ABSTRACT
A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles, while the same reaction afforded 3-cyano-benzopyrrolo-imidazoles under microwave irradiation. Two nonequivalent nucleophilic centers on benzimidazole moiety were manipulated elegantly by different reaction conditions to achieve the skeletal diversity.
Subject(s)
Benzimidazoles/chemical synthesis , Furans/chemical synthesis , Imidazoles/chemical synthesis , Nitriles/chemical synthesis , Pyrroles/chemical synthesis , Magnetic Resonance Imaging , Mass Spectrometry , Microwaves , Molecular Structure , StereoisomerismABSTRACT
In the present work a novel C,N-cyclometalated benzimidazole Ru(ii) arene complex (GY34) was characterized by applying an alternative, diverse approach considering both chemical and biological aspects. RP-HPLC-ICP-MS and RP-HPLC-ESI-MS analysis proved that GY34 in both RPMI-1640 cell medium and ammonium acetate buffer was transformed into several subspecies and the importance of evaluating and controlling analyte stability throughout experiments was demonstrated. Applying a novel cell fractionation protocol GY34 was found to target cell nuclei and mitochondria in Ehrlich Lettré Ascites (ELA) cells, with the intracellular distribution depending on GY34 concentration in the cell medium during incubation. In ELA cells 96 ± 0.2% of cytosolic GY34 was bound to high-molecular species. Furthermore, using the tracer technique GY34 was found to reduce uptake and increase release of the organic osmolyte taurine in ELA cells, with innate resistance to Cisplatin and in A2780 human ovarian cancer cells, with acquired resistance to Cisplatin. Importantly, FACS analysis revealed that GY34 induced apoptosis in ELA cells. The present data suggest the potential of GY34 in overcoming Cisplatin resistance. The methodology applied can be used as a general protocol and an additional tool in the initial evaluation of novel metal-based drugs.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Benzimidazoles/pharmacokinetics , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cell Line, Tumor , Female , Homeostasis/drug effects , Humans , Mice , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Ovary/drug effects , Ovary/metabolism , Ovary/pathology , Ruthenium/pharmacokinetics , Taurine/metabolismABSTRACT
A library of over 20 cycloplatinated compounds of the type [Pt(dmba-R)LCl] (dmba-R = C,N-dimethylbenzylamine-like ligand; R being MeO, Me, H, Br, F, CF3, and NO2 substituents in the R5 or R4 position of the phenyl ring; L = DMSO and P(C6H4CF3-p)3) has been prepared. All compounds are active in both human ovarian carcinoma A2780 cells and cisplatin-resistant A2780cisR cells, with most of the DMSO platinum complexes exhibiting IC50 values in the submicromolar range in the A2780 cell line. Interestingly, DMSO platinum complexes show low cytotoxicity in the nontumorigenic kidney cell line BGM and therefore high selectivity factors SF. In addition, some of the DMSO platinum complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926. These are the first platinum(II) complexes reported to inhibit angiogenesis at a close concentration to their IC50 in A2780 cells, turning them into dual cytotoxic and antiangiogenic compounds.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Chlorocebus aethiops , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Structure-Activity RelationshipABSTRACT
The design of small molecules that can target the aggregation of Aß as potential therapeutic agents for Alzheimer's disease is an area of study that has attracted a lot of attention recently. The novel ligand methyl 1-butyl-2-pyridyl-benzimidazole carboxylate was prepared for the synthesis of a series of new iridium(III), ruthenium(II), and platinum(II) 2-pyridyl-benzimidazole complexes. The crystal structure of the half-sandwich iridium(III) complex was established by X-ray diffraction. An arrangement of two cationic complexes in the unit cell is observed, and it seems to be organized by weak π···π interactions that are taking place between two symmetry-related benzimidazole ring systems. All new compounds inhibited aggregation of Aß1-42 in vitro as shown by both thioflavin T fluorescence assay and transmission electron microscopy. Among them the Ir compound rescued the toxicity of Aß1-42 in primary cortical neurons effectively.
Subject(s)
Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/toxicity , Benzimidazoles/chemistry , Neurons/drug effects , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Peptide Fragments/chemistry , Peptide Fragments/toxicity , Protein Multimerization/drug effects , Animals , Chemistry Techniques, Synthetic , Drug Design , Female , Iridium/chemistry , Ligands , Mice , Models, Molecular , Molecular Conformation , Neurons/cytology , Organometallic Compounds/chemistry , Platinum/chemistry , Pregnancy , Protein Structure, Secondary , Ruthenium/chemistryABSTRACT
A series of potent C,N-cycloplatinated(II) phosphine antitumor complexes containing fluorous substituents in the cyclometalated or the ancillary phosphine ligands [Pt(C-N)(PR3)Cl] or both have been synthesized and characterized. The crystal structure of [Pt(dmba){P(C6H4CF3-p)3}Cl]·2CH2Cl2 (dmba = dimethylaminomethyl)phenyl) has been established by X-ray diffraction. Values of IC50 of the new platinum complexes were calculated toward a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). Complexes containing P(C6H4CF3-p)3 as ancillary ligand (with a bulky and electronegative CF3 substituent in para position) were the most cytotoxic compounds in all the tested cancer cell lines. In some cases, the IC50 values were 16-fold smaller than that of cisplatin and 11-fold smaller than the non-fluorous analogue [Pt(dmba)(PPh3)Cl]. On the other hand, very low resistance factors (RF) in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF ≈ 1) for most of the new compounds. Analysis of cell cycle was done for the three more active compounds in A2780. They arrest cell growth in G0/G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. They are also good cathepsin B inhibitors (an enzyme implicated in a number of cancer related events).
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Phosphines/chemistry , Phosphines/pharmacology , Animals , Breast/drug effects , Breast/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cathepsin B/metabolism , Cattle , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Female , Halogenation , Humans , Ligands , Models, Molecular , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovary/drug effects , Ovary/pathologyABSTRACT
Smart design and efficient synthesis of benzimidazole Ru, Ir and Rh cyclometalated complexes are reported with promising cytotoxic activity against HT29, T47D, A2780 and A2780cisR cancer cell lines. Their apoptosis, accumulation, cell cycle arrest, protein binding and DNA binding effects are also discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Coordination Complexes/pharmacology , Iridium/pharmacology , Rhodium/pharmacology , Ruthenium/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzimidazoles/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , DNA/metabolism , Humans , Iridium/chemistry , Protein Binding , Rhodium/chemistry , Ruthenium/chemistry , Serum Albumin/metabolismABSTRACT
A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-ß-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron ß-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-ß-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.
Subject(s)
Alkaloids/chemical synthesis , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Polycyclic Compounds/chemical synthesis , Acylation , Alkaloids/chemistry , Crystallography, X-Ray , Cycloaddition Reaction , Heterocyclic Compounds, Bridged-Ring/chemistry , Molecular Structure , Polycyclic Compounds/chemistry , StereoisomerismABSTRACT
Two new steroidal 7-azaindole-based N-donor ligands 17-α-[7-azaindole-5-ethynyl]-17-ß-testosterone (ET-Haza) (1) and 17-α-[7-azaindole-5-ethynyl]-19-nortestosterone (LEV-Haza) (2), and two new DNA damaging warheads with an enhanced lipophilicity [Pt(dmba)Cl(L)] (dmba=N,N-dimethylbenzylamine-κN,κC; L=ET-Haza (3) and LEV-Haza (4)) have been prepared and characterized. Values of IC50 were calculated for complexes 3 and 4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cis) and breast cancers (T47D). At 48 h of incubation time 3 and 4 showed very low resistance factors (RF of 1) against an A2780 cell line which has acquired resistance to cisplatin, IC50 values of the new complexes towards normal human LLC-PK1 renal cells at 48 h being about double than that of cisplatin. 3 and 4 are able to react with 9-ethylguanine (9-EtG) yielding the corresponding monoadduct [Pt(dmba)(L)(9-EtG)](+) derivatives as followed by ESI-MS. Compound 3 interacts mainly with double-stranded (DS) oligonucleotides as shown by analysis with ESI-TOF-MS, being also able to displace ethidium bromide (EB) from DNA, as observed by an electrophoretic mobility study. 3 and 4 are good cathepsin B inhibitors. Theoretical calculations at the COSMO(CHCl3)/B3LYP-D/def2-TZVPPecp//B3LYP-D/def2-TZVPecp level and energy evaluations at the COSMO(CHCl3)/PWPB95-D3/def2-TZVPPecp level of theory on compound 4 and model systems have been done.
Subject(s)
Antineoplastic Agents/chemistry , Indoles/chemistry , Organoplatinum Compounds/chemistry , Platinum/chemistry , Steroids/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , DNA/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor/methods , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Structure , Oligonucleotides/metabolism , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Spectrometry, Mass, Electrospray IonizationABSTRACT
A novel base-catalyzed Povarov reaction of arylamines, aldehydes, and electron-deficient dienophiles has been developed. An unprecedented in situ [1,3] sigmatropic rearrangement leading to 4,10-dihydropyrimido[1,2-a]benzimidazoles has also been discovered. An insight of the plausible mechanism is discussed and supported by X-ray crystal study. This cascade reaction is achieved in a one-pot multicomponent fashion on soluble support under microwave conditions.
Subject(s)
Benzimidazoles/chemistry , Hydrogen/chemistry , Pyridines/chemistry , Catalysis , Crystallography, X-Ray , Models, Molecular , Molecular StructureABSTRACT
A tandem transformation that involves the formation of three bonds and two heterocyclic rings in a one-pot fashion through amino-alkylation of an ionic-liquid-immobilized diamine with keto acids followed by successive double intramolecular cyclizations to afford a tricyclic framework has been explored. This tandem cyclization has been utilized to develop a rapid and efficient method to synthesize various pyrrolo[1,2-a]benzimidazolones and pyrido[1,2-a]benzimidazolones on an ionic-liquid support by using focused microwave irradiation. The application of this tandem cyclization was further extended to the aromatic keto acids to provide isoindolinone-fused benzimidazoles, a structurally heterogeneous library with skeletal diversity. The outcome of the cascade reaction was confirmed by the X-ray crystallographic study of the product directly attached to the ionic-liquid support. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by regular conventional spectroscopic methods, whereas application of microwave irradiation greatly accelerates the rate of the reactions.
Subject(s)
Ionic Liquids/chemistry , Isoindoles/chemistry , Microwaves , Pyrroles/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Crystallography, X-Ray , Cyclization , Molecular ConformationABSTRACT
A novel strategy for an unconventional Pictet-Spengler reaction has been developed for the regioselective cyclization of the imidazole ring system at the C2 position. The developed strategy was utilized to develop a diversity-oriented parallel synthesis for bis(heterocyclic) skeletal novel analogs of benzimidazole-linked imidazoquinoxalines on a soluble polymer support under microwave conditions. Condensation of polymer-immobilized o-phenylenediamines with 4-fluoro-3-nitrobenzoic acid followed by nucleophilic aromatic substitution with an imidazole motif affords bis(heterocyclic) skeletal precursors for the Pictet-Spengler reaction. The unconventional Pictet-Spengler cyclization with various aldehydes was achieved regioselectively at the C2 position of the imidazole ring to furnish rare imidazole-fused quinoxaline skeletons. During the Pictet-Spengler cyclization, aldehydes bearing electron-donating groups afford 4,5-dihydro-imidazoquinoxalines, which then auto-aromatize into benzimidazole-linked imidazo[1,2-a]quinoxalines. However, interestingly, aldehydes bearing electron-withdrawing groups directly provide aromatized imidazo[1,2-a]quinoxalines, which unexpectedly afford novel benzimidazole-linked 4-methoxy-4,5-dihydro-imidazo[1,2-a]quinoxalines after polymer cleavage.
Subject(s)
Benzimidazoles/chemistry , Imidazoles/chemistry , Polymers/chemistry , Quinoxalines/chemistry , Cyclization , Microwaves , Quinoxalines/chemical synthesis , StereoisomerismABSTRACT
An efficient soluble polymer-supported method has been developed for the parallel synthesis of substituted benzimidazole linked benzoxazoles using focused microwave irradiation. The key step involves the amidation of 4-hydroxy-3-nitrobenzoic acid with polymer-immobilized o-phenylenediamine. Application of mild acidic conditions promoted the ring closure to furnish the benzimidazole ring. After hydrogenation of the nitro-group to amine, the resulted polymer conjugates underwent efficient ring closure with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer-bound benzimidazolyl benzoxazoles. The polymer-bound compounds were finally cleaved from the support to furnish benzimidazole linked benzoxazole derivatives. The efficacy of the resultant angular bis-heterocyclic library was studied against vascular endothelial growth factor receptor (VEGFR-3). The preliminary screening of these novel compounds exhibits moderate to high inhibition (IC(50) = 0.56-1.42 µM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics.
Subject(s)
Benzimidazoles/chemistry , Benzoxazoles/chemical synthesis , Polymers/chemistry , Protein Kinase Inhibitors/chemical synthesis , Vascular Endothelial Growth Factor Receptor-3/antagonists & inhibitors , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Microwaves , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacologyABSTRACT
An efficient microwave-assisted and soluble polymer-supported synthesis of medicinally important imidazole-fused benzimidazoles has been developed. The protocol involves the rapid condensation of polymer-bound amino benzimidazoles with various α-bromoketones and subsequent in situ intramolecular cyclization under microwave irradiation resulting in a one pot synthesis of imidazole interlacing benzimidazole polymer conjugates. The condensed product was obtained with excellent regioselectivity. The biologically interesting imidazo[1,2-a]benzimidazoles was released from polymer support at ambient temperature. Diversity in the triheterocyclic nucleus was achieved by the different substitutions at its 2, 3, and 9 positions. The new protocol has the advantages of short reaction time, easy workup process, excellent yields, reduced environmental impact, wide substrate scope and convenient procedure.
Subject(s)
Benzimidazoles/chemical synthesis , Microwaves , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , Solubility , StereoisomerismABSTRACT
The Pictet-Spengler reaction, using polyethylene glycol immobilized tryptophan ester with a variety of ketones, was achieved by refluxing condition in acidic chloroform. The linear as well as cyclic ketones were employed. All the ketones were reacted within 6-8 h to furnish soluble polymer-supported tetrahydro-ß-carboline in good yields. Further expansion at N-terminus of tetrahydro-ß-carbolines was achieved through a reaction with chloroacetyl chloride. Finally, the 2,5-diketopiperazine skeleton was constructed over a ß-carboline by amination of the resulting N-chloroacetamides and subsequent intramolecular cyclization leading to cleavage of the polymer; constitutes a traceless synthesis of tetracyclic molecular architecture. Significantly, this strategy affords a straightforward and efficient approach for the construction of biological promising molecules with high purity and good yields.
Subject(s)
Carbolines/chemical synthesis , Combinatorial Chemistry Techniques , Diketopiperazines/chemistry , Polymers/chemistry , Amines/chemistry , Carbolines/chemistry , Ketones/chemistry , Models, Chemical , SolubilityABSTRACT
A novel intramolecular cyclization was discovered during the reaction of soluble polymer supported bis-Boc-guanidines with amines under microwave irradiation, leading to an oxadiazinone skeleton. The cyclized polymer conjugates have been further utilized to generate substituted 1,3,5-oxadiazinones by a traceless synthesis.
Subject(s)
Azirines/chemistry , Dihydropyridines/chemistry , Guanidines/chemistry , Amines , Cyclization , Microwaves , Polyethylene GlycolsABSTRACT
A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of advantages such as rapid process, simple purification, and structural diversity in one shot. Microwave-assisted multistep synthetic protocol was used to construct the benzimidazole ring on soluble polymer support using activated aryl-fluorides. The PEG anchored aryl fluoride was condensed with selective primary amines via an ipso-fluoro displacement reaction followed by reduction of nitro group. The subsequent cyclization with cyanogen bromide is used as a key step to furnish immobilized benzimidazoles. Finally multicomponent condensation of resulted polymer bound benzimidazoles with various aldehydes and 1,3-diones under microwave irradiations provides rapid access for triaza-fluorenes with high purity and excellent yields. Microwave irradiation greatly accelerates the rate of all reactions while polymer support facilitates purifications by simple precipitation technique. This strategy dramatically increases efficiency of overall multistep synthesis.