RESUMO
The first total synthesis and absolute configuration assignment of asperilactone B (I) have been accomplished. Additionally, a revision of the absolute stereochemistry of asperilactone C has been done. The first total synthesis of the opposite enantiomer of asperilactone B (ent-I) has also been achieved, as well as that of C-7 epimers of both asperilactones B (8) and C (9).
RESUMO
Synthesis of protulactone A (PLA, 1) and twelve of its analogues have been achieved starting from d-galactose. PLA was isolated in the crystalline state, and its crystal structure was determined utilizing X-ray crystallography, which confirmed the assumed stereochemistry at all stereocenters. All tested compounds displayed antiproliferative activity against a panel of tumour cell lines, and all of them were non-cytotoxic toward the normal cells (MRC-5). Natural product PLA (1) was the most active against the K562 and MCF-7 cell lines (IC50 6.52 and 2.20 µM, respectively). Some of the synthesized derivatives showed very potent cytotoxicity, especially analogues 11, 13 and 15 (IC50 1.08-1.14 µM against MCF-7), and 9 and 14 (IC50 1.29 and 1.64 µM against K562). SAR analysis indicated important structural motifs for antiproliferative activity. Unfortunately, PLA (1), its C-7 epimer (2) and demethylated analogue (3) did not display a significant antimicrobial activity (two Gram-positive and two Gram-negative bacteria and one fungal strain) and they also cannot affect the ability to modulate bacterial communication.
Assuntos
Antineoplásicos , Produtos Biológicos , Antineoplásicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Galactose , Humanos , Estrutura Molecular , Poliésteres/farmacologia , Policetídeos , Relação Estrutura-Atividade , Raios XRESUMO
Using the "chiral pool" approach, two modified total syntheses of the biologically active δ-lactone cleistenolide (1) have been achieved starting from d-glucose. These approaches also enabled the preparation of novel analogues and derivatives of natural product 1. The applied strategy for the synthesis of 1 involves: the initial degradation of the chiral precursor for a single C-atom, C2-fragment chain extension using Z-selective Wittig reaction, and the final δ-lactonization. All tested cleistenolide analogues displayed antimicrobial activity against a panel of nine microbial strains, most of them superseding the activity of cleistenolide itself, and, in some cases, coming close in value to the observed minimal inhibitory concentrations of chloramphenicol. Increased lipophilicity of the derivatives and the non-sterically congested conjugated lactone moiety were a prerequisite for analogues with high inhibitory activity against S. aureus and, in general, Gram-positive bacteria.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Pironas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pironas/síntese química , Pironas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Prostate cancer is a common cause of death in men and a novel treating methods should be developed. In order to find a new drug for prostate cancer, a series of novel conformationally constrained analogues of (+)-goniofufurone and 7-epi-(+)-goniofufurone, as well as the newly synthesized styryl lactones containing the cinnamic acid ester groups were evaluated for in vitro cytotoxicity against prostate cancer cell (PC-3). Furthermore, prediction of physicochemical characteristics and drugability as well as in silico ADME-Tox tests of investigated compounds were performed. The 3D-QSAR model was established using the comparative molecular field analysis method. According to obtained results, the tricyclic compounds 9 and 10 had the highest potency with IC50 < 20 µM. Evaluation of structural features through 3D-QSAR model identified steric field feature on the cinnamic acid ester groups at C-7 as a crucial for the cytotoxic activity. This research suggests that most of the analysed compounds have desirable properties for drug candidates and high potential in drug development, which recommend them for further research in treatment of prostate cancer. Furthermore, obtained 3D-QSAR model is able to successfully identify styryl lactones that have significant cytotoxic activity and provide information for screening and design of novel inhibitors against PC-3 cell line that could be used as drugs in treatment of the prostate cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Lactonas/farmacologia , Relação Quantitativa Estrutura-Atividade , Estirenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/química , Lactonas/metabolismo , Modelos Moleculares , Células PC-3 , Estirenos/química , Estirenos/metabolismoRESUMO
Novel goniofufurone (1) and 7-epi-goniofufurone (2) derivatives bearing a methoxy group at the C-5 and/or C-7 positions were prepared and their in vitro antitumour activity against some human tumour cell lines was evaluated. Some of the analogues displayed powerful antiproliferative effects against the studied tumour cells, but almost all of them were non-cytotoxic toward the normal cells (MRC-5). A SAR study reveals that the introduction of a methoxy group at the C-7 position may increase the antiproliferative effects of the analogues. The most active compounds are 7-O-methyl derivatives of goniofufurone (3) and 7-epi-(+)-goniofufurone (6), which exhibited 1177- and 451-fold higher potencies than the leads 1 and 2 toward the MDA-MB 231 cell line. At the same time, compound 3 is almost 1.5-fold more active than the commercial drug doxorubicin (DOX) against the same cell line. Flow cytometry data confirmed that the cytotoxic effects of these analogues are mediated by apoptosis, additionally revealing that these molecules induced changes in the K562 cell cycle distribution.
RESUMO
A series of new antitumour lactones containing the [3.3.0] bicyclic furano-lactone core and the halogen or azido group at the C-7 position have been designed, synthesized, and evaluated for their in vitro antitumour activity against a panel of human tumour cell lines. Some of the analogues displayed powerful antiproliferative effects to certain human tumour cells, but all of them were devoid of any cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that may affect their antiproliferative activity. These are: the nature of substituent present at the C-7 position, stereochemistry at the C-7 position, the absence of phenyl group at the C-7 position. Flow cytometry data indicate that the cytotoxic effects of the synthesized analogues in a culture of K562 cells are mediated by apoptosis, additionally revealing that these molecules induced changes in cell cycle distribution of these cells. Results of Western blot analysis suggested that the most of synthesized compounds induce apoptosis in K562 cells in caspase-dependent way.
Assuntos
Antineoplásicos/farmacologia , Azidas/química , Desenho de Fármacos , Fibroblastos/citologia , Halogênios/química , Lactonas/farmacologia , Neoplasias/patologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A stereoselective total synthesis of (-)-cleistenolide (1) from d-glucose has been achieved. This new approach for the synthesis of (-)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC50 0.02µM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized δ-lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position.
Assuntos
Antineoplásicos/farmacologia , Lactonas/farmacologia , Pironas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/síntese química , Lactonas/química , Conformação Molecular , Pironas/síntese química , Pironas/química , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of styryl lactones containing the cinnamic acid ester groups such as (+)-crassalactones B (3a) and C (4a), 5,7-di-O-cinamoyl derivative 6, the corresponding 7-epimers and 7-deoxy derivatives have been synthesized, characterized and evaluated for their in vitro antitumour activity against a panel of several human tumour cell lines. Twelve new analogues such as 5-O- or 7-O-(4-methoxycinnamoyl), 5-O- or 7-O-(4-nitrocinnamoyl) and 5-O- or 7-O-(4-fluorocinnamoyl) esters of (+)-goniofufurone (3b-d), 7-epi-(+)-goniofufurone (epi-3b-d), as well as 7-deoxy derivatives 5b-d have been prepared to correlate all compounds in a SAR study. Some of the analogues displayed powerful antiproliferative effects on selected human tumour cell lines, but none of them demonstrated cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). Thus, for the 7-epi-crassalactone B (epi-3a) was found to be a potent inhibitor of HL-60 cells growth, with an IC50 value that is approximately 46-fold lower than that observed for the commercial antitumour drug doxorubicin in the culture of the same cells. A SAR analysis performed on these lactones reveals the main structural features that affect their antiproliferative activity, such as nature of the substituents at the C-4 in the aromatic rings of cinnamoyl moieties, the absolute stereochemistry, as well as the presence of a deoxy function at the C-7 position.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Desenho de Fármacos , Lactonas/química , Lactonas/farmacologia , Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Lactonas/síntese química , Relação Estrutura-AtividadeRESUMO
Synthesis of conformationally restricted (+)-goniofufurone (1) and 7-epi-(+)-goniofufurone (2) analogues, with embedded O-isopropylidene, O-methylidene or cyclic carbonate functions is disclosed starting from d-glucose. A number of potential bioisosteres of 1 and 2 bearing both 5,7-O-methylidene and 4-substituted cinnamoyloxy functions at the C-7 position have also been synthesized. In vitro cytotoxicity of target molecules against a number of human tumour cell lines were recorded and compared with those observed for the parent molecules 1 and 2. Some of the analogues displayed powerful antiproliferative effects on selected human tumour cell lines, but all of them were devoid of any cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that may increase their antiproliferative activity.
Assuntos
Antineoplásicos/farmacologia , Lactonas/farmacologia , 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 , Células HL-60 , Células HeLa , Humanos , Células Jurkat , Células K562 , Lactonas/síntese química , Lactonas/química , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Cytotoxic (+)-goniofufurone mimic such as benzoxepane 2 was preferentially formed after the treatment of 7-O-benzoyl-5-O-benzyl (+)-goniofufurone derivative 6 with titanium(IV) fluoride. However, the corresponding 7-epimer 5 (derivative of 7-epi-goniofufurone) under the similar reaction conditions gave mainly 7-deoxy derivative 7 as a result of an unexpected 1,5-hydride shift. Extension of this methodology to the enantiomer ent-6 provided cytotoxic (-)-goniofufurone mimics ent-2 and ent-7. Synthesized compounds showed diverse growth inhibitory effects against selected tumour cell lines, but were devoid of any significant toxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that are beneficial for their antiproliferative activity, such as presence of an additional oxepane ring, the absolute stereochemistry and the presence of a deoxy function at the C-7 position.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Lactonas/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Fluoretos/química , Humanos , Lactonas/síntese química , Lactonas/toxicidade , Estereoisomerismo , Relação Estrutura-Atividade , Titânio/químicaRESUMO
This paper describes a straightforward divergent synthesis of (+)-goniofufurone mimics (4, 5 and 6) starting from d-xylose. In a preliminary bioassay, analogues 4 and 5 exhibited a submicromolar antiproliferative activity towards HL-60 cells, while the corresponding parent compound 1 was completely inactive against this cell line. At the same time, these molecules showed approximately 10-fold stronger cytotoxicity in the same cell line when compared to the standard anticancer drug doxorubicin (DOX). Analogue 6 displayed 18- and 3-fold higher potency in Raji cell line when compared to control compounds 1 and DOX, respectively. A new divergent route for the preparation of (+)-goniofufurone (1) and (+)-crassalactone C (3) from d-xylose is also disclosed.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Lactonas/química , Lactonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Lactonas/síntese química , EstereoisomerismoRESUMO
A facile synthesis of 7-epi-(-)-goniofufurone as well as the first synthesis of (-)-crassalactone C was achieved starting from D-xylose. A comparison of their in vitro antitumour activities with those observed for the corresponding naturally occurring enantiomers was provided.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Xilose/química , Annonaceae/química , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células Jurkat , Lactonas/química , Estrutura Molecular , Plantas Medicinais/química , Estereoisomerismo , Células Tumorais CultivadasRESUMO
Two new (-)-muricatacin mimics bearing a furano-furanone ring and an oxygen isostere in the side chain have been designed and synthesized and their in vitro antiproliferative activity was evaluated against several human tumour cell lines. Both analogues showed an increased activity against HL-60 cells with 17- and 185-fold higher potency than (-)-muricatacin. A straightforward synthesis of (-)-muricatacin is also disclosed.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Furanos/síntese química , Furanos/farmacologia , Annonaceae/química , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Células HL-60 , Células HeLa , Humanos , Estrutura Molecular , Plantas Medicinais/química , EstereoisomerismoRESUMO
A new divergent approach to (+)-goniofufurone (1) and 7-epi-(+)-goniofufurone (2), as well as the first total synthesis of crassalactone C (3), has been achieved starting from D-xylose. In a preliminary bioassay, all three natural products 1, 2, and 3 showed remarkable in vitro antiproliferative activities against K562, Raji, and HeLa neoplastic cell lines.