ABSTRACT
Two novel sorbicillinoid analogues, (4'Z)-sorbicillin (1) and (2S)-2,3-dihydro-7-hydroxy-6-methyl-2-[(E)-prop-1-enyl]-chroman-4-one (2), together with three known compounds, (2S)-2,3-dihydro-7-hydroxy-6,8-dimethyl-2-[(E)-prop-1-enyl]-chroman-4-one (3), sorbicillin (4), and 2',3'-dihydrosorbicillin (5), were isolated from the culture broth of the fungus Trichoderma sp. associated with the seastar Acanthaster planci. Their structures were determined by analysis of the NMR and MS data. Compound I was the first example with a Z-configuration of the C-4'/C-5' double bond in the sorbyl side chain. Compounds 2 and 3 were uncommon monomeric sorbicillinoids with a cyclic sorbyl chain. 2, 3 and 5 showed moderate cytotoxic activities against various cancer cell lines.
Subject(s)
Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Chromans/chemistry , Chromans/pharmacology , Resorcinols/chemistry , Resorcinols/pharmacology , Starfish/microbiology , Trichoderma/chemistry , Animals , Cell Line, Tumor , Circular Dichroism , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Conformation , Spectrometry, Mass, Electrospray Ionization , Tetrazolium Salts , ThiazolesABSTRACT
A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , G-Quadruplexes , Indoles/chemical synthesis , Indoles/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Telomere/chemistry , Alkaloids/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell-Free System , Circular Dichroism , Dialysis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Indoles/chemistry , Ligands , Methylation , Models, Molecular , Potassium/chemistry , Quinolines/chemistry , Structure-Activity Relationship , Telomerase/antagonists & inhibitors , Telomerase/metabolism , Telomere/genetics , ThermodynamicsABSTRACT
Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Curcumin/analogs & derivatives , Curcumin/chemical synthesis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Furans/chemistry , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/chemistry , Tumor Cells, CulturedABSTRACT
Natural curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) isolated from Curcuma longa (turmeric), and synthetic curcumin analogs (A(1-7), B(1-7), C(1-6) and D(1-7)) were evaluated in vitro for the alpha-glucosidase inhibitory activity via UV and circular dichroism (CD) spectroscopy. The results indicated that natural curcuminoid compound 3 showed a remarkable inhibitory effect with IC(50) of 23.0 microM, and the synthetic compounds A(2), B(2), C(2) and D(2) showed potent inhibitory effects with IC(50) of 2.8, 2.6, 1.6 and 8.2 microM, respectively. Kinetic study exhibited that the mechanism of alpha-glucosidase inhibition of both 3 and C(2) was non-competitive. The structure activity relationship revealed that the ortho dihydroxyl groups could form a more tight interaction with alpha-glucosidase to exert more potential inhibitory activities.
