2‐amino‐4‐oxo‐6‐substituted‐pyrrolo[2,3‐d]pynmidines as potential inhibitors of thymidylate synthase

Classical, antifolate inhibitors of thymidylate synthase often suffer from a number of potential disadvantages when used as antitumor agents. These include impaired uptake due to an alteration of the active transport system required for cellular uptake, as well as the formation of long acting, non‐effluxing polygluta‐mates via folypolyglutamate synthetase, which are responsible for toxicity to normal cells. To overcome some of the disadvantages of classical thymidylate synthase inhibitors, there has been considerable interest in the synthesis and evaluation of nonclassical inhibitors, which could enter cells via passive diffusion and are not substrates for folypolyglutamate synthetase. A series of eight nonclassical 6‐substituted 2‐amino‐4‐oxo‐pyrrolo[2,3‐d]pyrimidines 2a‐2h were designed as potential inhibitors of thymidylate synthase. The synthesis of the target compounds 2a‐2h was achieved via regioselective iodination at the 6‐position of 5 , palladium‐catalyzed coupling with the appropriate phenylacetylenes, reduction of the C8‐C9 triple bond followed by saponification. Preliminary biological results indicated that none of the target compounds showed inhibitory activities against thymidylate synthase from Escherichia coli, Lactobacillus casei, rat or human thymidylate synthase at the concentrations tested. None of the target compounds showed inhibitory activity against dihydrofolate reductase from Escherichia coli, Lactobacillus casei, rat or human at 3.0 × 10^?5 M. However, 50% inhibition of dihydrofolate reductase from Pneumocystis carinii and from Toxoplasma gondii was achieved with compound 2d and with compound 2g at 3.0 × 10^?5 M.     

Novel Aryl‐Modified Benzoylamino‐N‐(5,6‐dimethoxy‐1H‐benzoimidazol‐2‐yl)‐heteroamides as Potent Inhibitors of Vascular Endothelial Growth Factor Receptors 1 and 2

Tumor angiogenesis has become an important target for antitumor therapy, with most current therapies aimed at blocking the vascular endothelial growth factor (VEGF) pathway. The VEGF and its receptors have been implicated as key factors in tumor angiogenesis and are major targets in cancer therapy. A series of aryl‐modified benzoylamino‐N‐(5,6‐dimethoxy‐1H‐benzoimidazol‐2‐yl)‐heteroamides were synthesized from 2‐amino‐5,6‐dimethoxy benzimidazole and aryl‐substituted benzoylamino hetero acids. The new compounds were tested for inhibition of VEGF receptors I and II (VEGFR‐1 and VEGFR‐2). Compound 6e displayed VEGFR‐2 inhibitory activity with a 50% inhibition concentration value as low as 0.020 μM in a homogeneous time‐resolved fluorescence enzymatic assay. VEGFR‐2 active compounds display good activity against VEGFR‐1 as well.     

A Convenient Regioselective Synthesis of Novel 1,4‐Phenylenemethylene‐6,6′‐bis‐([1,2,4‐triazolo]‐[4,3‐b][1,2,4]‐triazin‐7(1H)‐ones)

The target compounds 6,6′‐(1,4‐phenylenedimethylene)‐bis(3‐thioxo‐1,2,4‐triazin‐5(1H )‐one) 4,5 were prepared from reaction of oxazolone 1 with thiosemicarbazide and 4‐phenylthiosemicarbazide, in potassium hydroxide solution, respectively. Reaction of 4 with hydrazonoyl halides 6 afforded triazolotriazine derivatives 7 . Also, 5 reacted with 6 to give the corresponding substitution products 8 . Antimicrobial and antitumor activities for some compounds were studied.     

Design and Synthesis of 2‐(5‐Phenylindol‐3‐yl)benzimidazole Derivatives with Antiproliferative Effects towards Triple‐Negative Breast Cancer Cells by Activation of ROS‐Mediated Mitochondria Dysfunction

Benzimidazole derivatives are widely studied because of their broad‐spectrum biological activity, such as antitumor properties and excellent fluorescence performance. Herein, two types of 2‐(5‐phenylindol‐3‐yl)benzimidazole derivatives ( 1 a – 1 h and 2 a – 2 e ) were rationally designed and synthesized. When these compounds were investigated in vitro anti‐screening assays, we found that all of them possessed antitumor effect, in particular compound 1 b , which showed an outstanding antiproliferative effect on MDA‐MB‐231 cells (IC₅₀≈2.6 μm ). A study of the drug action mechanisms in cells showed that the antitumor activity of the compounds is proportional to their lipophilicity and cellular uptake; the tested compounds all entered the lysosome of MDA‐MB‐231 cells and caused changes in the levels of reactive oxygen species (ROS), and then caused mitochondrial damage. Apparent differences in the ROS levels for each compound suggest that the lethality of these compounds towards MDA‐MB‐231 cells is closely related to the ROS levels. Taken together, this study not only provides a theoretical basis for 2‐(5‐phenylindol‐3‐yl)benzimidazole anticarcinogens but also offers new thinking on the rational design of next‐generation antitumor benzimidazole derivatives.     

One‐Step Synthesis of 3,4‐Diphenyl‐2‐pyrrolinones by Solvent‐Free and Bi2O3‐Catalyzed Approaches and Cytotoxicity Screening Against Glioma Cells

Multifunctionalized 2‐pyrrolinones were synthesized from the formal aza‐[3 + 2] cycloaddition reaction of acyclic enaminones and diphenylcyclopropenone. For primary enaminones, solventless reaction under microwave heating was developed. On the other hand, catalysis by Bi₂O₃ under conventional heating was the more suitable strategy when secondary enaminones were employed. These conditions allowed the synthesis of a set of 2‐pyrrolinones with two vicinal phenyl substituents, which were evaluated for cytotoxicity against U251 and C6 glioblastoma cells. In general, all tested 2‐pyrrolinones with two vicinal phenyl rings were more active than those without this structural moiety, and 1‐butyl‐5‐methyl‐5‐(2‐oxopropyl)‐3,4‐diphenyl‐1,5‐dihydro‐2H‐pyrrol‐2‐one was the most cytotoxic and appears to be a new possibility as an antitumor scaffold to this aggressive brain tumor.     

A Convenient Synthesis and Biological Research of Novel 5,6,7,8‐Tetrahydro‐1,6‐naphthyridin‐2(1H)‐one Derivatives Hydrochloride as Cytotoxic Agents

A series of 5,6,7,8‐tetrahydro‐1,6‐naphthyridin‐2(1H)‐one derivatives hydrochloride were obtained using a convenient and mild method from 4‐piperidone monohydrate hydrochloride. The newly synthesized compounds and their derivatives were characterized by ¹H NMR, ¹³C NMR, and high‐resolution mass spectrometry. Furthermore, cytotoxicity in vitro of the synthesized compounds were screened using MTT or CCK8 assay. The results showed that some of the compounds showed potential antitumor activity. Among of them, compound 10a had effects against tumor cells (MOLM‐13), and the half maximal inhibitory concentration value was 76 μmol/L.     

Selected Methodologies Convenient for the Synthesis of N,5‐Diaryloxazole‐2‐amine Pharmacophore

N,5‐Diaryloxazole‐2‐amine moiety is a strong pharmacophore found in 775 biologically active compounds possessing antitumor, anti‐infective, immunosuppressive, anti‐inflammatory, and other activities. Despite a broad biological exploitation, synthesis of N,5‐diaryloxazole‐2‐amine‐containing compounds is still not well developed. Preparation of oxazole‐2‐amine moiety is a relatively complex topic, and often low yields are observed. In this article, we discussed four synthetic methodologies and provided some generalization of their advantages, as well as further synthetic development. Using these methodologies, we prepared all together 10 new oxazole‐2‐amine derivatives and discovered presence of urea and enamine side products.     

Ferrocene‐substituted 3,3′‐diindolylmethanes with improved anticancer activity

A series of ferrocene‐substituted derivatives ( 2a , 2b , 2c , 2d , 2e , 2f , 2g ) of the known drug 3,3′‐diindolylmethane ( DIM ) were prepared and tested for their in vitro antitumor activity. The derivatives 2a (featuring indole moiety), 2b (featuring 2‐methylindole moiety) and 2f (featuring 5‐nitroindole moiety) were growth‐inhibiting in vitro at lower concentrations than DIM in various tumor cells including pancreas cancer (BcPC‐3), three DIM‐resistant cancer cell lines (518 A2, KB‐V1/Vbl, HT‐29), triple‐negative breast cancer (MDA‐MB‐231) and prostate cancer (PC‐3). Derivatives 2a , 2b and 2f were the most active compounds of this series, qualifying as drug candidates for various cancer diseases. Copyright © 2016 John Wiley & Sons, Ltd.     

Organotin Carboxylates based on 3‐(1,3‐Dioxo‐2,3‐dihydro‐1H‐phenalen‐2‐yl)benzoic Acid and the Influence of Solvent on the Molecular Structure

Self‐assembly of dibutyltin oxide with 3‐(1,3‐dioxo‐2,3‐dihydro‐1H‐phenalen‐2‐yl)benzoic acid (HL) produces (nBu)₂SnL₂ ( 1 ) when benzene is used as solvent, whereas the reaction generates {[(nBu)₂SnO]₂L}₂ · C₇H₈ ( 2 ) when toluene is the reactive solvent. The novel organotin carboxylate (nBu)₂SnL₂ ( 1 ) was characterized by elemental analysis, as well as IR, ¹H, ¹³C, and ¹¹⁹Sn NMR spectroscopy. Single crystal X‐ray study reveals that 1 is a dialkyltin carboxylate monomer possessing crystallographically imposed twofold symmetry. Ligand HL in 1 chelates with tin atom in bidentate coordination mode. The molecules of 1 build complicate 1D, 2D, and 3D structures via intermolecular hydrogen bonds, and π ··· π interactions can be found in the 3D architecture. The preliminary fluorescence activity and antitumor activity of the complex were also studied.     

Synthesis of Novel 5,6‐Dihydropyrrolo[2,1‐a]isoquinolines via Grob Reaction between (E)‐1,1,1‐Trifluoro‐3‐nitro‐2‐butene and 3,4‐Dihydroisoquinolines

Uncatalyzed cycloaddition of 3,4‐dihydroisoquinolines to (E)‐1,1,1‐trifluoro‐3‐nitro‐2‐butene via Grob reaction provide a simple one‐step route to the 5,6‐dihydropyrrolo[2,1‐a]isoquinolines, which represent the basic structural framework of the antitumor active alkaloid crispine.     

Chemie freier cyclischer vicinaler Tricarbonyl‐Verbindungen (‘1,2,3‐Trione') Teil 2. Redox‐Reaktionen von 1,2,3‐Trionen mit En‐1,2‐diolen (‘Reduktonen'), 2‐Alkoxy‐en‐1‐olen,En‐1,2‐diaminen und verwandten Spezies

Chemistry of Free Cyclic Vicinal Tricarbonyl Compounds (‘1,2,3‐Triones'). Part 2. Redox Reactions of 1,2,3‐Triones with Ene‐1,2‐diols (‘Reductones'), 2‐Alkoxy‐en‐1‐ols, Ene‐1,2‐diamines, and Related Species . Midstanding carbonyl groups of cyclic 1,2,3‐triones 4 possess outstanding electrophilic (electron‐pair accepting) as well as oxidizing (one‐electron accepting) properties. Their reactions with selected electron‐rich CC bonds as efficient nucleophiles (A_N reactions) and as efficient reducing agents (SET (single electron transfer) reactions) are studied. In a few cases, short‐lived charge‐transfer colors could be observed. Particularly, free didehydro‐5,6‐O‐isopropyliden‐L ‐ascorbic acid ( 4g ), its O,C‐adduct 8g to 5,6‐O‐isopropylidene‐L ‐ascorbic acid ( 1g ), and – via an independent pathway – the ostensible C,C‐dimer 10a of mono‐dehydrodimedone reductone were prepared. Intermediate radical anions 4 ^.− can be considered to be ideal representatives of dicapto‐dative radicals. Novel large‐scale syntheses of 3,4‐dihydroxyfuran‐2(5H)‐one ( 1e ) and of its vicinal trione 4e are presented.     

Synthesis of 2‐amino‐4‐oxo‐5‐substitutedbenzylthiopyrrolo[2,3‐d]‐pyrimidines as potential inhibitors of thymidylate synthase

A series of ten novel 2‐amino‐4‐oxo‐5‐[(substitutedbenzyl)thio]pyrrolo[2,3‐d]pyrimidines 2‐11 were synthesized as potential inhibitors of thymidylate synthase and as antitumor agents. The analogues contain various electron withdrawing and electron donating substituents on the benzylsulfanyl ring of the side chains and were synthesized from the key intermediate 2‐amino‐4‐oxo‐6‐methylpyrrolo[2,3‐d]pyrimidine, 14 . Appropriately substituted benzyl mercaptans were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against human, Escherichia coli and Toxoplasma gondii thymidylate synthase and against human, Escherichia coli and Toxoplasma gondii dihydrofolate reductase. The most potent inhibitor, ( 6 ) which has a 4′‐methoxy substituent on the side chain, has an IC₅₀=25 μM against human thymidylate synthase. Contrary to analogues of general structure 1 , electron donating or electron withdrawing substituents on the side chain of 2‐11 had little or no influence on the human thymidylate synthase inhibitory activity.     

Synthesis and Docking Studies of Some 1,2,3‐Benzotriazine‐4‐one Derivatives as Potential Anticancer Agents

Newly synthesized 1,2,3‐benzotriazine‐4‐one derivatives substituted at position‐3 were characterized by various analytical and spectral techniques. The in vitro antitumor activity was evaluated against three different cell lines (liver cells cancer, colorectal cancer, and breast cancer), where compounds 7b , 15 , and 25 showed strong antitumor activity with IC₅₀ ranging from 5.54 to 16.26 μM. In addition, molecular modeling studies using MOE were performed to investigate their binding modes to the C‐Met kinase active site. Docking results demonstrated that all new compounds recognized the active sites of C‐Met kinase and form different types of bonding interactions with key active site amino acid residues.     

In situ fabrication of paclitaxel‐loaded core‐crosslinked micelles via thiol‐ene “click” chemistry for reduction‐responsive drug release

In this study, a facile method to fabricate reduction‐responsive core‐crosslinked micelles via in situ thiol‐ene “click” reaction was reported. A series of biodegradable poly(ether‐ester)s with multiple pendent mercapto groups were first synthesized by melt polycondensation of diol poly(ethylene glycol), 1,4‐butanediol, and mercaptosuccinic acid using scandium trifluoromethanesulfonate [Sc(OTf)₃] as the catalyst. Then paclitaxel (PTX)‐loaded core‐crosslinked (CCL) micelles were successfully prepared by in situ crosslinking hydrophobic polyester blocks in aqueous media via thiol‐ene “click” chemistry using 2,2′‐dithiodiethanol diacrylate as the crosslinker. These PTX‐loaded CCL micelles with disulfide bonds exhibited reduction‐responsive behaviors in the presence of dithiothreitol (DTT). The drug release profile of the PTX‐loaded CCL micelles revealed that only a small amount of loaded PTX was released slowly in phosphate buffer solution (PBS) without DTT, while quick release was observed in the presence of 10.0 mM DTT. Cell count kit (CCK‐8) assays revealed that the reduction‐sensitive PTX‐loaded CCL micelles showed high antitumor activity toward HeLa cells, which was significantly higher than that of reduction‐insensitive counterparts and free PTX. This kind of biodegradable and biocompatible CCL micelles could serve as a bioreducible nanocarrier for the controlled antitumor drug release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 99–107     

An Efficient and Convenient Synthesis of Ethyl 1‐(4‐Methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate

The “click chemistry” of using organic azides and terminal alkynes is arguably the most efficient and straightforward route to the synthesis of 1,2,3‐triazoles. In this paper, an alternative and direct access to ethyl 1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate is described. Treatment of ethyl diazoacetate with 4‐methoxyaniline derived aryl imines in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene provided fully substituted 1,2,3‐triazoles in good to high chemical yields. The base‐mediated reaction tolerates various substituted phenyl imines as well as ethyl diazoacetate or the more bulky diazoacetamide. A reasonable mechanism is proposed that involves the addition of an imine nitrogen atom to the terminal nitrogen atom of the diazo compound, followed by aromatization to give the 1,2,3‐triazole. The presence of the 4‐carboxy group is advantageous as it can be easily transformed into other functional groups.     

Preparation and Reactions of 2‐Methyl‐7‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐arylthiazolo[3,2‐a]‐pyrimido[4,5‐d]oxazin‐4(5H)‐one

Ethyl 7‐amino‐3‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐aryl‐5H‐thiazolo[3,2‐a]pyrimidine‐6‐carboxylate was hydrolyzed with an ethanolic sodium hydroxide and the sodium salt thus formed underwent cyclization with acetic anhydride to afford 2‐methyl‐7‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐arylthiazolo[3,2‐a]pyrimido[4,5‐d]oxazin‐4(5H)‐one. This compound was transformed to related heterocyclic systems via its reaction with various reagents. The biological activity of the prepared compounds was tested against Gram positive and Gram negative bacteria as well as yeast‐like and filamentous fungi. They revealed in some cases excellent biocidal properties.     

Synthesis and bioactivities of 1,3,2‐benzodiazaphosphorin‐2‐carboxamide 2‐oxides containing α‐aminophosphonate groups

In order to search for novel antitumor and antiviral agents with high activity and low toxicity, a series of 1‐ethoxycarbonylmethyl‐3‐ethyl‐1,2,3,4‐tetrahydro‐4‐oxo‐1,3,2‐benzodiazaphosphorin‐2‐carboxamide 2‐oxides containing α‐aminophosphonate groups have been designed and synthesized by a convenient one‐pot procedure in good yields. The structures of products were confirmed by ¹H NMR, ³¹P NMR, IR spectra, and elemental analyses. The bioassay results showed that some of them possess excellent anti–tobacco mosaic virus activities and exhibit higher inhibitory effects compared with that of the contrast drug 2,4‐dioxyhexahydro‐1,3,5‐triazine. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:97–101, 2001     

Rigid‐rod polyamides and polyimides prepared from 4,3″‐diamino‐2′,6′‐di(2‐naphthyl)‐p‐terphenyl and 2′,6′,3‴,5‴‐tetra(2‐naphthyl)‐4,4″‐diamino‐p‐quinquephenyl

A series of rigid‐rod polyamides and polyimides containing p‐terphenyl or p‐quinquephenyl moieties in backbone as well as naphthyl pendent groups were synthesized from two new aromatic diamines. The polymers were characterized by inherent viscosity, elemental analysis, FT‐IR, ¹H‐NMR, ¹³C‐NMR, X‐ray, differential scanning calorimetry (DSC), thermomechanical analysis (TMA), thermal gravimetric analysis (TGA), isothermal gravimetric analysis, and moisture absorption. All polymers were amorphous and displayed T_g values at 304–337°C. Polyamides dissolved upon heating in polar aprotic solvents containing LiCl as well as CCl₃COOH, whereas polyimides were partially soluble in these solvents. No weight loss was observed up to 377–422°C in N₂ and 355–397°C in air. The anaerobic char yields were 57–69% at 800°C. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 15–24, 1999     

New trans/cis tetrahydroisoquinolines. 1. trans‐2‐benzyl‐3‐(l‐methyl‐1h‐pyrrol‐2‐yl)‐4‐substituted‐1,2,3,4‐tetrahydroisoquinolin‐1‐ones and corresponding tetrahydroisoquinolines

The reaction of homophthalic anhydride and N‐(1‐methyl‐1H‐pyrrol‐2‐yl‐methylidene)‐benzylamine in boiling benzene afforded as a main product the expected substituted trans‐1,2,3,4‐tetrahydroisoquinoline‐4‐carboxylic acid 5 . The carboxylic group of 5 was transformed in four steps into cyclic amino‐methyl groups yielding numerous new tetrahydroisoquinolinones 11a‐j incorporating a given fragment of pharmacological interest. Reduction of 11a‐j was studied.     

Synthesis and antitumor activities of 2‐(substituted)phenyl‐1,2,4‐triazolo[1,5‐a]pyridines

Twenty‐three 2‐(substituted)phenyl‐1,2,4‐triazolo[1,5‐a]pyridines have been synthesized by cycloadditison reaction between N‐amino methylpyridinium mesitylenesulfonates and substituted benzonitriles under the presence of potassium hydroxide at room temperature. The structures of all products were confirmed by ¹H NMR, MS and elemental analyses. The antitumor activities of these compounds were evaluated against human ovary cancer cell line (HO‐8910) in vitro by MTT method. The preliminary results showed that compound 1e (IC₅₀ 28μM) and compound 1w (IC₅₀ 31μM) exhibited stronger antitumor activities than cisplatin (IC₅₀ 35μM) in vitro. Hence, 1e and 1w have potential antitumor activities and are worth further investigation.