ABSTRACT
Over-expression of the Bcl-2 anti-apoptotic proteins is closely related to tumorigenesis and associated with drug resistance. Here we report that luteolin, a main substance found in Flos Chrysanthemi, directly binds to and shows inhibitory activity against the Bcl-2 protein. We studied the binding mode of luteolin and its derivatives with target proteins, their structure-activity relationship, and their effect on the human leukemia cell line HL-60. The results suggest that luteolin and its derivatives with a benzyl group introduced to the B ring, are new small molecule Bcl-2 protein inhibitors, and their anti-tumor activity is likely related to their effect on the Bcl-2 protein.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Chrysanthemum/chemistry , Flowers/chemistry , Luteolin/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Luteolin/chemistry , Luteolin/isolation & purification , Models, Molecular , Molecular Structure , Small Molecule Libraries/chemistry , Small Molecule Libraries/isolation & purification , Structure-Activity RelationshipABSTRACT
A series of 1-benzylidene-3,4-dihydronaphthalen-2-one derivatives were designed and synthesized, and their biological activities in vitro and in vivo were evaluated. The results showed a number of the title compounds exhibiting potent nanomolar activity in several human cancer cell lines. Of these, compound 22b showed the strongest inhibitory activity against human CEM, MDA-MBA-435, and K562 cells (IC(50) = 1 nM), displayed in vitro inhibition of tubulin polymerization (IC(50) = 3.93 µM), and significantly induced cell cycle arrest in G2/M phase. In addition, compound 22b could inhibit the tumor growth in colon nude mouse xenograft tumor model significantly and seemed safer than CA-4 when achieving a similar tumor suppression. This study provided a new molecular scaffold for the further development of antitumor agents that target tubulin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Cycle/drug effects , Cell Line, Tumor , Chemistry Techniques, Synthetic , Female , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Models, Molecular , Naphthalenes/chemistry , Naphthalenes/toxicity , Protein Multimerization/drug effects , Protein Structure, Quaternary , Tubulin/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/toxicity , Xenograft Model Antitumor AssaysABSTRACT
The asymmetric unit of the title compound, C(12)H(12)N(2)O(3), contains two mol-ecules in which the benzene and isoxazole rings are almost coplanar, the dihedral angles between their mean planes being 1.76â (9) and 5.85â (8)°. The two mol-ecules inter-act with each other via N-Hâ¯N and N-Hâ¯O hydrogen bonds, which link the mol-ecules into layers parallel to the ac plane. The layers stack in a parallel mode with an inter-layer distance of 3.36â (7)â Å.
ABSTRACT
A series of 1-phenyl-3,4-dihydroisoquinoline derivatives and several 1-phenyl-1,2,3,4-tetrahydroisoquinoline, 1-phenyl-isoquinoline analogues were synthesized, and their cytotoxicity and tubulin polymerization inhibitory activity were evaluated. The 1-phenyl-3,4-dihydroisoquinoline compounds were found to be potential tubulin polymerization inhibitors. Compound 5n, bearing a 3'-OH and 4'-OCH(3) substituted 1-phenyl B-ring, was shown to confer optimal bioactivity. The single-crystal structure of 5n was further determined by X-ray diffraction, and the binding mode of 5n to tubulin was obtained by molecular docking, which can explain the structure-activity relationships. The studies presented here provide a new structural type for the development of novel antitumor agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Isoquinolines/chemical synthesis , Microtubules/drug effects , Tetrahydroisoquinolines/chemical synthesis , Tubulin Modulators/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity Relationship , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacology , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
On the basis of the comparison of the structure of the Bim BH3: Bcl-x(L) complex and that of the ABT-737: Bcl-x(L) complex, a series of class A compounds were designed. These compounds had the basic skeleton of ABT-737 and the h2 residues of Bim BH3. These residues had shown themselves to be relevant to Bim BH3's broad-spectrum binding properties in saturation mutagenesis assays. Unlike ABT-737, which is a selective inhibitor of anti-apoptotic members of the Bcl-2 protein family, the class A compounds showed broad-spectrum binding activity to target proteins similar to those of Bim BH3 peptide. Then class B compounds were synthesized by modifying the structure of the most effective class A compound, A-4. Most of these class B compounds showed better binding affinity to the target proteins than the class A compounds had. They also showed themselves more effective than ABT-737 at inhibiting growth in multiple tumor cell lines known to express Bcl-x(L), Bcl-2, and Mcl-1 proteins at high levels. Compounds B-11 and B-12 had the strongest anti-tumor activity of any compounds we produced. This study suggests that it is feasible to design small-molecule inhibitors based on the structure of Bim BH3, which shows broad-spectrum binding to Bcl-x(L), Bcl-2, and Mcl-1 proteins. Our results also suggest that the broad-spectrum properties of small-molecule inhibitors binding to target proteins play a critical role in inhibiting the growth of many tumor cells. Finally, our study provides a series of lead compounds that merit further research into anti-cancer therapeutics.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis , Chemistry, Pharmaceutical/methods , Drug Design , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Models, Chemical , Mutagenesis , Myeloid Cell Leukemia Sequence 1 Protein , Nitrophenols/pharmacology , Piperazines/pharmacology , Protein Binding , Proto-Oncogene Proteins c-bcl-2/chemistry , Sulfonamides/pharmacology , bcl-X Protein/antagonists & inhibitorsABSTRACT
A series of novel combretastatin-A4 analogues in which the cis-olefinic bridge is replaced by an imidazolone-amide were synthesized, and their cytotoxicity and tubulin-polymerization inhibitory activities were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors. Compounds 10, 9b and 9c, bearing 3'-NH2-4'-OCH3, 4'-CH3 and 3'-CH3-substituted 1-phenyl B-ring, confer optimal bioactivity. The binding modes of these compounds to tubulin were obtained by molecular docking, which can explain the compounds' structure-activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.
Subject(s)
Amides/chemistry , Imidazoles/chemistry , Stilbenes/chemistry , Tubulin Modulators/chemical synthesis , Tubulin/chemistry , Binding Sites , Cell Line, Tumor , Computer Simulation , Humans , Isomerism , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/pharmacology , Tubulin Modulators/toxicityABSTRACT
A series of novel pyrazino[2,1-a]isoquinolin compounds were designed, synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the title compounds exhibited antifungal activities. Most of them exhibited stronger antifungal activities than the lead compounds; compound 7c is more potent than fluconazole against two of the three tested fungal strains. The studies presented here provide a new structural type for the development of novel antifungal agents.
