Synthesis of Novel Pyrimido[4,5‐b]quinolin‐4‐ones with Potential Antitumor Activity

The 5,6,7,8,9,10‐hexahydro‐2‐methylthiopyrimido[4,5‐b]quinolines 4a , 4b , 4c , 4d , 5a , 5b , 5c , 5d and their oxidized forms 6a , 6b , 6c , 6d , 7a , 7b , 7c , 7d were obtained from the reaction of 6‐amino‐2‐(methylthio)pyrimidin‐4(3H)‐one 2 or 6‐amino‐3‐methyl‐2‐(methylthio)pyrimidin‐4(3H)‐one 3 and α,β‐unsaturated ketones 1a , 1b , 1c , 1d using BF₃.OEt₂ as catalyst and p‐chloranil as oxidizing agent. Some of the new compounds were evaluated in the US National Cancer Institute (NCI), where compound 5a presented remarkable activity against 46 cancer cell lines, with the most important GI₅₀ values ranging from 0.72 to 18.4 μM from in vitro assays.     

Synthesis of dihydrofuro[2,3‐b]pyridines by the reaction of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles with α,β‐unsaturated carbonyl compounds

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles 1a‐d with α,β‐unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a‐d , 3a‐d and 4a‐d. Compounds 2a‐d and 3a‐c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a‐alkoxyhexahydrofuro[2,3‐b]pyridines 5a‐d, 6a‐d, 7a‐c and 8a‐c . Treatment of 5a‐d, 6a‐d, 7a‐c and 8a‐c with potassium tert‐butoxide produced the corresponding dihydrofuro[2,3‐b]pyridines 9a‐d and 10a‐c . The reaction of 4a‐c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro‐furo[2,3‐b]pyridines 11a‐c .     

Quinolone analogues 1. A convenient synthesis of 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylic acids

The reaction of the alkylhydrazinoquinoxaline N‐oxides 2a‐d with dimethyl acetylenedicarboxylate gave the dimethyl 1‐alkyl‐1,5‐dihydropyridazino[3,4‐b]qumoxaline‐3,4‐dicarboxylates 3a‐d , whose reaction with nitrous acid effected the C₄‐oxidation to afford the dimethyl 1‐alkyl‐4‐hydroxy‐1,4‐dihydropyridazino‐[3,4‐b]quinoxaline‐3,4‐dicarboxylates 4a‐d , respectively. The reaction of compounds 4a‐d with 1,8‐diazabicyclo[5.4.0]‐7‐undecene in ethanol provided the ethyl 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxa‐line‐3‐carboxylates 5a‐d , while the reaction of compounds 4a‐d with potassium hydroxide furnished the 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylic acids 6a‐d , respectively. Compounds 6c,d were also obtained by the reaction of compounds 5c,d with potassium hydroxide, respectively.     

Light and pH Dual‐Degradable Triblock Copolymer Micelles for Controlled Intracellular Drug Release

A novel amphiphilic ABA‐type triblock copolymer poly(ethylene glycol)‐b‐poly(ethanedithiol‐alt‐nitrobenzyl)‐b‐poly(ethylene glycol) (PEG‐b‐PEDNB‐b‐PEG) is successfully prepared by sequential thiol‐acrylate Michael addition polymerization in one pot. PEG‐b‐PEDNB‐b‐PEG is designed to have light‐cleavable o‐nitrobenzyl linkages and acid‐labile β‐thiopropionate linkages positioned repeatedly in the main chain of the hydrophobic block. The light and pH dual degradation of PEG‐b‐PEDNB‐b‐PEG is traced by gel permeation chromatography (GPC). Such triblock copolymer can self‐assemble into micelles, which can be used to encapsulate anticancer drug doxorubicin (DOX). Because of the different degradation chemistry of o‐nitrobenzyl linkages and β‐thiopropionate linkages, DOX can be released from the micelles by two different manners, i.e., light‐induced rapid burst release and pH‐induced slow sustained release. Confocal laser scanning microscopy (CLSM) results indicated that DOX‐loaded micelles exhibited faster drug release in A549 cells after UV irradiation. Furthermore, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) results show that the DOX‐loaded micelles under UV light degradation exhibit better anticancer activity against A549 cells than that of the nonirradiated ones.

     

Design and Synthesis of Some Novel 2,3,4,5‐Tetrahydro‐1H‐pyrido[4,3‐b]indoles as Potential c‐Met Inhibitors

Since deregulation of the tyrosine‐kinase receptor c‐Met is implicated in several human cancers and is an attractive target for small‐molecule‐drug discovery, we report herein the synthesis of 2,3,4,5‐tetrahydro‐8‐[1‐(quinolin‐6‐ylmethyl)‐1H‐1,2,3‐triazolo[4,5‐b]pyrazin‐6‐yl]‐1H‐pyrido[4,3‐b]indoles 4a – 4c and 2,3,4,5‐tetrahydro‐8‐[3‐(quinolin‐6‐ylmethyl)‐1,2,4‐triazolo[4,3‐b]pyridazin‐6‐yl]‐1H‐pyrido[4,3‐b]indoles 5a – 5c . These indole derivatives demonstrated inhibition of c‐Met kinase activity. Concurrently, five key intermediates were synthesized. These compounds could be prepared in good yields.     

Fabrication of Metal‐Block‐Copolymer Composite Films by a Palladium‐Catalyzed Electroless Nickel‐Plating Process

Summary: Homogeneous films of PI‐b‐PDMAEMA are prepared on top of silicon (100) substrates. The free film surface shows microdomains of PDMAEMA within a PI matrix. These microdomains act as templates for the highly site‐selective synthesis of metal nanoparticles via palladium‐catalyzed electroless nickel plating. The particle formation is studied by atomic force microscopy in tapping mode and implications for a redox reaction and a nanoparticle growth mechanism on the surface of nanopatterned films are discussed.

Chemical structure of the PI‐b‐PDMAEMA copolymer and AFM phase image of a PI‐b‐PDMAEMA film on Si (100) substrate.     

Synthesis and self‐assembly of amphiphilic brush‐dendritic‐linear poly[poly(ethylene glycol) methyl ether methacrylate]‐b‐ polyamidoamine‐b‐poly(ε‐caprolactone) copolymers

A series of novel amphiphilic brush‐dendritic‐linear poly[poly(ethylene glycol) methyl ether methacrylate]‐b‐polyamidoamine‐b‐poly(ε‐caprolactone) copolymers (PPEGMEMA‐b‐D_m‐b‐PCL) (m = 1, 2, and 3: the generation number of dendron) were synthesized by the combination techniques of click chemistry, atom transfer radical polymerization (ATRP), and ring‐opening polymerization (ROP). The brush‐dendritic copolymers bearing hydrophilic brush PPEGMEMA and hydrophobic dendron polyamidoamine protected by the tert‐butoxycarbonyl (Boc) groups [D_m‐(Boc) (m = 1, 2, and 3)] were for the first time prepared by ATRP of poly(ethylene glycol) methyl ether methacrylate monomer (PEGMEMA) initiated with the dendron initiator, which was prepared from 2′‐azidoethyl‐2‐bromoisobutyrate (AEBIB) and D_m‐(Boc) terminated with a clickable alkyne by click chemistry. Then, the brush‐dendritic copolymers with primary amine groups (PPEGMEMA‐b‐D_m) were obtained from the removal of the protected Boc groups of the brush‐dendritic copolymers in the presence of trifluoroacetic acid. The brush‐dendritic‐linear PPEGMEMA‐b‐D_m‐b‐PCL copolymers were synthesized from ROP of ε‐caprolactone monomer using PPEGMEMA‐b‐D_m as the macroinitiators and stannous octoate as catalyst in toluene at 130 °C. To the best of our knowledge, this is the first report that integrates hydrophilic brush polymer PPEGMEMA with hydrophobic polyamidoamine (PAMAM) dendron and PCL to form amphiphilic brush‐dendritic‐linear copolymers. The amphiphilic brush‐dendritic‐linear copolymers can self‐assemble into spherical micellar structures in aqueous solution. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Ultrathin and Large‐area Macroporous Polymeric Membranes Formed Through Self‐assembly of Sub‐10 nm Elastic Nanoparticles

A variety of sub‐10 nm nanoparticles are successfully prepared by crosslinking of polystyrene‐b‐poly(1,3‐butadiene) (PS‐b‐PB) and polystyrene‐b‐poly(4‐vinyl pyridine) (PS‐b‐P4VP) block copolymer micelles and inverse micelles. Among them, the core‐crosslinked PS‐b‐PB micelles can self‐assemble into ultrathin (< 10 nm) macroporous (pore size <1 µm) membranes in a facile way, i.e., by simply drop‐coating the particle solution onto a mica surface. No continuous/porous membranes are produced from shell‐crosslinked PS‐b‐PB micelles and both forms of PS‐b‐P4VP micelles. This suggests that the unique structure of the block copolymer precursor, including the very flexible core‐forming block and the glassy corona‐forming block and the specific block length ratio, directly determines the formation of the macroporous membrane.

     

Multi‐Morphological Complex Aggregates Formed from Amphiphilic Poly(ethylene oxide)‐block‐Polydimethylsiloxane‐block‐Poly(ethylene oxide) Triblock Copolymers

Summary: Amphiphilic triblock copolymers (PEO_x‐b‐PDMS_y‐b‐PEO_x) with different block lengths were synthesized and multi‐morphological complex crew‐cut, star‐like, and short‐chain aggregates were prepared by self‐assembly of the given copolymers. The morphologies and dimensions of the aggregates can be well controlled by variation of the preparation conditions. TEM, SEM, FFR‐TEM, and LLS studies show the resulting morphologies range from LCMs, unilamellar or multilayer vesicles, LCVs, porous spheres to nanorods.

TEM images of the vesicles formed from PEO‐b‐PDMS‐b‐PEO.     

Highly Ordered Structure Formation in RAFT‐Synthesized PtBOS‐b‐P4VP Diblock Copolymers

Linear poly(4‐tert‐butoxystyrene)‐b‐poly(4‐vinylpyridine) (PtBOS‐b‐P4VP) diblock copolymers are synthesized using reversible addition–fragmentation chain transfer polymerization. The self‐assembly of four different PtBOS‐b‐P4VP diblock copolymers is studied using small‐angle X‐ray scattering and transmission electron microscopy and a number of interesting observations are made. A tBOS₆₂‐b‐4VP₂₈ diblock copolymer with a weight fraction P4VP of 0.21 shows a disordered morphology of P4VP spheres with liquid‐like short‐range order despite an estimated value of of the order of 50. Increasing the length of the 4VP block to tBOS₆₂‐b‐4VP₁₉₉ results in a diblock copolymer with a weight fraction P4VP of 0.66. It forms a remarkably well‐ordered lamellar structure. Likewise, a tBOS₁₄₆‐b‐4VP₁₂₀ diblock copolymer with a weight fraction P4VP of 0.33 forms an extremely well‐ordered hexagonal structure of P4VP cylinders. Increasing the P4VP block of this block copolymer to tBOS₁₄₆‐b‐4VP₁₉₀ with a weight fraction P4VP of 0.44 results in a bicontinuous gyroid morphology despite the estimated strong segregation of . These results are discussed in terms of the architectural dissimilarity of the two monomers, characterized by the presence of the large side group of PtBOS, and the previously reported value of the interaction parameter, , for this polymer pair.

     

Using Cyclopenta[2,1‐b:3,4‐c′]dithiophene‐4‐one as a Building Block for Low‐Bandgap Conjugated Copolymers Applied in Solar Cells

A novel electron‐accepting unit cyclopenta[2,1‐b:3,4‐c′]dithiophene‐4‐one (CPDTO‐c′), which is an isomer of CPDTO‐b′ was developed. CPDTO‐c′ can be incorporated into the D–A backbone through 5, 7 positions. The 2 position of CPDTO‐c′ can be easily functionalized with an electron‐withdrawing chain. By copolymerizing CPDTO‐c′ with four different donor units: benzo[1,2‐b:4,5‐b′]dithiophene (BDT), dithieno[3,2‐b:2′,3′‐d]silole (DTS), carbazole, and fluorene, four new conjugated copolymers P1 – P4 were obtained. All these polymers have good solubility and low‐lying HOMO energy levels (−5.41 ∼ −5.92 eV). Among them, P1 and P2 exhibit broad absorption and narrow optical bandgaps of 1.91 and 1.72 eV, respectively. Solar cells based on P1 /PC₇₁BM afforded a PCE up to 2.72% and a high V_oc up to ∼0.9 V.     

Effect of Coordination on the Glucose‐Responsiveness of PEG‐b‐(PAA‐co‐PAAPBA) Micelles

Poly(ethylene glycol)‐block‐poly(acrylic acid) (PEG‐PAA) is modified by 3‐aminophenylboronic acid (APBA) with different modification degrees, such as PEG₁₁₄‐b‐(PAA_0.37‐co‐PAAPBA_0.63)₁₇₀, PEG₁₁₄‐b‐(PAA_0.23‐co‐PAAPBA_0.77)₁₇₀ and PEG₁₁₄‐b‐(PAA_0.02‐co‐PAAPBA_0.98)₁₇₀. Micelles self‐assembled from these three copolymers possess glucose‐responsiveness at varying pH values. Micelles self‐assembled from PEG₁₁₄‐b‐(PAA_0.37‐co‐PAAPBA_0.63)₁₇₀ have glucose‐responsiveness at the physiological pH (7.4), endowing them with potential applications in the treatment of diabetes. ¹¹B magic‐angle spinning nuclear magnetic resonance (¹¹B MAS NMR) analysis indicates that interactions between PAAPBA segments and PAA segments induce boron changes from the trigonal planar form to the tetrahedral form, resulting in glucose‐responsiveness of PEG₁₁₄‐b‐(PAA_0.37‐co‐PAAPBA_0.63)₁₇₀ micelles at pH 7.4.

     

Reaction of cyclic imidates with α,β‐unsaturated esters: Synthesis of new pyrrolo[2,1‐b]‐1,3‐oxazine and pyrido[2,1‐b]‐1,3‐oxazine derivatives

The cycloaddition reaction of cyclic imidates, 2‐benzyl‐5,6‐dihydro‐4H‐1,3‐oxazines 1a , 1b , 1c , 1d , 1e , 1f , with dimethyl acetylenedicarboxylate 2 , trimethyl ethylenetricarboxylate 4 , or dimethyl 2‐(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, such as methyl (6‐oxo‐3,4‐dihydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐ylidene)acetates 3a , 3b , 3c , 3d , 3e , 3f (71–79%), dimethyl 2‐(6‐oxo‐3,4,6,7‐tetrahydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐yl)malonates 5b , 5c , 5d , 5e , 5f (43–71%), or methyl 6‐oxo‐3,4‐dihydro‐2H,6H‐pyrido[2,1‐b]‐1,3‐oxazine‐7‐carboxylates 7a , 7b , 7c , 7d , 7e , 7f (32–59%), respectively. In these reactions, 1a , 1b , 1c , 1d , 1e , 1f (cyclic imidates, iminoethers) functioned as their N,C‐tautomers (enaminoethers) 2 to α,β‐unsaturated esters 2 , 4, and 6 to give annulation products 3 , 5 , and 7 following to the elimination of methanol, respectively. J. Heterocyclic Chem., (2011).     

Characterization and discrimination of raw and vinegar‐baked Bupleuri radix based on UHPLC‐Q‐TOF‐MS coupled with multivariate statistical analysis

Bupleuri Radix is a commonly used herb in clinic, and raw and vinegar‐baked Bupleuri Radix are both documented in the Pharmacopoeia of People's Republic of China. According to the theories of traditional Chinese medicine, Bupleuri Radix possesses different therapeutic effects before and after processing. However, the chemical mechanism of this processing is still unknown. In this study, ultra‐high‐performance liquid chromatography with quadruple time‐of‐flight mass spectrometry coupled with multivariate statistical analysis including principal component analysis and orthogonal partial least square‐discriminant analysis was developed to holistically compare the difference between raw and vinegar‐baked Bupleuri Radix for the first time. As a result, 50 peaks in raw and processed Bupleuri Radix were detected, respectively, and a total of 49 peak chemical compounds were identified. Saikosaponin a, saikosaponin d, saikosaponin b₃, saikosaponin e, saikosaponin c, saikosaponin b₂, saikosaponin b₁, 4′′‐O‐acetyl‐saikosaponin d, hyperoside and 3′,4′‐dimethoxy quercetin were explored as potential markers of raw and vinegar‐baked Bupleuri Radix. This study has been successfully applied for global analysis of raw and vinegar‐processed samples. Furthermore, the underlying hepatoprotective mechanism of Bupleuri Radix was predicted, which was related to the changes of chemical profiling.     

Preparation of Polyamide‐6 Submicrometer‐Sized Spheres by In Situ Polymerization

Polyamide‐6 (PA6) submicron‐sized spheres are prepared by two steps: (1) anionic ring‐opening polymerization of ε‐caprolactam in the presence of poly(ethylene glycol)‐block‐poly‐(propylene glycol)‐block‐poly(ethylene glycol)(PEG‐b‐PPG‐b‐PEG) and (2) separation of PA6 spheres by dissolving PEG‐b‐PPG‐b‐PEG from the prepared blends. The PA6 microspheres obtained are regular spherical, with diameter ranging from 200 nm to 2 μm and narrow size distribution, as confirmed by scanning electron microscopy. By comparison with PA6/PS and PA6/PEG systems, it is denominated that the PEG blocks in PEG‐b‐PPG‐b‐PEG can effectively reduce the surface tension of PA6 droplets and further decrease the diameter of the PA6 microspheres. The PPG block in PEG‐b‐PPG‐b‐PEG can prevent the PA6 droplets coalescing with each other, and isolated spherical particles can be obtained finally. The phase inversion of the PA6/PEG‐b‐PPG‐b‐PEG blends occurs at very low PEG‐b‐PPG‐b‐PEG content; the PEG‐b‐PPG‐b‐PEG phase can be removed by water easily. The whole experiment can be finished in a short time (approximately in half an hour) without using any organic solvents; it is an efficient strategy for the preparation of submicron‐sized PA6 microspheres.

     

Quinolone analogues 6 [1‐5]. Synthesis of 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones

The reaction of the quinoxaline N‐oxides 7a,b with diethyl ethoxymethylenemalonate gave the 1‐methylpyridazino[3,4‐b]quinoxaline‐4,4‐dicarboxylates 8a,b , whose reaction with N‐bromosuccinimide or N‐chlorosuccinimide afforded the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxaline‐4,4‐dicarboxylates 9a‐d. The reaction of compounds 9a‐d with hydrazine hydrate resulted in hydrolysis and decarboxylation to provide the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxaline‐4‐carboxylates 10a‐d , whose reaction with nitrous acid effected oxidation to furnish the 3‐halogeno‐4‐hydroxy‐1‐methylpyridazino[3,4‐b]quinoxaline‐4‐carboxylates 11a‐d , respectively. The reaction of compounds 11a‐d with hydrazine hydrate afforded the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4‐ols 12a‐d , whose oxidation provided the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones 6a‐d , respectively. Compounds 6a‐d had antifungal activities in vitro.     

Co‐delivery of 10‐Hydroxycamptothecin with Doxorubicin Conjugated Prodrugs for Enhanced Anticancer Efficacy

Well‐defined amphiphilic linear‐dendritic prodrugs (MPEG‐b‐PAMAM‐DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG‐b‐PAMAM through the acid‐labile hydrazone bond. The amphiphilic prodrugs form self‐assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10‐hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co‐delivery system reveal that both drugs are released in a pH‐dependent manner and effectively taken up by MCF‐7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug‐induced apoptosis tests demonstrate the HCPT‐loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG‐b‐PAMAM‐DOX prodrugs, free HCPT, and physical mixtures of MPEG‐b‐PAMAM‐DOX and HCPT at equivalent DOX or HCPT doses.

     

Kinetics of Core‐Shell Nanoparticle Formation by Two‐Dimensional Nuclear Magnetic Resonance

We have studied the kinetics of polymeric nanoparticle formation for poly(styrene‐block‐4‐vinylpyridine) [P(S‐b‐4‐VPy)], chains in a non‐selective solvent using 1,4‐dibromobutane (DBB) as a cross‐linker by means of different nuclear magnetic resonance (NMR) spectroscopy techniques. The kinetic process was followed using ¹H, ¹³C, and 2‐D Heteronuclear Single Quantum Correlation (HSQC) NMR experiments. The kinetic data obtained from 2‐D HSQC and ¹H NMR experiments were in good agreement between them, proving the reliability of the 2‐D HSQC NMR technique for the in situ study of the kinetics of core‐shell nanoparticle formation. A value of 1.5 × 10⁻⁵ s⁻¹ was determined for the apparent kinetic constant of the P(S‐b‐4‐VPy)‐DBB core‐shell nanoparticle formation process.

     

Synthesis of Aminoazobenzene‐Containing Diblock Copolymer and Photoinduced Deformation Behavior of its Micelle‐Like Aggregates

A precursor polymer PEO‐b‐PEMA that contains anilino moieties is synthesized from EPAEMA by ATRP by using a PEOBr macroinitiator and CuBr/HMTETA catalyst system. The aminoazobenzene‐containing block copolymer PEO‐b‐PCN is obtained by the azo‐coupling reaction between PEO‐b‐PEMA and the diazonium salt of 4‐aminobenzonitrile. Results show that PEO‐b‐PCN has a narrow molecular weight distribution and the repeat unit numbers of the hydrophilic and hydrophobic blocks are 122 and 200, respectively. PEO‐b‐PCN can form uniform spherical aggregates by gradually adding water into its THF solution. Upon irradiation with a linearly polarized Ar⁺ laser beam, the spherical aggregates can be significantly elongated in the polarization direction of the light.

     

Fabrication of Poly(L‐lactide)‐block‐Poly(ethylene glycol)‐block‐Poly(L‐lactide) Triblock Copolymer Thin Films with Nanochannels: An AFM Study

This paper aims to report the fabrication of biodegradable thin films with micro‐domains of cylindrical nanochannels through the solvent‐induced microphase separation of poly(L ‐lactide)‐block‐poly(ethylene glycol)‐block‐poly(L ‐lactide) (PLA‐b‐PEG‐b‐PLA) triblock copolymers with different block ratios. In our experimental scope, an increase in each of the block lengths of the PLA and PEG blocks led to both a variation in the average number density (146 to 32 per 100 µm²) and the size of the micro‐domains (140 to 427 nm). Analyses by atomic force microscopy (AFM) and fluorescence microscopy indicated that the hydrophilic PEG nanochannels were dispersed in the PLA matrix of the PLA‐b‐PEG‐b‐PLA films. We demonstrated that the micro‐domain morphology could be controlled not only by the block length of PEG, but also by the solvent evaporation conditions.