Convenient synthetic method for 3-(3-substituted indol-2-yl)quinoxalin-2-ones as VEGF inhibitor

It has already been reported that 3-(indol-2-yl)quinoxalin-2-ones have a potent inhibitory effect on the growth of tumor cells based on anti-angiogenesis activity. We have also carried out a structure-activity relationship (SAR) study of 3-(indol-2-yl)quinoxalin-2-ones, which showed a potent inhibitory activity toward the vascular endothelial growth factor (VEGF)-induced proliferation of human mesangial cells and the VEGF-induced auto-phosphorylation of human umbilical vein endothelial cells. Moreover, one of these compounds has a potent medicinal effect based on anti-angiogenic action, by oral administration (Chart 1, 9). However, since the existing synthetic methods for the preparation of 3-(indol-2-yl)quinoxalin-2-ones consist of multiple steps some of which require strict anhydrous conditions, a convenient and simple synthetic method in place of the existing method is desirable. As a result of the investigations into the synthetic procedures, 3-(3-substituted indol-2-yl)quinoxalin-2-ones can be easily prepared by the condensation of 3-substituted indoles with quinoxalin-2-ones in the presence of trifluoroacetic acid (TFA). Herein, we report the examination of these reaction conditions and the application of this new synthetic method to the synthesis of the derivatives as VEGF inhibitors.     

A New Synthesis for Methyl 2-Benzyloxylphenylacetate

A new synthetic method for methyl 2-benzyloxylphenylacetate, a key intermediate of a new type of fungicides, had been found, which has only 3 steps. The 80% yield of the new method is a major improvement over the 30% 6-step-process reported by the literature.     

Study on a New Method for Synthesis of Mirabegron

Mirabegron is a muscle relaxing drug for the treatment of overactive bladder. The existing synthetic methods for mirabegron produced intermediate product 4‐(2‐(phenethylamino)ethyl)aniline, which complicated the final product purification process. In this study, we designed a new synthetic route for mirabegron with low cost starting materials and a production of mirabegron at a 99.6% purity and a 61% overall yield. Particularly, this new synthetic route did not produce side product 4‐(2‐(phenethylamino)ethyl)aniline, which significantly simplified the product purification process.     

Synthetic Strategies for Fused Benzothiazoles: Past,Present, and Future

Benzothiazole is used as a building block in organic synthesis, which serves as a key template for the development of various therapeutic agents and shows a wide spectrum of activities. The attractive application of benzothiazole in organic synthesis is undoubtedly due to the highly reactive C-2 amino group, which is responsible for the change in its bioactivity. The construction of a poly-heterocyclic compound with the fused hetero-systems has attracted increasing attention because of the diverse range of potential therapeutic activities. Significant efforts have been undertaken to exploit different synthetic routes to these compounds. This article gives a comprehensive account of the synthetic utility of benzothiazole employed in the design and synthesis of different types of compounds containing fused heterocyclic rings with greater emphasis on recent literature.     

An Efficacious Synthetic Strategy for cis-Clerodane Diterpenoids

Clerodane diterpenoids are widely distributed in nature and constitute one of the largest and, yet, still rapidly growing family of secondary metabolites. Of the relatively few clerodanes tested for biological activity, many were found to possess interesting antifeedant and medicinal properties and are potentially useful as insecticidal, antitumour, antifungal, antibiotic, anti-peptic ulcer, and psychotropic agents. The structural complexity and biological activity associated with this class of natural products have attracted extensive effort towards their total synthesis. In most of the reported syntheses, the synthetic sequence is specific to the target molecule. We have recently developed a versatile synthetic approach which is applicable to the synthesis of a large number of target molecules with minor modifications. The key operation of this approach is the face-selective Diels-Alder reaction of dienone ester 1. The successful application of this approach has culminated in the total synthesis of several cisclerodane diterpenoids. We have since made considerable improvement on this general synthetic approach, in terms of the overall efficiency, making use of compounds 2 and 3 as dienophiles. This newly developed general synthetic approach towards clerodane diterpenoids will be presented.     

The facile synthesis of 5-formylporphyrin

A facile synthetic route of 5-formylporphyrin(2) has been developed.Using pyrrole and pivaldehyde as the starting materials,2 was obtained through several facile reactions.The synthetic route is easy to perform and can be scaled up,which gives the compound a better application perspective.     

New method for synthesis of EZH2 methyltransferase inhibitor GSK126

GSK126 is a potent small-molecule inhibitor of S-adenosyl-methionine-competitive EZH2 methyltransferase and has the potential to be used clinically for preventing unwanted histone methylation of tumor suppressor genes. In this article, we describe a new synthetic route that has been developed for synthesizing the title compound through nine steps, starting from 2,5-dibromobenzoic acid. This synthetic method is economical and suitable for multigram-scale preparation of GSK126 and related N-alkylated indole derivatives.     

A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher''s attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

A non-classical ring opening radical clock reaction using the innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis has been demonstrated, providing a brand-new synthetic approach to access a variety of alkynyl derivatives.     

Fe-N-C 类催化剂在碱性燃料电池中的研究进展

随着阴离子交换膜的出现、发展和应用,碱性燃料电池的优势日趋明显,针对碱性燃料电池的研究也更广泛而深刻. 在碱性燃料电池中,除了其固有的对催化剂的高包容性和动力学优越性,阴离子交换膜让阴离子定向迁移,从而实现了很好的水相管理,降低了电池中“水涝”的几率,也提供了更广阔的燃料选择空间. 氧还原反应是碱性燃料电池中的重要部分,且其反应动力学相较于氢氧化反应缓慢. 因此,选择并研制合适的阴极氧还原反应催化剂,是提高碱性燃料电池性能和促进燃料电池规模化使用的关键. Fe-N-C类催化剂因其在碱性条件下接近甚至优于 Pt 基催化剂的性能,被视为最有潜力替代 Pt 的非贵金属催化剂. 本文从近 5 年来 Fe-N-C 类催化剂的合成方法、催化活性位点和氧还原反应机理以及在燃料电池中的应用三方面进行了综述.      

Aurora kinase A,a synthetic lethal target for precision cancer medicine

Recent advances in high-throughput sequencing technologies and data science have facilitated the development of precision medicine to treat cancer patients. Synthetic lethality is one of the core methodologies employed in precision cancer medicine. Synthetic lethality describes the phenomenon of the interplay between two genes in which deficiency of a single gene does not abolish cell viability but combined deficiency of two genes leads to cell death. In cancer treatment, synthetic lethality is leveraged to exploit the dependency of cancer cells on a pathway that is essential for cell survival when a tumor suppressor is mutated. This approach enables pharmacological targeting of mutant tumor suppressors that are theoretically undruggable. Successful clinical introduction of BRCA-PARP synthetic lethality in cancer treatment led to additional discoveries of novel synthetic lethal partners of other tumor suppressors, including p53, PTEN, and RB1, using high-throughput screening. Recent work has highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple tumor suppressors. AURKA is a serine/threonine kinase involved in a number of central biological processes, such as the G2/M transition, mitotic spindle assembly, and DNA replication. This review introduces synthetic lethal interactions between AURKA and its tumor suppressor partners and discusses the potential of AURKA inhibitors in precision cancer medicine.Subject terms: Targeted therapies, Drug discovery     

Biohybrid photosynthetic antenna complexes for enhanced light-harvesting

Biohybrid antenna systems have been constructed that contain synthetic chromophores attached to 31mer analogues of the bacterial photosynthetic core light-harvesting (LH1) β-polypeptide. The peptides are engineered with a Cys site for bioconjugation with maleimide-terminated chromophores, which include synthetic bacteriochlorins (BC1, BC2) with strong near-infrared absorption and commercial dyes Oregon green (OGR) and rhodamine red (RR) with strong absorption in the blue-green to yellow-orange regions. The peptides place the Cys 14 (or 6) residues before a native His site that binds bacteriochlorophyll a (BChl-a) and, like the native LH proteins, have high helical content as probed by single-reflection IR spectroscopy. The His residue associates with BChl-a as in the native LH1 β-polypeptide to form dimeric ββ-subunit complexes [31mer(-14Cys)X/BChl](2), where X is one of the synthetic chromophores. The native-like BChl-a dimer has Q(y) absorption at 820 nm and serves as the acceptor for energy from light absorbed by the appended synthetic chromophore. The energy-transfer characteristics of biohybrid complexes have been characterized by steady-state and time-resolved fluorescence and absorption measurements. The quantum yields of energy transfer from a synthetic chromophore located 14 residues from the BChl-coordinating His site are as follows: OGR (0.30) < RR (0.60) < BC2 (0.90). Oligomeric assemblies of the subunit complexes [31mer(-14Cys)X/BChl](n) are accompanied by a bathochromic shift of the Q(y) absorption of the BChl-a oligomer as far as the 850-nm position found in cyclic native photosynthetic LH2 complexes. Room-temperature stabilized oligomeric biohybrids have energy-transfer quantum yields comparable to those of the dimeric subunit complexes as follows: OGR (0.20) < RR (0.80) < BC1 (0.90). Thus, the new biohybrid antennas retain the energy-transfer and self-assembly characteristics of the native antenna complexes, offer enhanced coverage of the solar spectrum, and illustrate a versatile paradigm for the construction of artificial LH systems.     

An hermaphroditic [c2]daisy chain

A cyclic dimeric daisy chain compound, which has been assembled from a disfunctional [2]rotaxane in a sequence of noncovalent and covalent synthetic steps, the most important of which is a bis-Wittig reaction, has been characterised by X-ray crystallography.     

Chemical synthesis of cross-link lesions found in nitrous acid treated DNA: a general method for the preparation of N2-substituted 2'-deoxyguanosines

Treatment of DNA with nitrous acid results in the formation of DNA-DNA cross-links. Two cross-link lesions have previously been isolated and their structures assigned based on spectroscopic data. The major lesion has been proposed to consist of two deoxyguanosine (dG) nucleosides sharing a common N2 atom (1), while the structure of the minor lesion has been proposed to consist of a common nitrogen atom linking C2 of a dG nucleoside to C6 of deoxyadenosine (2). The chemical synthesis of 1 and 2, utilizing a palladium-catalyzed coupling, is described herein. It is demonstrated that the spectroscopic properties of synthetic 1 are identical to that of lesion 1 obtained from nitrous acid cross-linked DNA, thus providing a proof of its structure. Comparison of the limited spectroscopic data available for lesion 2 originating from nitrous acid cross-linked DNA to synthetic 2 supports its structural assignment. The synthetic approach used for synthesis of 1 and 2 is shown to be a general method for the preparation of a variety of N2-substituted dG nucleosides in good yields.     

Highly effective synthetic methods for substituted 2-arylbenzofurans using [3,3]-sigmatropic rearrangement: short syntheses of stemofuran a and eupomatenoid 6

A new and efficient synthesis of 2-arylbenzofurans has been achieved via a route involving acylation and subsequent [3,3]-sigmatropic rearrangement of oxime ethers. Its synthetic utility is demonstrated by a short synthesis of stemofuran A and eupomatenoid 6 in which no procedure for protection of the phenolic hydroxyl groups is needed. [reaction--see text]     

Cationic starches as substitute for synthetic cationic flocculants in solid-liquid separation of harbor sludge

Harbor sludge (about 25% total solid) has to be dredged to keep the waterways free. Thus, annually 1.2 million m3 of dredged material has to be cleaned. For this process, three different synthetic flocculants with optimal molar masses, ionogenities, and concentrations are added in order to get a good dewatering efficiency and shear strength of the flocs. But as synthetic flocculants bring about unwanted fish toxicity and insufficient biodegradability, this study intends to check whether these flocculants can successively be substituted by cationic starches which have already been proven to be less toxic than synthetic flocculants. Five different starch derivatives with an average degree of substitution higher than 0.5 were characterized, especially in terms of the molar mass and coil size distribution, and flocculation tests, zeta potential measurements and filtrate turbidity tests were carried out in order to create optimum flocculation conditions. The flocculation and dewatering measurements clearly show that the synthetic cationic flocculant PA (0.2 kg/tTS) can be best substituted by cationic starch KS 2 (c = 0.1 kg/tTS, Mw = 1.1 e+08). For substitution of PTAC (c = 0.3 kg/tTS) by cationic starches, we observed that a maximal dewatering efficiency is reached with an approximately 3-fold dose of KS 1 (1 kg/tTS, Mw = 8.1 e+07).     

A process in need is a process indeed: scalable enantioselective synthesis of chiral compounds for the pharmaceutical industry

This report deals with enantioselective synthesis of viracept 1 (nelfinavir mesylate, AG 1343), a potent HIV protease inhibitor, and 3-hydroxytetradecanoic acid 3, a component of lipid A comprising lipopolysaccharide embedded in the cell surface of Gram-negative bacteria, from both strategic and practical perspectives. As regards the synthesis of 1, the synthetic approaches to its central intermediate 2 possessing the common structural motif of 1,4-differentially substituted-2-amino-3-hydroxylbutane are mainly discussed with emphasis on the molecular symmetry that has helped streamline the synthetic strategy. In the discussion of the synthetic strategies to access a single enantiomer of 3, the chiral methodologies that have been applied so far are assessed for industrial viability; the synthetic alternatives explored include resolution via diastereomeric salt formation, lipase-catalyzed kinetic resolution, asymmetric synthesis, and chiral pool approaches.     

Two mixed-valence copper(I,II) imidazolate coordination polymers: metal-valence tuning approach for new topological structures

A new metal-valence tuning synthetic approach has been utilized to generate two new mixed-valence Cu(I,II) coordination polymers Cu(2)(im)(3) and Cu(3)(im)(4)(Him = imidazole), which are an unprecedented uninodal 4-connected 4.8(5) topological net and a 4-connected (4,4) net, respectively.     

Copper-Catalyzed Dual Cyclization for the Synthesis of Quinindolines

A synthetic approach to quinindoline derivatives by the Cu-catalyzed dual cyclization has been developed. This catalytic reaction is a practical method for the systematic synthesis of quinindoline core structure, which contains a limited-step synthetic strategy and can tolerant a wide variety of substituents. In addition, the mechanistic study reveals that the reaction initiates from a Lewis acid accelerated addition of aniline to nitrile and provides the indole substructure, and then the subsequent Cu-catalyzed C-N coupling reaction furnishes the quinoline subunit and affords the quinindoline structure.     

RASA: a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules

In this account, a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules, called RASA (Retrosynthesis-based Assessment of Synthetic Accessibility) is devised. RASA first constructs a synthesis tree for the target molecule based on retrosynthetic analysis; in this process a series of strategies are suggested for limiting combinatorial explosion of the synthesis tree. A scoring function (RASA-score) for the assessment of synthetic accessibility is then proposed based on the optional effective synthetic routes, the complexity of reaction, and the difficulty of separation/purification associated with the most favorable synthetic route. The contributions of individual components are calibrated by linear regression analysis based on the synthetic accessibility estimates of a training set (100 compounds) given by a group of medicinal chemists (G1). Two external test sets (TS1 and TS2), whose synthetic accessibility estimates were given by the group G1 medicinal chemists and another group (G2) of medicinal chemists (from literature), respectively, were adopted for the evaluation of RASA. The correlation coefficient between the calculated RASA-score values and the estimated scores by medicinal chemists for TS1 is 0.807 and that for TS2 is 0.792, which demonstrate the validity and reliability of RASA. The validity and reliability as well as the high speed of RASA and its capability of suggesting synthetic routes enable it a useful tool in drug discovery.     

A Convenient Synthesis of 2,4(3H,5H)-Furandione (β-Tetronic Acid)

The chemical versatility of 2,4(3H,5H)-furandione (β-tetronic acid, 1) and its synthetic applicability are of considerable current interest^1b,2a-k. The multifunctional character of this small molecule confers an intriguing synthetic potential which has prompted us to develop synthetic schemes utilizing it as a synthon for certain heterocyclic systems.