RESUMO
Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.
Assuntos
Actinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos , Leucemia P388/tratamento farmacológico , Modelos Moleculares , Conformação Molecular , Animais , Depsipeptídeos/síntese química , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia P388/patologia , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A combination of HPLC-MS and HPLC-NMR techniques has been used to analyse the cytotoxic fractions of the dichloromethane extract of bark of Stauranthus perforatus. Six furanocoumarins (byakangelicol, heraclenin, heraclenol, imperatorin, isopimpinellin and xanthotoxin) and nine quinoline alkaloids (two known compounds, veprisine and 5-hydroxy-1-methyl-2-phenyl-4-quinolone, along with seven novel compounds, stauranthine, 3',4'-dihydroxy-3',4'-dihydroveprisine, 3',4'-dihydroxy-3',4'-dihydrostauranthine, 3',6'-dihydroxy-3',6'-dihydroveprisine, 3',6'-dihydroxy-3',6'-dihydrostauranthine, 6'-hydroxy-3'-ketoveprisine and 6'-hydroxy-3'-ketostauranthine) have been identified in the fractions.
Assuntos
Casca de Planta/química , Extratos Vegetais/química , Rutaceae/química , Alcaloides/análise , Alcaloides/química , Cromatografia Líquida de Alta Pressão , Furocumarinas/análise , Furocumarinas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Quinolinas/análise , Quinolinas/químicaRESUMO
The synthesis of a lyngbyastatin 1-Ibu-epilyngbyastatin 1 mixture combined with NMR and molecular modeling studies proved that natural lyngbyastatin 1 was only one Ibu epimer rather than a mixture of both and that the configuration of this epimer in the Ibu unit was R. The substance isolated with lyngbyastatin 1 was Ibu-epidolastatin 12. The extreme broadness in the proton NMR spectra of lyngbyastatin 1 and Ibu-epidolastatin 12 was exchange broadening due to rotation about the Ibu-Ala amide bond. It was a consequence of (1) a small energy difference between the cis and trans forms of this bond, (2) a substantial difference in conformation between these forms, and (3) a lowered barrier between them compared to most amide bonds (due to steric hindrance). The synthetic lyngbyastatin 1-Ibu-epilyngbyastatin 1 mixture had significant activities against cancer cells and in stimulating actin polymerization, but was less active than dolastatin 11 in all assays.
Assuntos
Antineoplásicos/síntese química , Depsipeptídeos , Oligopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Alga Marinha/química , Actinas/antagonistas & inibidores , Actinas/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares , Masculino , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Neoplasias da Próstata , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Arganine C (1) and a new saponin, tieghemelin (2), were isolated from Tieghemella heckelii fruits. Arganine C (1) strongly inhibited HIV entry into cells in a cell fusion assay. The less potent tieghemelin (2) was converted into arganine C (1) by reduction of its ethyl ester with sodium borohydride. The removal of the four-sugar chains from arganine C (1) and tieghemelin (2) to give 16alpha-hydroxyprotobassic acid 3-O-beta-D-glucopyranoside (3) and 16alpha-hydroxyprotobassic acid 3-O-beta-D-glucuronopyranoside (4), respectively, caused total loss of activity in both cases. Arganine C (1) was not significantly cytotoxic to HeLa-CD4(+) cells at the level required to reduce the syncytium count to zero, suggesting it to be a promising candidate for further study as an antiviral drug.
