cas 29745-04-8, EXO-7-OXABICYCLO[2.2.1]HEPTANE-2,3-DICARBOXYLIC ANHYDRIDE

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Structural studies on cycloadducts of furan, 2-methoxyfuran, and 5-trimethylsilylcyclopentadiene with maleic anhydride and N-methylmaleimide
(Chemical Equation Presented) The early stages of the retro-Diels-Alder reaction are clearly apparent in the structures of the cycloadducts formed between furan or 5-trimethylsilylcyclopentadiene with maleic anhydride and N-methylmaleimide. The degree of lengthening of the C-C bonds that break in this reaction is clearly related to the known reactivity of these cycloadducts toward this reaction. In the structures of the cycloadducts 21 and 22 derived from 2-methoxyfuran, the early stages of an alternative fragmentation reaction are apparent, consistent with the reactivity of these compounds in solution.
Yit, Wooi Goh,Pool, Brett R.,White, Jonathan M.
p. 151 - 156
(2008)
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Synthesis and extraction studies with a rationally designed diamide ligand selectIVe to actinide(IV) pertinent to the plutonium uranium redox extraction process
A new class of conformationally constrained oxa-bridged tricyclo-dicarboxamide (OTDA) ligand was rationally designed for the selective extraction of tetravalent actinides pertinent to the Plutonium Uranium Redox EXtraction (PUREX) process. Two of the designed diamide ligands were synthesized and extraction studies were performed for Pu(iv) from HNO3 medium. The mechanism of extraction was investigated by studying various parameters such as feed HNO3, NaNO3 and OTDA concentrations. The nature of the extracted species was found to be [Pu(NO3)4(OTDA)]. One of the OTDA ligands was elaborately tested and showed the selective extraction of Pu(iv) and Np(iv) over other actinide species, viz., U(vi), Np(v), Am(iii), lanthanides and fission products contained in a nuclear waste from the PUREX process. DFT calculations predicted the charge density on each of the coordinating 'O' atoms of OTDA supporting its high Pu(iv) selectivity over other ions studied and also provided the energy optimized structure of OTDA and its Pu(iv) complex.
Sharma, Shikha,Panja, Surajit,Bhattacharyya, Arunasis,Dhami, Prem S.,Gandhi, Preetam M.,Ghosh, Sunil K.
p. 7737 - 7747
(2016)
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Crystal structures of (3R,3aR,4S,7R,7aS)-3-(allyloxy)hexahydro-4,7- epoxyisobenzofuran-1(3H)-one and (3S,3aR,4S,7R,7aS)-3-((E)-but-2-en-1-yloxy) hexahydro-4,7-epoxyisobenzofuran-1(3H)-one: Confirmation of NMR predicted stereocentre geometry
Crystal structures of two isomeric norcantharidin derivatives (3R,3aR,4S,7R,7aS)-3-(allyloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one (7b), and (3S,3aR, 4S,7R,7aS)-3-((E)-but-2-en-1-yloxy)hexahydro-4,7- epoxyisobenzofuran- 1(3H)-one (8a) have been determined. In both instances the equivalent enantiomer was also obtained. The crystal structures of these compounds clarify the stereochemistry inferred only by NMR analysis before. Springer Science+Business Media, LLC 2012.
Tarleton, Mark,Bernhardt, Paul V.,McCluskey, Adam
p. 639 - 644
(2012)
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From Spanish fly to room-temperature ionic liquids (RTILs): Synthesis, thermal stability and inhibition of dynamin 1 GTPase by a novel class of RTILs
In a series of simple synthetic manipulations the active component of the aphrodisiac Spanish fly has resulted in the generation of a new family of room-temperature ionic liquids (RTILs). These RTILs are synthesized in high yield from readily attainable starting materials and can be generated in either meso or chiral forms dependant on the starting furan analogue. Substituted furans (2-methyl and 2-ethyl) afford chiral RTILs, furan affords a family of meso RTILs. In all cases the counterion was crucial, with CH3SO 3- consistently displaying the lowest melting points. Of the RTILs synthesized, TGA plots showed most to be stable up to at least 250°C. We had sought to use these RTILs in a series of dynamic combinatorial chemistry (DCC) assembly reactions via solubulisation of dynamin GTPases pleckstrin homology (PH) domain, as such all analogues were screened as potential inhibitors. Screening reveals that these RTILs display varying levels of dynamin GTPase inhibition with a number amongst the most potent inhibitors of dynamin GTPase yet discovered, e.g.13 IC50 = 2.3 ± 0.3 μM (4-(N,N-dimethyl-N-octadecyl-N-ethyl)-4-aza-10-oxatricyclo[5.2.1]decane-3, 5-dione bromide. Accordingly these RTILs have limited utility for DCC assembly with dynamin GTPase, but may be of use with other proteins or in other fields of study. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
Zhang, Jie,Lawrance, Geoffrey A.,Chau, Ngoc,Robinson, Phillip J.,McCluskey, Adam
p. 28 - 36
(2008)
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Synthesis and anticancer activity of a series of norcantharidin analogues
Cantharidin (1) and norcantharidin (2) display high levels of anticancer activity against a broad range of tumour cell lines. Synthetic manipulation of norcantharidin yields (3S,3aR,4S,7R,7aS)-3-hydroxyhexahydro-4,7- epoxyisobenzofuran-1(3H)-one (3), which also displays a high level of anticancer activity against tumour cells but interestingly, shows selectivity towards HT29 (colon; GI50 = 14 μM) and SJ-G2 (glioblastoma; GI50 = 15 μM) cell lines. Substitution at the hydroxyl group of the cyclic lactone within (3) produces a diasteromeric pair of products that have no difference in cytotoxicity over the cell lines tested. Incorporation of an isopropyl tail at this position (16) produced the most promising compound of this series to date, with strong selectivity towards HT29 (colon; GI50 = 19 μM) and SJ-G2 (glioblastoma; GI50 = 21 μM) cell lines but completely void of any activity against the remaining tumour cell lines (GI50 > 100 μM), as per the parent molecule. We also discovered that the introduction of a terminal phosphate moiety (28) at the same position produced a different trend in cytotoxicity with strong activity in BE2-C (neuroblastoma; GI 50 = 9 μM) cells; suggestive of an alternate mode of action.
Tarleton, Mark,Gilbert, Jayne,Sakoff, Jennette A.,McCluskey, Adam
p. 573 - 581
(2012)
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Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity
Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low μM IC50s) comparable to that of norcantharidin (PP1 IC50 = 10.3 ± 1.37 μM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC50 = 2.69 ± 1.37 μM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC50 = 6.5 ± 2.3 μM; and PP2A IC50 = 7.9 ± 0.82 μM (PP1/PP2A = 0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC50 = 48 ± 9; and PP2A IC5 85 ± 3 μM (PP1/PP2A = 0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC50s of 89 ± 6 and 42 ± 3 μM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date. Crown Copyright
Stewart, Scott G.,Hill, Timothy A.,Gilbert, Jayne,Ackland, Stephen P.,Sakoff, Jennette A.,McCluskey, Adam
p. 7301 - 7310
(2007)
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Cyclohexanedicarboxylic acid derivative with bridge ring and pharmaceutical composition and application thereof
The invention discloses a cyclohexane dicarboxylic acid derivative with a bridged ring represented by general formula (I). The application of the stereoisomers and the pharmaceutically acceptable salts in the preparation of antitumor drugs has obvious inhibition effects on leukemia, liver cancer, lung cancer, gastric cancer and ovarian cancer. The compound disclosed by the invention has high anti-tumor activity, wide anti-tumor spectrum and low toxicity, and is suitable for preparing anti-cancer drugs.
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Paragraph 0081-0083; 0100-0101

(2021/11/10)

Synthesis of l-ascorbic acid-amino acid-norcantharidin conjugates and their biological activity evaluation in vitro
Three components of L-ascorbic acid, amino acid and functionalized norcantharidins were constructed together in several steps to form 42 norcantharidin derivatives in a high yield. The structure of these synthesized l-ascorbic acid-amino acid-norcantharidin conjugates are determined by 1HNMR, 13CNMR and MS spectrum. The results showed that compounds 6e, 6g, 6j, 6l, 6m, 6b, 6e, 6i, and 6n showed high cytotoxicity to HepG2 and compounds 6b, 6e-g, 6l, 6n, 7b, 7d, 7h, 7i, 7n, 8g, 8i exhibited high cytotoxicity to SW480; Meanwhile, besides 6b, 6e, 6g, and 6k, the other compounds showed less toxic to LO2 at a concentration of 50 μg/mg after 72 h. Compound 6g can induce Mφ-type macrophages derived from mouse bone marrow to polarize to M1-type macrophages.
Wang, Xianheng,Wu, Caoyuan,Zhang, Jidong,Zhao, Changkuo,Zhou, Yiqi
(2022/01/06)

Norcantharidin carboxylic acid trifluorobenzyl ester as well as synthesis method and application thereof
A norcantharidin carboxylic acid trifluorobenzyl ester as well as a synthesis method and application thereof are provided. The specific structure of the norcantharidin carboxylic acid trifluorobenzylester as shown in the formula I is shown in the specification. Activity tests show that the norcantharidin carboxylic acid trifluorobenzyl ester as shown in the formula I is a suitable anti-tumor candidate drug, especially as an anti-liver cancer candidate drug. Compared with positive control drugs norcantharidin and sodium norcantharidate, the water solubility, the stability and the anti-tumor activity are improved. In addition, the synthesis method of the norcantharidin carboxylic acid trifluorobenzyl ester has the advantages that the raw materials are easy to obtain, and the operation and the implementation are very easy.
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Paragraph 0043-0045

(2020/07/02)

Synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester
The invention provides synthesis and anti-tumor application of norcantharidin carboxylic acid difluorobenzyl ester with a structural formula shown as I in the specification. The specific structure ofthe norcantharidin carboxylic acid difluorobenzyl ester as shown in the formula I is shown in the specification, and activity tests show that the norcantharidin carboxylic acid difluorobenzyl ester asshown in the formula I, which is designed and synthesized by the invention, is a suitable anti-tumor candidate drug, especially as a candidate anti-liver-cancer drug. Compared with positive control drugs norcantharidin and sodium norcantharidate, the water solubility, the stability and the anti-tumor activity are improved. In addition, the synthesis method of norcantharidin carboxylic acid difluorobenzyl ester has the advantages that the raw materials are easy to obtain, and the operation and the implementation are very easy.
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Paragraph 0038-0039

(2020/07/13)

Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof
The invention discloses tetrafluorobenzyl norcantharidin carboxylate and a synthesis method thereof. The structural formula is shown as a formula I, the specific structure of tetrafluorobenzyl norcantharidin carboxylate shown in a formula I is shown in the specification and the synthesis method comprises the following steps that side-chain tetrafluorobenzyl alcohol (compound 5) and norcantharidin(compound 4) undergo a reaction in an organic solvent at a certain temperature under the action of an organic alkali to obtain tetrafluorobenzyl norcantharidin carboxylate shown as a formula I. The synthesis route is shown as follows that: carboxyl is introduced into the molecular structure of the compound disclosed by the invention, so that the water solubility and stability are improved, and dueto the introduction of a fluorine-containing group, the physical property, the chemical property and the biological activity of parent molecules can be remarkably changed, so that the pharmacokineticefficacy can be enhanced. In addition, the raw materials of the synthesis method are easy to obtain, and operation and implementation are very easy.
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Paragraph 0042-0043

(2020/07/15)

Norcantharidin fluorine-containing benzyl ester salt derivative as well as synthesis method and anti-tumor application thereof
The invention discloses a norcantharidin fluorine-containing benzyl ester salt derivative as well as a synthesis method and anti-tumor application thereof. The specific structure of the norcantharidinfluorine-containing benzyl ester salt derivative as shown in the formula I is shown in the specification, and activity tests show that the norcantharidin fluorine-containing benzyl ester salt derivative as shown in the formula I, which is designed and synthesized by the invention, is a suitable anti-tumor candidate drug, especially as an anti-liver cancer candidate drug. Compared with a positivecontrol drug norcantharidin, the norcantharidin sodium salt has the advantage that the water solubility, the stability and the anti-tumor activity are improved.
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Paragraph 0031; 0038-0039

(2020/06/20)

Camptothecin - hydroxyacetic acid - norcantharidin conjugate and application thereof
The present invention provides camptothecin-hydroxyacetic acid-norcantharidin conjugates I: The dotted line I in Formula, represents that the bond on the position is saturated or unsaturated double bond ;R is selected from the group C1 - C6 of alkyl,substituted alkyl, cycloalkyl, benzyl or substituted benzyl ;R2 selected from hydrogen or halogen. activity tests prove, cost-effective I-target product yield high, and easy to prepare for, The method, of the present invention provides good antitumor effect . particularly liver cancer, stomach cancer I colon cancer and pancreatic cancer . The invention can be prepared by, % by weight of the synthesized camptothecin conjugate, according to the. present invention.
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Paragraph 0029-0031

(2020/03/17)

Natural drug composition modified derivative and anti-tumor application thereof
The invention discloses a camptothecin derivative I and a synthesis method thereof in the field of new drug design and synthesis. The structural formula of the camptothecin derivative I is as shown inthe specification, R in the formula I is selected from H, Br or dehydrogenation, and R1 is selected from C1-C3 alkyl, naphthenic base, benzyl and substituted benzyl. Activity tests prove that the designed and synthesized camptothecin derivative I has excellent anti-tumor effects and particularly is high in liver cancer, stomach cancer, colon cancer and pancreatic cancer activity.
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Paragraph 0022; 0025; 0026

(2019/04/17)

Sealed tube promoted coupling of camptothecin and norcantharidin acid ester and their preliminary biological activity evaluation in vitro
A facile synthetic method was developed for the novel acid-sensitive camptothecin norcantharidin acid ester derivatives 3 in sealed tube. This method offers several advantages including high yield and simple work procedure which can be extended for the synthesis of analogs. The new synthetic compounds 3 have shown better activity against several tumor cell lines in vitro test.
Wang, Xian H.,Yang, Fu H.,Zhao, Chang K.,Gao, Lei,Li, Chan
p. 406 - 411
(2017/09/27)

NOVEL LIPOPHILIC N-SUBSTITUTED NORCANTHARIMIDE DERIVATIVES AND USE THEREOF
PROBLEM TO BE SOLVED: To provide novel N-substituted norcantharimide derivatives that exhibit excellent selective cytotoxicity to cancerous cells. SOLUTION: The N-substituted norcantharimide derivatives are represented by formula (I). EFFECT: The N-substituted norcantharimide derivatives are useful as lead compounds for producing pharmaceutical compositions for treating cancer, particularly leukemia. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPO&INPIT
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Paragraph 0064; 0066

(2017/04/03)

NOVEL LIPOPHILIC N-SUBSTITUTED NORCANTHARIMIDE DERIVATIVES AND USES THEREO
Novel N-substituted norcantharimide derivatives are disclosed herein. The novel N-substituted norcantharimide derivatives are useful as lead compounds for manufacturing a medicament or a pharmaceutical composition for treating cancer, particularly for treating leukemia.
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Paragraph 0069-0072; 0078; 0079

(2017/04/28)

Containing chromon structure pyrromonazole Norcantharidin derivative and its preparation method and application
The invention discloses a novel chromone structure-containing pyrazole norcantharidin derivative, and a preparation method and an application thereof. The preparation method comprises the following steps of: introducing a pyrazole ring to the sites C5 and C6 in the norcantharidin structure by a 1,3-dipolar cycloaddition method, and reacting the norcantharidin with the pyrazole ring with chromone derivatives to import the chromone structure to synthesize a series of total 6 novel chromone structure-containing pyrazole norcantharidin derivatives; as a result, the activity of the norcantharidin is improved. The chromone structure-containing pyrazole norcantharidin derivatives provided by the invention are applied to the synthesis of anti-tumor drugs, and have wide application prospect.
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Paragraph 0018; 0036

(2017/02/24)

Fluoro-substituted galactoside structure containing triazole norcantharidin derivative, preparation method therefor and application of fluoro-substituted galactoside structure containing triazole norcantharidin derivative
The invention discloses a fluoro-substituted galactoside structure containing triazole norcantharidin derivative, a preparation method therefor and an application of the fluoro-substituted galactoside structure containing triazole norcantharidin derivative. According to the preparation method, the fluoro-substituted galactoside structure containing triazole norcantharidin derivative is synthesized through introducing 1,2,3-triazole to C5 and C6 bits of a structure of norcantharidin by a 1,3-dipole cycloaddition method, and carrying out a reaction with 1-azido-peracetyl galactose to introduce a galactoside structure. The compound has diversified biological activities and can be applied to the preparation of antitumor drugs.
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Paragraph 0028; 0029

(2017/04/21)

Fluoro-substituted triazole norcantharidin derivative containing arabinoside structure, and preparation method and application thereof
The invention discloses a fluoro-substituted triazole norcantharidin derivative containing an arabinoside structure, and a preparation method and application thereof. The preparation method comprises the following steps: introducing 1,2,3-triazole at the position C5 and position C6 of a norcantharidin structure by using a 1,3-dipolar cycloaddition method; and then carrying out a reaction with triacetyl arabinose azide so as to introduce the arabinoside structure, thereby synthesizing the 1,2,3-triazole norcantharidin derivative containing the arabinoside structure. The derivative has a plurality of biological activities and can be used for preparation of antitumor drugs.
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Paragraph 0032; 0033; 0034

(2017/06/02)

Synthesis and biological evaluation of norcantharidin derivatives as protein phosphatase-1 inhibitors
Cantharidin and norcantharidin display anticancer activity against a broad range of tumor cell lines. In this study, we have synthesized a series of norcantharidin derivatives and evaluated their cytotoxic effects on four human tumor cell lines together with the genetically normal human diploid fibroblast line WI-38. One of our compounds (1S,4R)-3-((4-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl) phenyl)carbamoyl)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (12) exhibited potent cytotoxic effects on the tumor cell lines A-549, HepG2, HeLa, and HCT-8, whereas it was less toxic to WI-38 cells than its parent compound, norcantharidin. In addition, this compound inhibited protein phosphatase-1 activity and microtubule formation in HeLa cells, and it also interacts with calf thymus DNA.
Zhao, Jie,Guan, Xiao-Wen,Chen, Shi-Wu,Hui, Ling
p. 363 - 366
(2015/02/19)

Expanding the utility of flow hydrogenation - A robust protocol restricting hydrodehalogenation
A commonly observed limitation of conducting hydrogenations under flow chemistry conditions is hydrodehalogenation. In a bid to circumvent this limitation a series of hydrogenation catalysts were screened, with 5% Pt/C (sulfided) catalyst identified as an effective catalyst to selectively effect reductive aminations, nitro reduction, and alkene reductions in the presence of halogen atoms. Additionally the optimised protocol cleanly reduced imines in the presence of a furan moiety indicating potential amenability to other labile functionalities.
Hizartzidis, Lacey,Cossar, Peter J.,Robertson, Mark J.,Simone, Michela I.,Young, Kelly A.,McCluskey, Adam,Gordon, Christopher P.
p. 56743 - 56748
(2014/12/12)

Synthesis and antiproliferative assay of norcantharidin derivatives in cancer cells
Diels-Alder reaction between furan and maleic anhydride resulted in 5,6-dehydro norcantharidin, then norcantharidin was obtained by reduction. The substituted-carboxylic acid was condensed with N-aminothiourea in presence of phosphorus oxychloride, yielding 2-amino-1,3,4-thiadiazole derivatives. Novel norcantharidin derivatives were synthesized with acylation, then intramolecular condensation using norcantharidin (or 5,6-dehydro norcantharidin) and 2-amino-1,3,4-thiadiazole derivatives. All the target compounds were confirmed by IR, 1HNMR, ESI-MS and were reported for the first time. Norcantharidin derivatives antiproliferative assay was tested by MTT method against A549 and PC-3 cell lines. The results showed that all the norcantharidin derivatives displayed moderate inhibitory activities.
Tu, Guo Gang,Zhan, Jian Feng,Lv, Qiao Li,Wang, Jia Qi,Kuang, Bin Hai,Li, Shao Hua
p. 376 - 381
(2014/05/20)

Synthesis of novel lipophilic N-Substituted norcantharimide derivatives and evaluation of their anticancer activities
This research attempted to study the effect of lipophilicity on the anticancer activity of N-substituted norcantharimide derivatives. Twenty-three compounds were synthesized and their cytotoxicities against five human cancer cell lines studied. The lipophilicity of each derivative was altered by its substituent, an alkyl, alkyloxy, terpenyl or terpenyloxy group at the N-position of norcantharimide. Further, among all synthesized derivatives studied, the compounds N-farnesyloxy-7-oxabicyclo[2.2.1]heptane-2,3- dicarboximide (9), and N-farnesyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboximide (18), have shown the highest cytotoxicity, anti-proliferative and apoptotic effect against human liver carcinoma HepG2 cell lines, yet displayed no significant cytotoxic effect on normal murine embryonic liver BNL CL.2 cells. Their overall performance led us to believe that these two compounds might be potential candidates for anticancer drugs development.
Wu, Jin-Yi,Kuo, Cheng-Deng,Chu, Chien-Yu,Chen, Min-Shin,Lin, Jia-Hua,Chen, Yu-Jen,Liao, Hui-Fen
p. 6911 - 6928
(2014/07/08)

Synthesis and characterization of a renewable polyester containing oxabicyclic dicarboxylate derived from furfural
Techniques using biomass-based materials have become important to reduce the impacts of global warming and the depletion of petroleum resources. Changing biomass from edible to inedible is essential to solve global food issues. Furan derivatives are ideal chemicals for green chemistry because they are produced from inedible biomass resources. Here, we report the preparation of a biomass-based oxabicyclic dicarboxylic anhydride derived from furan derivatives and its polymerization with several α,ω-diols to polyoxabicyclates. 1H NMR spectra and MALDI-TOF MS measurements verified the chemical structure of the polyoxabicyclates. Polyoxabicyclates prepared using 1,3-propanediol or 1,4-butanediol could be moulded into elastic films by melt pressing. Tensile strength testing of the films indicated that they were highly elastic. Furthermore, the films had good transparency in the visible region.
Tachibana, Yuya,Yamahata, Masayuki,Kasuya, Ken-Ichi
p. 1318 - 1325
(2013/06/26)

A flow chemistry approach to norcantharidin analogues
Acid-ester and acid-amide norcantharidin derivatives are prepared using a 'one-pot' synthetic procedure utilizing the ThalesNano H-cube flow hydrogenator. Traditionally, rapid library generation and reaction scale up of these analogues was limited by the batch wise hydrogenation of 5,6-dehydronorcantharidin. This was resolved with the use of flow chemistry. With no associated scale up issues, a method was devised to produce norcantharidin, along with acid-ester and acid-amide analogues on any scale necessary for biological screening.
Tarleton, Mark,Young, Kelly A.,Unicomb, Elli,McCluskey, Siobhann N.,Robertson, Mark J.,Gordon, Christopher P.,McCluskey, Adam
scheme or table
p. 568 - 574
(2012/06/05)

Synthesis and characterization of novel bi- and tricyclic α-amino acids
As part of a medicinal chemistry collaboration, a number of novel bi- and tricyclic aamino acids were prepared through various routes and characterized by 1 H nuclearOverhauser effect difference experiments. The syntheses provide a number of routes to access some highly substituted amino acid derivatives that have not been reported previously. It is envisaged that the chemistry described here could be applied to the synthesis of other unique substrates Taylor & Francis Group, LLC.
Johnson, Matthew R.,Gauuan, Jolicia F.,Guo, Cheng,Guzzo, Peter R.,Le, Van-Duc,Shenoy, Rajesh A.,Hamby, James,Roark, Howard,Stier, Michael,Mangette, John E.
experimental part
p. 2769 - 2793
(2011/08/22)

A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines
The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl nitriles (2a-e) afforded rapid access to a family of α,β-unsaturated nitriles (3a-e) in good yields (67-78%). Flow hydrogenation (ThalesNano H-cube) at 60 °C, 50 bar H2 pressure, 1.0 mL/min through a 10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a-e). Use of a Raney Nickel catalyst at 70 °C, 70 bar H2 pressure and flow rates of 0.5-1.0 mL/min afforded quantitative conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile bonds (5a-e). The versatility of this approach was further exemplified by reaction of 5a and 5c with norcantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A inhibitors.
Tarleton, Mark,McCluskey, Adam
scheme or table
p. 1583 - 1586
(2011/04/26)

Norcantharimide analogues possessing terminal phosphate esters and their anti-cancer activity
A family of norcantharidin analogues possessing a terminal alcohol (ethanol, propanol, butanol, pentanol, hexanol and cyclohexanol) moiety were treated with either chlorodiethyl, chlorodiphenyl or chloro-bis-trichloroethyl- phosphate to afford highly focused libraries of the corresponding phosphate esters. Subsequent biological screening against a panel of nine human cancer cell lines identified a trend between the ease of phosphate unmasking (phosphate ester hydrolysis) and cell death. The most potent analogues possessed either a diphenyl or a bis-trichloroethyl moiety. The effect of alkyl spacer was also examined with the hexyl analogues typically more potent. 4-Aza-4-(3-{bis(2,2,2- trichloroethyl)phosphate}propyl)-10-oxatricyclo[5.2.1.0]decane-3,5-dione (10b) was the most potent analogue synthesised with an average GI50 of 11 μM across a panel of nine human carcinoma cell lines: colon carcinoma (HT29 and SW480); breast carcinoma (MCF-7); ovarian carcinoma (A2780); lung carcinoma (H460); skin carcinoma (A431); prostate carcinoma (DU145); neuronal carcinoma (BE2-C) and brain carcinoma (SJ-G2). This represents a fivefold improvement in anti-proliferative activity relative to the lead, norcantharidin.
Robertson, Mark J.,Gordon, Christopher P.,Gilbert, Jayne,McCluskey, Adam,Sakoff, Jennette A.
scheme or table
p. 5734 - 5741
(2011/10/13)

Norcantharidin analogues with nematocidal activity in Haemonchus contortus
With the major problems with resistance in parasitic nematodes of livestock to anthelmintic drugs, there is an urgent need to develop new nematocides. In the present study, we employed a targeted approach for the design of a series of norcantharidin analogues (n = 54) for activity testing against the barber's pole worm (Haemonchus contortus) of small ruminants in a larval development assay (LDA) and also for toxicity testing on nine distinct human cell lines. Although none of the 54 analogues synthesized were toxic to any of these cell lines, three of them (N-octyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B2), N-decyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B3) and 4-[(4-methyl)-3-ethyl-2-methyl-5-phenylfuran-10-oxa-4-azatricyclo[5.2.1] decane-3,5-dione (B21) reproducibly displayed 99-100% lethality to H. contortus in LDA, with LD50s of 25-40 μM. The high 'hit rate' (5.6%) indicates that the approach taken here has advantages over conventional drug screening methods. A major advantage of norcantharidin analogues over some other currently available anthelmintics is that they can be produced in one to two steps in large amounts at low cost and high purity, and do not require any additional steps for the isolation of the active isomer. This positions them well for commercial development.
Campbell, Bronwyn E.,Tarleton, Mark,Gordon, Christopher P.,Sakoff, Jennette A.,Gilbert, Jayne,McCluskey, Adam,Gasser, Robin B.
experimental part
p. 3277 - 3281
(2011/07/07)

METHOD FOR THE PREPARATION OF FUSED HETEROCYCLIC SUCCINIMIDE COMPOUNDS AND ANALOGS THEREOF
Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.
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(2008/06/13)

Design and synthesis of N-maleimido-functionalized hydrophilic polymers via copper-mediated living radical polymerization: A suitable alternative to pegylation chemistry
A series of α-functional maleimide polymethacrylates (Mn = 4.1-35.4 kDa, PDi = 1.06-1.27) have been prepared via copper-catalyzed living radical polymerization (LRP). Two independent synthetic protocols have been successfully developed and the polymers obtained in multigram scale, with an 80-100% content of maleimide reactive chain ends, depending on the method employed. A method for the synthesis of amino-terminated polymers, starting from Boc-protected amino initiators, has also been developed, as these derivatives are key intermediates in one of the two processes studied in the present work. The alternative synthetic pathway involves an initiator containing a maleimide unit "protected" as a Diels-Alder adduct. After the polymerization step, the maleimide functionality has been reintroduced by retro-Diels-Alder reaction, by simply refluxing those polymers in toluene for 7 h. These maleimido-terminated materials, poly(methoxyPEG(475)) methacrylates and poly(glycerol) methacrylates, differ for both the nature and size of the polymer side branches and showed an excellent solubility in water, a property that made them an ideal candidate for the synthesis of new polymer-(poly)peptide biomaterials. These functional polymers have been successfully employed in conjugation reactions in the presence of thiol-containing model substrates, namely, reduced glutathione (γ-Glu-Cys-Gly) and the carrier protein, bovine serum albumin (BSA), in 100 mM phosphate buffer (pH 6.8-7.4) and ambient temperature.
Mantovani, Giuseppe,Lecolley, Francois,Tao, Lei,Haddleton, David M.,Clerx, Joost,Cornelissen, Jeroen J. L. M.,Velonia, Kelly
p. 2966 - 2973
(2007/10/03)

Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.
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(2008/06/13)

Structure-based design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (calcineurin)
Protein serine/threonine phosphatases (PP1, PP2A and PP2B) play important roles in intracellular signal transductions. The immunosuppressant drugs FK506 and cyclosporin A (CsA) bind to immunophilins, and these complexes selectively inhibit PP2B (calcineurin), leading to the suppression of T-cell proliferation. Both FK506 and CsA must, however, form complexes with immunophilins to exert their inhibitory action on PP2B. Thus, it is of interest to find a direct and selective inhibitor of PP2B that does not involve the immunophilins as a biological tool for studies of PP2B and also as a candidate therapeutic agent. We selected the simple natural product cantharidin, a known PP2A-selective inhibitor, as a lead compound for this project. Primary SAR indicated that norcantharidin (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride) inhibits not only PP1 and PP2A but also PP2B, and a binding model of norcantharidin carboxylate to the PP2B catalytic site was computationally constructed. Based on this binding model, we designed and synthesized several cantharidin derivatives. Among these compounds, 1,5-dibenzoyloxymethyl-substituted norcantharidin was found to inhibit PP2B without inhibiting PP1 or PP2A. To our knowledge, this is the first highly selective catalytic site-directed inhibitor of PP2B.
Baba, Yoshiyasu,Hirukawa, Nozomu,Tanohira, Naoto,Sodeoka, Mikiko
p. 9740 - 9749
(2007/10/03)

Monolith- And Silica-Supported Carboxylate-Based Grubbs -Herrmann-Type Metathesis Catalysts
The synthesis of silica- and monolith-supported Grubbs-Herrmann-type catalysts is described. Two polymerizable, carboxylate-containing ligands, exo, exo-7-oxanorborn-2-ene-5,6-dicarboxylic anhydride and 7-oxanorborn-2-ene-5- carboxylic acid were surface-immobilized onto silica- and ring-opening metathesis (ROMP-) derived monolithic supports using "grafting-from" techniques. The "1st generation Grubbs catalyst", RuCl 2(=CHPh)(PCy3)2, was used for these purposes. In addition, a poly(norborn-2-ene-b-exo, exo-norborn-2-ene-5,6-dicarboxylic anhydride) -coated silica 60 was prepared. The polymer supported anhydride and carboxylate groups were converted into the corresponding mono- and disilver salts, respectively, and reacted with the Grubbs-Herrmann catalyst RuCl 2(=CHPh)(IMesH2)(PCy3) [IMesH2 = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]. Heterogenization was accomplished by exchange of one chlorine ligand with the polymeric, immobilized silver carboxylates to yield monolith-supported catalysts 4, 5, and 6 as well as silica-supported systems 7, 8 and 9. The actual composition of these heterogenized catalysts was proven by the synthesis of a homogeneous analogue, RuCl[7-oxanorbornan-2-(COOAg)-3-COO](=CHPh)(IMesH2) (PCy3) (3). All homogeneous and heterogeneous catalysts were used in ring-closing metathesis (RCM) of diethyl diallylmalonate, 1,7-octadiene, diallyldiphenylsilane, methyl trans-3-pentenoate, diallyl ether, N,N-diallyltrifluoracetamide and t-butyl N,N-diallylcarbamate allowing turnover numbers (TON's) close to 1000. In a flow-through set-up, an auxiliary effect of pendant silver carboxylates was observed with catalyst 5, where the silver moiety functions as a (reversible) phosphine scavenger that both accelerates initiation and stabilizes the catalyst by preventing phosphine elution. Detailed catalytic studies were carried out with the monolith-supported systems 4 and 6 in order to investigate the effects of temperature and chain-transfer agents (CTA's) such as cis-1,4-diacetoxybut-2-ene. In all RCM experiments Ru-leaching was low, resulting in a Ru-content of the RCM products ≤3.5 μg/g (3.5 ppm).
Krause, Jens O.,Lubbad, Said,Nuyken, Oskar,Buchmeiser, Michael R.
p. 996 - 1004
(2007/10/03)

Selective androgen receptor modulators and methods for their identification, design and use
Selective androgen receptor modulators (SARMs) having antagonist activity in hormone-dependent tumors while exhibiting no activity or agonist activity against other nontumor tissues containing the androgen receptor as well as methods for identifying, designing and using SARMs are provided.
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(2008/06/13)

[4 + 2] Cycloadditions of rigid s-cis dienes to C60. A synchronous Diels-Alder reaction
(Matrix presented) The Diels-Alder reaction of rigid s-cis dienes with C60 occurs by a concerted mechanism, via a symmetrical transition state.
Chronakis, Nikos,Orfanopoulos, Michael
p. 545 - 548
(2007/10/03)

Anhydride modified cantharidin analogues: Synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity
Two series of anhydride modified cantharidin analogues were synthesised and screened for their phosphatase inhibition (PP1 and PP2A) and cytotoxicity in various cancer cell lines (Ovarian A2780, ADDP; Osteosarcoma 143B; and Colon HCT116 and HT29). One series was synthesised by a novel, high yielding one-pot hydrogenation-ring-opening-esterification procedure, the other by acid catalysed acetal formation. Analogues 5-7 and 9 displayed moderate PP2A selectivity (ca. 5- to 20-fold) and inhibition typically in the low μM range (comparable, in some cases to cantharidin). The anticancer activity of these analogues varied with the cell line under study; however, many of them showed selective cytotoxicity for the colon tumour cell lines. (C) 2000 Elsevier Science Ltd. All rights reserved.
McCluskey, Adam,Bowyer, Michael C.,Collins, Elizabeth,Sim, Alistair T.R.,Sakoff, Jennette A.,Baldwin, Monique L.
p. 1687 - 1690
(2007/10/03)

Practical and Highly Enantioselective Ring Opening of Cyclic Meso-Anhydrides Mediated by Cinchona Alkaloids
The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of methanol leading to optically active hemiesters is described. Very structurally diverse anhydrides are converted into their corresponding methyl monoesters, and either enantiomer can be obtained with up to 99% ee by using quinine or quinidine as directing additive. After the reaction, the alkaloids can be recovered almost quantitatively and reused without loss of enantioselectivity. Additionally, a catalytic protocol which permits the substoichiometric use of quinidine in the presence of easily accessible pentamethylpiperidine (pempidine) is presented.
Bolm, Carsten,Schiffers, Ingo,Dinter, Christian L.,Gerlach, Arne
p. 6984 - 6991
(2007/10/03)

A convenient reduction of unsaturated bicyclic anhydrides
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Csende, Ferenc,Stajer, Geza
p. 220 - 222
(2007/10/03)

Highly Enantioselective Ring Opening of Cyclic Meso-Anhydrides to Isopropyl Hemiesters with Ti-TADDOLates: An Alternative to Hydrolytic Enzymes?
The Lewis acid mediated transfer of an alkoxide ligand from the chiral ligand sphere of Ti - TADDOLate (1) to cyclic meso anhydrides to afford the corresponding hemiesters is described. By using this method a variety of structurally different anhydrides can be converted to isopropyl hemiesters with high enantioselectivities (enantiomer ratios up to 99:1). We have also investigated Lewis acidic titanium complexes, which differ from 1 in the chiral ligand or the alkoxide ligand that is transferred. Finally, a catalytic version, which allows the substoichiometric use of Ti- TADDOLate in the presence of stoichiometric amounts of Al(Oi-Pr)3, is presented.
Jaeschke, Georg,Seebach, Dieter
p. 1190 - 1197
(2007/10/03)

Structure-activity relationship of cantharidin derivatives to protein phosphatases 1, 2A1, and 2B
The effects of structural modification of cantharidin on the inhibition of protein Ser/Thr phosphatases are described. Removal of the methyl substituents at C2 and C3 in cantharidin improved the inhibition of PP2B. In contrast, introduction of a substituent to C1/C4-position drastically decreased inhibition of PP1 and PP2A1. PP2B was found to be quite tolerant to modifications at the C5 position.
Sodeoka, Mikiko,Baba, Yoshiyasu,Kobayashi, Satoko,Hirukawa, Nozomu
p. 1833 - 1836
(2007/10/03)

Oxazaborolidine catalysed enantioselective reduction of cyclic meso-imides
Full details of the enantioselective reduction of cyclic meso-imides catalysed by an enantiopure oxazaborolidine derived from (S)-α,α-diphenylprolinol are reported. Treatment of the imides with borane in the presence of the catalyst led to a mixture of cis- and trans-hydroxylactams and, after subsequent ethanolysis, to the corresponding diastereomerically pure trans-ethoxylactams. The enantiomeric excesses were shown to be 68-94% by HPLC-determination. One example, in which the ethoxylactam was converted into the benzenesulfonyllactam, could be crystallized to >99% enantiomeric purity.
Ostendorf, Martin,Romagnoli, Romeo,Pereiro, Isabel Cabeza,Roos, Eric C.,Moolenaar, Marinus J.,Speckamp, W. Nico,Hiemstra, Henk
p. 1773 - 1789
(2007/10/03)

Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-b icyclo[2.2.1]heptanedicarboxime (Tandospirone) and related compounds
A series of cyclic imides bearing a ω-(4-aryl and 4-heteroaryl-1-piperazinyl)alkyl moieties was synthesized and tested in vivo for anxiolytic activity. The in vitro binding affinities of these compounds were also examined for 5-HT(1A) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (1: tandospirone), was found to be equipotent with buspirone in its anxiolytic activity and more anxio-selective than buspirone and diazepam. Tandospirone (1) is currently undergoing clinical evaluation as a selective anxiolytic agent.
Ishizumi,Kojima,Antoku
p. 2288 - 2300
(2007/10/02)

TANDEM CYCLOADDITION-ENZYMATIC TRANSESTERIFICATION. AN ENANTIOSELECTIVE DIELS-ALDER REACTION EQUIVALENT
Tandem cycloaddition-enzymatic transesterification with pancreatic pig lipase or the lipase from Candida ciclindracea carried out in ethyl, vinyl, or isopropenyl acetate gives rise to optically active Diels-Alder type derivatives from symmetrical precursors with both high enantioselectivity and chemical yield.
Andreu, Cecilia,Marco, J. Alberto,Asensio, Gregorio
p. 3209 - 3210
(2007/10/02)

Enzymes in organic synthesis. 32. Stereospecific horse liver alcohol dehydrogenase-catalyzed oxidations of exo- and endo-oxabicyclic meso diols
Preparative-scale horse liver alcohol dehydrogenase-catalyzed oxidation of meso exo- and endo-7-oxabicycloheptane diols provides a direct one-step route to enantiomerically pure chiral γ-lactones of the oxabicyclic series.
Jones, J. Bryan,Francis, Christopher J.
p. 2578 - 2582
(2007/10/02)

Novel Synthesis of Five- and Six-Membered Spiro γ-Lactones in Rigid Bicyclic Systems
The reaction of bis(bromomagnesio)alkanes with bridged tricyclic endo- and exo-dicarboxylic anhydrides and their dihydro derivatives provides a general and versatile route to corresponding tricyclic spiro γ-butanolides.Futher extension of this methodology to the dianhydride of bicyclooctene showed appreciable regioselectivity.The subsequent transformation of spiro γ-lactones into 4-spiro-2-butenolides by retro-Diels-Alder reaction has provided a simple and convenient synthesis of these molecules.Proton and 13C NMR spectra are reported for most of the compounds.
Cannone, Persephone,Belanger, Denis,Lemay, Gilles
p. 3953 - 3959
(2007/10/02)