493 results found
Cavalli ES, Mies T, Rzepa HS, et al., 2022, Pyrimidine nucleosides syntheses by late-stage base heterocyclization reactions, Organic Letters, Vol: 24, Pages: 8931-8935, ISSN: 1523-7052
An efficient two-step procedure for the syntheses of pyrimidine nucleosides is presented. A series of glycosyl 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives were prepared from β-anomeric isonitriles by reaction with Meldrum’s acid or by allowing aminomethylene Meldrum’s acid to react with an 1-aldofuranosyl halide or acetate. The resultant 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives underwent reaction with benzyl- or 2,4-dimethoxybenzyl isocyanate via transacylation to provide uridine-5-carboxylic acid derivatives and related nucleosides. These nucleoside carboxylic acids were converted into other C-5 derivatives by bromo-decarboxylation with N-bromosuccinimide.
Mies T, Schurmann C, Ito S, et al., 2022, Synthesis and Characterization of a Calcium-Pyrazolonato Complex. Observation of In-Situ Desolvation During Micro-Electron Diffraction, ZEITSCHRIFT FUR ANORGANISCHE UND ALLGEMEINE CHEMIE, ISSN: 0044-2313
Howell SJ, Kenny LM, Lord S, et al., 2022, A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Mies T, White AJP, Parsons PJ, et al., 2021, Photolytic Studies on the Generation and Trapping of 6-Oxomethylidenecyclohexa-2,4-diene-1-one Derivatives with Various Nucleophiles, HELVETICA CHIMICA ACTA, Vol: 104, ISSN: 0018-019X
Mies T, White AJP, Parsons PJ, et al., 2021, Conversion of 5-methyl-4H-benzo[d][1,3]dioxin-4-one derivatives into functionalized 8-hydroxyisochroman-1-one under basic conditions, TETRAHEDRON LETTERS, Vol: 81, ISSN: 0040-4039
Krebs MG, Lord S, Kenny L, et al., 2021, First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S458-S458, ISSN: 0923-7534
Barrett AGM, Cavalli ES, 2021, Medicinal Chemistry in South America: From Tropical Diseases to Cancers and Other Major Afflictions, ACS MEDICINAL CHEMISTRY LETTERS, Vol: 12, Pages: 1350-1356, ISSN: 1948-5875
Mies T, Patel C, Parsons PJ, et al., 2021, Biomimetic total syntheses of amorfrutins A, B, (S)-D and (R)-D and formal synthesis of amorfrutin C, European Journal of Organic Chemistry, Vol: 2021, Pages: 2540-2548, ISSN: 1099-0690
Bibenzyl natural products, such as the amorfrutins, contain a heavily substituted aromatic core and display a diverse range of biological activities (anti-tumor, anti-diabetic, antimicrobial, and antibiotic). In this study, we report unified syntheses of amorfrutin A to D either through total or formal synthesis by employing a dual biomimetic strategy of polyketide aromatization followed by remote terpene functionalization. The key core structures were synthesized from β-keto dioxinone esters through a magnesium(II) mediated regioselective C-acylation, palladium catalyzed decarboxylative allylic rearrangement, and dehydrative cyclization.
Riedel R, Seel AG, Malko D, et al., 2021, Superalkali-alkalide interactions and ion pairing in low-polarity solvents, Journal of the American Chemical Society, Vol: 143, Pages: 3934-3943, ISSN: 0002-7863
The nature of anionic alkali metals in solution is traditionally thought to be “gaslike” and unperturbed. In contrast to this noninteracting picture, we present experimental and computational data herein that support ion pairing in alkalide solutions. Concentration dependent ionic conductivity, dielectric spectroscopy, and neutron scattering results are consistent with the presence of superalkali–alkalide ion pairs in solution, whose stability and properties have been further investigated by DFT calculations. Our temperature dependent alkali metal NMR measurements reveal that the dynamics of the alkalide species is both reversible and thermally activated suggesting a complicated exchange process for the ion paired species. The results of this study go beyond a picture of alkalides being a “gaslike” anion in solution and highlight the significance of the interaction of the alkalide with its complex countercation (superalkali).
Patel C, Mies T, White AJP, et al., 2021, Biomimetic syntheses of amorfrutin C and C-5 substituted amorfrutin analogues, European Journal of Organic Chemistry, Vol: 2021, Pages: 1258-1265, ISSN: 1099-0690
Amorfrutin C, a C-5 prenyl amorfrutin, its allyl analog and an amorfrutin C-5 aldehyde have been synthesized using a biomimetic strategy from non-aromatic precursors. In this approach, a dioxinone derived β,δ-diketo ester underwent a decarboxylative Pd(0) catalyzed prenyl migration to give a β,δ-diketo dioxinone, which readily aromatized giving the amorfrutin core. The introduction of prenyl and allyl moieties at the C-5 position of the scaffold was accomplished using a Claisen rearrangement. Alternatively, iodination, lithium-iodine exchange and trapping with DMF gave the amorfrutin aldehyde and an amorfrutin alcohol when excess n-BuLi was used.
Mies T, White AJP, Parsons PJ, et al., 2021, Biomimetic syntheses of analogs of hongoquercin A and B by late-stage derivatization, Journal of Organic Chemistry, Vol: 86, Pages: 1802-1817, ISSN: 0022-3263
The hongoquercins are tetracyclic meroterpenoid natural products with the trans–transoid decalin-dihydrobenzopyran ring system, which display a range of different bioactivities. In this study, the syntheses of a range of hongoquercins using gold-catalyzed enyne cyclization reactions and further derivatization are described. The parent enyne resorcylate precursors were synthesized biomimetically from the corresponding dioxinone keto ester via regioselective acylation, Tsuji-Trost allylic decarboxylative rearrangement, and aromatization. The dioxinone keto ester 12 was prepared in 6 steps from geraniol using allylic functionalization and alkyne synthesis.
Qu T, White AJP, Barrett AGM, 2020, Four-directional synthesis of adamantane derivatives, ARKIVOC, Vol: 4, Pages: 18-50, ISSN: 1551-7004
1-Adamantanemethanol, 1,3-adamantanedimethanol and 1,3,5,7-adamantanetetramethanol were convertedinto adamantanes functionalized with one or four (2R,1S)-2-formyl-1-cyclopropyl residues using Charetteenantioselective cyclopropanation reactions and with one, two or four 4-ethoxy- (or 4-t-butoxy)-3-diazo-2,4-dioxobutyl residues from aldehyde and diazo-acetate ester condensation reactions by 1-directional, 2-directional or 4-directional syntheses. The synthesis of adamantane fused to cyclopentadiene is also reported.
Ma T-K, Parsons P, Barrett A, 2020, Synthesis, aromatization and derivatization reactions of 2-(9-(tert-butoxycarbonyl)-4-oxo-1,5-dioxa-9-azaspiro[5.5]undec-2-en-2-yl)acetic acid, European Journal of Organic Chemistry, Vol: 2020, Pages: 28-34, ISSN: 1434-193X
A series of natural product inspired piperidines spiro‐fused with resorcylic, chromenic and chromanic amides were prepared from a general derivative of a N ‐Boc‐4‐oxo‐4 H ‐spiro[benzo[ d ][1,3]dioxinone‐2,4‐piperidine], which was prepared via biomimetic aromatization of a b , d ‐diketo‐dioxinone, in turn synthesized from N ‐Boc‐4‐piperidone and geraniol using ketene coupling reagents.
Mies T, Ma T-K, Barrett AGM, 2020, Syntheses of polyfunctional aromatic compounds from non-aromatic precursors, Russian Chemical Reviews, Vol: 89, Pages: 917-965, ISSN: 0036-021X
Syntheses of polyfunctional benzene derivatives from both cyclic and acyclic non-aromatic precursors are reviewed. Such aromatizations include transformations that use Diels – Alder reactions, transition metal-catalyzed reactions, base mediated aldol or Michael addition reactions or electrocyclic and pericyclic reactions. This review is limited to research that has been published since the last reviews in 2006, 2008, 2015 and 2018 and is specifically focused on aromatic and heteroaromatic compounds synthesized by construction of the benzene ring. It excludes heterocyclic compounds that lack a monocyclic benzene core. Applications of such aromatization reactions for the total syntheses of natural products as well as potential medicinal chemical entities are included.
Goldup SM, Pilkington CJ, White AJP, et al., 2019, Correction to "A Simple, Short, and Flexible Synthesis of Viridiofungin Derivatives", Journal of Organic Chemistry, Vol: 84, Pages: 6546-6546, ISSN: 0022-3263
Ma T-K, Parsons PJ, Barrett AGM, 2019, Meroterpenoid synthesis via sequential polyketide aromatization and radical anion cascade triene cyclization: Biomimetic total syntheses of austalide natural products, The Journal of Organic Chemistry, Vol: 84, Pages: 4961-4970, ISSN: 0022-3263
The first total synthesis of five austalide natural products, (±)-17S-dihydroaustalide K, (±)-austalide K, (±)-13-deacetoxyaustalide I, (±)-austalide P, and (±)-13-deoxyaustalide Q acid, was accomplished via a series of biomimetic transformations. Key steps involved polyketide aromatization of a trans,trans-farnesol-derived β,δ-diketodioxinone into the corresponding β-resorcylate, followed by titanium(III)-mediated reductive radical cyclization of an epoxide to furnish the drimene core. Subsequent phenylselenonium ion induced diastereoselective cyclization of the drimene completed the essential carbon framework of the austalides to access (±)-17S-dihydroaustalide K, (±)-austalide K, and (±)-13-deacetoxyaustalide I via sequential oxidations. Furthermore, (±)-13-deacetoxyaustalide I could serve as a common intermediate to be derivatized into other related natural products, (±)-austalide P and (±)-13-deoxyaustalide Q acid, by functionalizing the cyclic lactone moiety.
Barrett AGM, Ma T-K, Mies T, 2019, Recent developments in polyene cyclizations and their applications in natural product synthesis, Synthesis, Vol: 51, Pages: 67-82, ISSN: 0039-7881
Cascade polyene cyclization reactions are highly efficient and elegant bioinspired transformations that involve simultaneous multiple bond constructions to rapidly generate complex polycyclic molecules. This review summarizes the most prominent work on a variety of cationic and radical cascade cyclizations and their applications in natural product synthesis published between 2014 and 2018.
Ma T-K, Elliott DC, Reid S, et al., 2018, Meroterpenoid synthesis via sequential polyketide aromatization and cationic polyene cyclization: total syntheses of (+)-Hongoquercin A and B and related meroterpenoids., Journal of Organic Chemistry, Vol: 83, Pages: 13276-13286, ISSN: 0022-3263
(+)-Hongoquercin A and B were synthesized from commercially available trans, trans-farnesol in six and eleven steps, respectively, using dual biomimetic strategies with polyketide aromatization and subsequent polyene functionalization from a common farnesyl-resorcylate intermediate. Key steps involve Pd(0)-catalyzed decarboxylative allylic rearrangement of a dioxinone β,δ-diketo ester to a β,δ-diketo dioxinone, which was readily aromatized into the corresponding resorcylate, and subsequent polyene cyclization via enantioselective protonation or regioselective terminal alkene oxidation and cationic cyclization of enantiomerically enriched epoxide to furnish the tetracyclic natural product cores. Analogues of the hongoquercin were synthesized via halonium-induced polyene cyclizations, and the meroterpenoid could be further functionalized via saponification, hydrolytic decarboxylation, reduction, and amidation reactions.
Cookson R, White AJP, Barrett AGM, 2018, Synthesis of the C1 to C13 tetrahydropyranyl-resorcylate core of paecilomycin B, TETRAHEDRON, Vol: 74, Pages: 5040-5048, ISSN: 0040-4020
A d-Glucose derived tetrahydropyran was converted into the C1 to C13 tetrahydropyranyl-resorcylate core of paecilomycin B in seven steps. Key transformations included the synthesis of a diketo-ester dioxinone, which upon thermolysis underwent a retro-hetero-Diels-Alder fragmentation to generate an acyl ketene. This was subsequently trapped by a secondary alcohol affording a triketo-ester, which was efficiently aromatized to produce the advanced resorcylate intermediate.
Almond-Thynne J, Han J, White AJP, et al., 2018, Bidirectional synthesis of di-t-butyl (2S,6S,8S)- and (2R,6R,8R)-1,7-diazaspiro[5.5]undecane-2,8-dicarboxylate and related spirodiamines, Journal of Organic Chemistry, Vol: 83, Pages: 6783-6787, ISSN: 0022-3263
Efficient syntheses of both enantiomers of a spirodiamine diester from (L)- and (D)-aspartic acid are described. The key transformation was the conversion of Boc-protected t-butyl aspartate into the derived aldehyde, two directional Horner Emmons olefination, hydrogenation and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approaches to derivatives of 1,7-diazaspiro[5.5]undecane is described.
Ali S, Patel H, Periyasamy M, et al., 2018, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment, Molecular Cancer Therapeutics, ISSN: 1535-7163
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.
Hazel P, Kroll SHB, Bondke A, et al., 2018, Corrigendum: Inhibitor selectivity for cyclin-dependent kinase 7: a structural, thermodynamic, and modelling study, ChemMedChem, Vol: 13, Pages: 207-207, ISSN: 1860-7187
Almond-Thynne J, White AJP, Polyzos A, et al., 2017, Synthesis and reactions of benzannulated spiroaminals: tetrahydrospirobiquinolines, ACS Omega, Vol: 2, Pages: 3241-3249, ISSN: 2470-1343
An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o′-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation–spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core.
Kandela IK, McAuliffe KJ, Cochran LE, et al., 2017, Discovery of the antitumor effects of a porphyrazine diol (Pz 285) in MDA-MB-231 breast tumor xenograft models in mice, ACS Medicinal Chemistry Letters, Vol: 8, Pages: 705-709, ISSN: 1948-5875
A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cellsin vitro. The leadPz 285was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs.Pz 285shows marked antitumor effectsin vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups.Pz 285is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.
Ma TK, White AJP, Barrett AGM, 2017, Meroterpenoid total synthesis: conversion of geraniol and farnesol intoamorphastilbol, grifolin and grifolic acid by dioxinone-β-keto-acylation,palladium catalyzed decarboxylative allylic rearrangement and aromatization, Tetrahedron Letters, Vol: 58, Pages: 2765-2767, ISSN: 1873-3581
Biomimetic total syntheses of resorcinols amorphastilbol, grifolin and grifolic acid have been completed in four steps starting from geraniol and farnesol without the use of phenolic protection. The key steps involve C-acylation of dioxinone-β-keto esters, followed by palladium catalyzed decarboxylative allylic rearrangement and biomimetic aromatization.
Hazel P, Kroll SH, Bondke A, et al., 2017, Inhibitor selectivity for cyclin-dependent kinase 7: a structural, thermodynamic, and modelling study, Chemmedchem, Vol: 12, Pages: 372-380, ISSN: 1860-7187
Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, cancer in particular. We identified small-molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell-cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we used a combination of structural, biophysical, and modelling approaches. We determined the crystal structures of the CDK7-selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics (MD) simulations of inhibitors bound to CDK2 and CDK7 generated possible models of inhibitor binding. To experimentally validate these models, we gathered isothermal titration calorimetry (ITC) binding data for recombinant wild-type and binding site mutants of CDK7 and CDK2. We identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our MD simulations also show that the flexibility of the G-rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.
Ali S, Patel H, Periyasamy M, et al., 2016, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for breast cancer, UK Breast Cancer Research Symposium, Publisher: Springer Verlag, Pages: 195-195, ISSN: 0167-6806
Barrett AGM, Elliott D, Ma T, et al., 2016, Sequential Ketene Generation from Dioxane-4,6-dione-keto-dioxinones for the Synthesis of Terpenoid Resorcylates, Organic Letters, Vol: 18, Pages: 1800-1803, ISSN: 1523-7060
Trapping of the ketene generated from the thermolysis of 2-methyl-2-phenyl-1,3-dioxane-4,6-dione-ketodioxinoneat 50 °C with primary, secondary, or tertiary alcohols gave the corresponding dioxinone β-keto-esters in good yieldunder neutral conditions. These intermediates were converted by palladium(0)-catalyzed decarboxylative allyl migration andaromatization into the corresponding β-resorcylates. These transformations were applied to the syntheses of the natural products(±)-cannabiorcichromenic and (±)-daurichromenic acid.
Doepner AM, Aboagye EO, Barrett AGM, 2015, 2 '-Deoxy-2 ',2 '-difluorothymidine analogues for radiolabeling with fluorine-18 and other biomedical applications, TETRAHEDRON LETTERS, Vol: 56, Pages: 3293-3297, ISSN: 0040-4039
Cookson R, Barrett TN, Barrett AGM, 2015, beta-Keto-dioxinones and beta,delta-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis, ACCOUNTS OF CHEMICAL RESEARCH, Vol: 48, Pages: 628-642, ISSN: 0001-4842
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