinines) using selective hydrolysis procedure and strategic protective groups. The evaluation of cytotoxicity of prepared compounds on several tumor cell lines using an MTT test was our interest. It was found that hydrolysis of acetates in betulinines afforded compounds with higher cytotoxicity in case of 18-lupene-21-ones (e.g., ethyl 3beta-hydroxy-21-oxolup-18-en-28-oate), whereas hydrolysis of the 18-lupene-21,22-diones gave less active derivatives.


Assuntos
Antineoplásicos/síntese química , Triterpenos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroxilação , Concentração Inibidora 50 , Relação Estrutura-Atividade , Triterpenos/farmacologia
17.
Bioorg Med Chem ; 13(10): 3447-54, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15848757

RESUMO

Synthesis of 3beta-O-phthalic esters from betulinic acid and its esters and synthesis of phthalic esters from betulin and its monoacetates using classical acylation procedure with phthalic anhydride. The evaluation of cytotoxicity of the prepared compounds was using numbers of tumor cell lines in MTT test. It was discovered that hemiphthalic esters had better cytotoxicity than starting compounds as betulinic acid or quite inactive betulin.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Ácidos Ftálicos , Triterpenos , Acilação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/química , Humanos , Neoplasias/tratamento farmacológico , Triterpenos Pentacíclicos , Ácidos Ftálicos/síntese química , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Triterpenos/síntese química , Triterpenos/química , Triterpenos/farmacologia , Células Tumorais Cultivadas , Ácido Betulínico
18.
J Nat Prod ; 67(7): 1100-5, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15270560

RESUMO

In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).


Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Técnicas de Química Combinatória , Triterpenos/síntese química , Triterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Triterpenos Pentacíclicos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ácido Betulínico
19.
J Med Chem ; 46(25): 5402-15, 2003 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-14640549

RESUMO

Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure-activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure-activity relationship.


Assuntos
Antineoplásicos/síntese química , Apoptose , Triterpenos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...