Synthesis of bioactive indolocarbazoles: synthesis, nucleophilic ring-opening and chiral base desymmetrisation of a cyclic sulfate intermediate

A number of new functionalised bridged indolocarbazole systems have been prepared by ring-opening reactions of a key cyclic sulfate intermediate, prepared from the corresponding diol by the action of sulfuryl diimidazole and DBU. The same cyclic sulfate also undergoes an unprecedented asymmetric rearrangement to a chiral ketone, on treatment with a chiral lithium amide base.     

Streptocarbazoles A and B, two novel indolocarbazoles from the marine-derived actinomycete strain Streptomyces sp. FMA

Streptocarbazoles A (1) and B (2), two novel indolocarbazoles featuring unprecedented cyclic N-glycosidic linkages between 1,3-carbon atoms of the glycosyl moiety and two indole nitrogen atoms of the indolocarbazole core, were isolated from the marine-derived actinomycetes strain Streptomyces sp. FMA. Their structures were established by spectroscopic methods, CD spectra, and ECD quantum mechanical calculations. Compound 1 was cytotoxic on HL-60 and A-549 cell lines and could arrest the cell cycle of Hela cells at the G(2)/M phase.     

Indolocarbazole natural products: occurrence, biosynthesis, and biological activity

The indolocarbazole family of natural products, including the biosynthetically related bisindolylmaleimides, is reviewed (with 316 references cited). The isolation of indolocarbazoles from natural sources and the biosynthesis of this class of compounds are thoroughly reviewed, including recent developments in molecular genetics, enzymology and metabolic engineering. The biological activities and underlying modes of action displayed by natural and synthetic indolocarbazoles is also presented, with an emphasis on the development of analogs that have entered clinical trials for its future use against cancer or other diseases.     

Deciphering indolocarbazole and enediyne aminodideoxypentose biosynthesis through comparative genomics: insights from the AT2433 biosynthetic locus

AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases--one common to AT2433 and rebeccamycin, the other unique to AT2433--as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.     

Highly Enantioselective Catalytic Asymmetric [2+2] Cycloadditions of Cyclic α‐Alkylidene β‐Oxo Imides with Ynamides

Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic α‐alkylidene β‐oxo imides with ynamides are described. The high reactivity of the cyclic α‐alkylidene β‐oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at low temperature. The X‐ray crystallographic analysis of the product suggests that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic α‐alkylidene β‐oxo imide coordinates with Cu^II through the two imide carbonyls. The imide group in the product can be transformed to amide, nitrile, and ester groups; moreover, it is removable.     

Bisarylmaleimides & the Corresponding Indolocarbazoles as Kinase Inhibitors

Cyclin dependent kinases (CDKs) have recently raised considerable attention because of their central role in the regulation of cell cycle progression. A high incidence of genetic mutation of CDK substrates and deregulation of CDK modulators were found in a number of disease states, particularly in cancer. A novel series of unsymmetrical substituted indolocarbazoles were synthesized and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles were found to b…     

聚芳醚酮（砜）亚胺的裂解色谱质谱鉴定

本文通过对聚芳醚酮亚胺和聚芳醚砜亚胺两类聚合物的裂解色谱质谱的解析,归纳出适合于正确鉴定这两类新型聚合物的表征化合物。     

Synthesis of conformationally constrained aryl- or heteroarylpiperazinyl derivatives of selected imides as 5-HT1A receptor ligands

The preparation of a number of cyclic imide 5-HT(1A) receptor ligand derivatives has been described. Their structures were conformationally constrained by introducing rigid linkers containing unsaturated bonds or aromatic benzene rings. These compounds are expected to possess anxiolytic and antidepressant activity.     

Stereochemical definition and chirospecific synthesis of the peptide deformylase inhibitor Sch 382583

The recently reported natural product Sch 382583 (1), an inhibitor of peptide deformylase, has been synthesized in 16 steps from commercially available starting materials. The three chiral centers were set by a combination of chiral auxiliary and chiral pool approaches. The succinate 5 and piperazic acid 9 moieties were obtained by Evans oxazolidinone imide enolate alkylation and hydrazination/cyclization, respectively, and the aminohexanone side chain 13 was prepared via Grignard substitution of the Weinreb amide derived from l-valine. Spectroscopic data for the resulting synthetic material, compared with the data reported for the natural product, established that the previously unassigned valine ketone stereocenter (C-4) has the S-configuration.     

3D-QSAR和分子对接研究吲哚咔唑类细胞周期蛋白激酶抑制剂的选择性

细胞周期蛋白激酶(cyclin-dependent kinases, CDKs)是近年来治疗肿瘤的重要靶标. 由于大多数激酶ATP结合位点的保守性, CDK选择性激酶抑制剂的开发成为当前的研发难点和热点. 针对吲哚咔唑类CDK抑制剂, 我们采用比较分子力场分析方法(CoMFA)建立了CDK2-QSAR(quantitative structure-activity relationship)和CDK4-QSSR(quantitative structure-selectivity relationship)模型. 所建模型的交叉验证系数q2分别为0.722和0.703; 非交叉验证系数r2分别为0.977和0.946, 表明其具有较好的预测能力. 同时, 用分子对接的方法分析了这类化合物与CDK4同源模建结构的作用模式, 根据这两个模型发现, 吲哚咔唑类化合物的R5和R6位长链取代对CDK4的选择性具有一定的影响, 而且结合其作用模式比较合理地解释了这类抑制剂的选择性原因, 这对CDKs的选择性研究具有一定的指导意义.     

Magnetic Field Effects on the Dynamics of Radical Pairs in Micelles: A New Approach to Understanding the "Cage Effect"

The effect of temperature on the photolysis of dibenzyl ketone and 4-methyldibenzyl ketone in sodium dodecyl sulfate micelles was studied by laser flash photolysis and product distributions derived from steady-state photolysis. At high temperatures, the product distribution and radical decay kinetics are primarily due to random encounters of radicals, and the "cage effect" cannot be rationalized by geminate recombination reactions that occur before the radicals escape from the micelles. A mechanism is proposed in which the enhancement of the crosstermination product derived from random encounters is due to the different partitioning of each radical species between the micelles and the aqueous phase, thereby leading to different rates for the self-termination reactions.     

The biosynthetic gene cluster for the antitumor rebeccamycin: characterization and generation of indolocarbazole derivatives

Rebeccamycin, a halogenated natural product of the indolocarbazole family, is produced by Saccharothrix aerocolonigenes ATCC39243. Several rebeccamycin analogues, which target DNA topoisomerase I or II, have already entered clinical trials as anticancer drugs. Using as a probe an internal fragment of ngt, a Saccharothrix aerocolonigenes gene encoding an indolocarbazole N-glycosyltransferase, we isolated a DNA region that directed the biosynthesis of rebeccamycin when introduced into Streptomyces albus. Sequence analysis of 25.6 kb revealed genes for indolocarbazole core formation, halogenation, glycosylation, and sugar methylation, as well as a regulatory gene and two resistance/secretion genes. Heterologous expression of subsets of these genes resulted in production of deschloro-rebeccamycin, 4'-demethyldeschloro-rebeccamycin, and deschloro-rebeccamycin aglycone. The cloned genes should help to elucidate the molecular basis for indolocarbazole biosynthesis and set the stage for the generation of novel indolocarbazole analogues by genetic engineering.     

Imide--amide rearangement of cylic phosphorimidates: a mechanistic study

Studies aimed at the development of new synthetic pathways for the preparation of chiral cyclic oxaza and diaza phosphoramides suitable for use in asymmetric chemistry led us to the investigation of the imide -amide rearrangement of cyclic phosphorimidates. As a result of this work new types of oligomeric organophosphorus compounds, formed by a novel 1,4-addition type ring opening polymerisation, were identified. These compounds are the stable intermediates of the imide-amide rearrangement, which upon heating yield the previously reported rearranged product. A detailed study of the mechanism of the Lewis acid catalysed imide-amide rearrangement and stereochemical control of the final products is reported. As a result, the full mechanism was elucidated and evidence of retention of configuration at the rearranged carbon atom is presented. Substituent effects were rationalised based on molecular modelling calculations.     

A concise synthesis of unnatural (+)-5-epi-nojirimycin-δ-lactam via asymmetric reduction of a meso-imide

Nojirimycin-δ-lactam skeleton was synthesized by asymmetric reduction of a cyclic triacetyloxy meso imide with a chiral β-amino thiol ligand. The resulting product was converted to unnatural (+)-5-epi-nojirimycin-δ-lactam.     

A solution to the cyclic aldol problem

[formula: see text] A protocol for achieving stereoselective aldol reactions with cyclic ketones is presented. In terms of yield, the process is particularly effective when a quaternary center at the alpha-carbon of the beta-hydroxy ketone product is created. The stereochemical outcome, anti or syn, is achieved by the Lewis acid-mediated ring expansion of stereochemically homogeneous epoxides in a reaction related to the pinacol rearrangement.     

Ozonolysis of 3-Caren-5-one

Cleavage by ozonolysis of a cyclic unsaturated ketone, 3-caren-5-one, was investigated under different conditions. The main reaction product is ketocaronic acid. A scheme of ketocaronic acid formation was suggested basing on kinetics of ozone reaction with 3-caren-5-one and thermal decomposition of peroxides.     

Dibromomethane as one-carbon source in organic synthesis: microwave-accelerated α-methylenation of ketones with dibromomethane and diethylamine

The reactivity of aryl alkyl ketone with a preheated mixture of dibromomethane and diethylamine is poor and gives an α-methylenation product in very low yield even under refluxing condition. It can be accelerated dramatically by microwave irradiation. Under microwave condition, the cyclic 1,3-dicarbonyls, aryl alkyl ketones, heteroaryl alkyl ketones and acyclic benzyl ketone give α-methylenation products in modest to good yields.     

Divergent cyclisations of 2-(5-amino-4-carbamoyl-1H-pyrazol-3-yl)acetic acids with formyl and acetyl electrophiles

The reaction of 2-(5-amino-4-carbamoyl-1-methyl-1H-pyrazol-3-yl)acetic acid and triethylorthoformate did not give the expected dihydropyrazolo[4,3-c]pyridin-4-one product as described in literature, but formed an alternative cyclic imide product, fully characterised by NMR and X-ray crystallography. This mode of reaction was shown to be general to other 1-substituted-2-(5-amino-4-carbamoyl-1H-pyrazol-3-yl)acetic acids. The outcome of the cyclisation was highly sensitive both to the nature of the reagents used and also to the acidity of the reaction medium, such that a number of interesting bicyclic heterocycles could be produced in a controlled fashion from the single starting material. The major tautomeric forms of the bicyclic products in solution were found to vary according to their substitution pattern.     

1,2-Cyclic sulfite and sulfate furanoside diesters: improved syntheses and stability

The facile syntheses of 1,2- and 3,5-cyclic sulfite and sulfate furanoside diesters were conducted in molecular solvents and ionic liquids in the presence of immobilised morpholine. Molecular solvents and ionic liquids performed similarly with regards to overall yields. However, the use of ILs allowed for the reactions to be carried out under atmospheric conditions and showed good recyclability. Additionally, increases in product stability was achieved in ILs over organic solvents, in particular, in bis{(trifluoromethanesulfonyl)imide} and trispentafluoro-ethyltrifluorophosphate-based ionic liquids, which were also excellent media to control the hydrolysis of thionyl chloride and sulfuryl chloride.     

A comparative study on aldol‐type condensation reactions of cyclic,acyclic and substituted cyclic ketones by the W(CO)6/CCl4/UV system

Aldol‐type condensation reactions of a number of cyclic, acyclic and substituted cyclic ketones were investigated using the W(CO)₆/CCl₄/UV system. The progress of the reactions was followed by IR and GC‐MS techniques. The cyclic ketone derivatives with β‐ and γ‐substituent gave the expected condensation products. However, the α‐substituted cyclic, acyclic and unsubstituted cyclic ketones with rings larger than six did not. Formation of [W]–ketone complexes with all of the ketones used was observed by FTIR. With respect to our studies, a mechanism involving an intermediate seven‐coordinate tungsten complex has been proposed. Copyright © 2005 John Wiley & Sons, Ltd.