An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• Nicky J. Willis Elliott D. Bayle George Papageorgiou David Steadman Benjamin N. Atkinson William Mahy Paul V. Fish Alzheimer’s Research UK UCL Drug Discovery Institute, The Cruciform Building, University College London, Gower Street, London WC1E 6BT, UK The Francis Crick Institute, 1 Midland Road

• biology of Notum and build target validation to underpin new drug discovery programs. Results: An improved, scalable synthesis of 1 is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki–Miyaura cross-coupling reaction with MIDA

• to 1 which contains functional groups sensitive to certain reagents employed (vide infra). An improved synthetic route should allow 1 to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs for

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• prospect of the tetrazole hybridization strategy in drug discovery. Among the most versatile methods for obtaining tetrazoles are the Ugi-azide four-component reaction (Ugi-azide-4CR) [14][15][16] and the 1,3-dipolar cycloaddition of azides with (acyl)cyanides [17][18]. The Ugi-azide-4CR enables the

Perspective isomorphs – a new classification of molecular structures based on artistic and chemical concepts

• Jannis Neumann,
• Ansgar Schnurr and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2019, 15, 2319–2326, doi:10.3762/bjoc.15.224

• collection of molecular models and scientific posters (see Supporting Information File 1). Connection to modeling in drug discovery The classification of compounds by shape has a long tradition in drug discovery [18][19]. With the development in computer technology powerful programs have been developed that

Isolation of fungi using the diffusion chamber device FIND technology

• Benjamin Libor,
• Henrik Harms,
• Stefan Kehraus,
• Ekaterina Egereva,
• Max Crüsemann and
• Gabriele M. König

Beilstein J. Org. Chem. 2019, 15, 2191–2203, doi:10.3762/bjoc.15.216

• play a prominent role as lead structures in drug discovery [1]. Apart from bacteria, fungi are an impressive group of microorganisms in this respect, due to the high structural diversity of their rich secondary metabolism. Fungi are known as producers of many therapeutically important drugs, such as

An overview of the cycloaddition chemistry of fulvenes and emerging applications

• Ellen Swan,
• Kirsten Platts and
• Anton Blencowe

Beilstein J. Org. Chem. 2019, 15, 2113–2132, doi:10.3762/bjoc.15.209

• reactivity and mechanisms of action. Dynamic combinatorial chemistry Dynamic combinatorial chemistry (DCC) is an emerging field with promising applications in drug discovery. DCC involves the generation of new molecules via reversible reactions of simple building blocks, referred to as a dynamic

Genome mining in Trichoderma viride J1-030: discovery and identification of novel sesquiterpene synthase and its products

• Xiang Sun,
• You-Sheng Cai,
• Yujie Yuan,
• Guangkai Bian,
• Ziling Ye,
• Zixin Deng and
• Tiangang Liu

Beilstein J. Org. Chem. 2019, 15, 2052–2058, doi:10.3762/bjoc.15.202

• Xiang Sun You-Sheng Cai Yujie Yuan Guangkai Bian Ziling Ye Zixin Deng Tiangang Liu Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P. R. China 10.3762/bjoc.15.202 Abstract Sesquiterpene

Installation of -SO₂F groups onto primary amides

• Jing Liu,
• Shi-Meng Wang,
• Njud S. Alharbi and
• Hua-Li Qin

Beilstein J. Org. Chem. 2019, 15, 1907–1912, doi:10.3762/bjoc.15.186

• Sharpless and co-workers in 2014, for creating molecular connections based on the unique stability–reactivity pattern of the S(VI)–F bond with reliability and efficiency, which has been widely applied in organic synthesis, chemical biology and drug discovery [1][2][3][4][5][6][7][8][9][10][11][12][13][14

• novel sulfonyl fluorides for SuFEx click chemistry with great potential to be applied in the development of covalent inhibitors. Further studies of this class of molecules in chemical biology and drug discovery are underway in our laboratory. Representative sulfonyl fluoride compounds applied in

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• recognition of a far greater taxonomic diversity of microbes that can produce bioactive compounds [1][2][3]. The exploration of previously neglected taxa has been demonstrated to bear significant potential for finding new natural products and is thus highly promising from a drug discovery perspective [4][5

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• biological actions: antiproliferative [6][7][8][9], antimicrobial [10][11], anxiolytic [12], analgesic [13], hypnotic [13], antiviral [13], anti-HIV [13] activities, etc. Soural et al. [14] explored different data and showed the relevance of compounds composed of two or more heterocyclic rings for drug

• discovery. The target products containing a heterocyclic core bound to a peptide-like chain also showed a broad spectrum of biological activity: β-secretase (BACE1) inhibitory activity [15]; inducing apoptosis in colorectal cancer cells [16]; antimalarial activity against a chloroquine (CQ) non-resistant

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• materials for relevant MCRs such as those based on imine and isocyanide. The focus is mainly posed on proving the amenability of MCRs for the diversity-oriented derivatization of naturally occurring steroids and the construction of complex steroid-based platforms for drug discovery, chemical biology and

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• the disruptors of microtubule dynamics, therefore are of great interest in cancer drug discovery [6]. Thereby, the stereocontrolled total synthesis of marine alkaloids such as axinellamines [16] and the search of new 2-aminoimidazole and pyrrole containing compounds with a core structure that mimics

SO₂F₂-mediated transformation of 2'-hydroxyacetophenones to benzo-oxetes

• Revathi Lekkala,
• Ravindar Lekkala,
• Balakrishna Moku,
• K. P. Rakesh and
• Hua-Li Qin

Beilstein J. Org. Chem. 2019, 15, 976–980, doi:10.3762/bjoc.15.95

• excellent yields. The highlight of this work is the design and synthesis of strained four-membered oxete rings. Keywords: benzo-oxetes; 2'-hydroxyacetophenones; sulfuryl fluoride; Introduction Oxetanes are versatile elements in drug discovery and synthesis [1][2], and represent important moieties in some

• , and less lipophilic molecular units in drug discovery [7][8]. In view of the broad applicability of oxetanes in materials sciences, organic synthesis, and medicinal chemistry [7][8][9][10][11][12][13][14][15], the progress of synthetic routes for the formation of a range of oxetanes is highly

Catalytic asymmetric oxo-Diels–Alder reactions with chiral atropisomeric biphenyl diols

• Chi-Tung Yeung,
• Wesley Ting Kwok Chan,
• Wai-Sum Lo,
• Ga-Lai Law and
• Wing-Tak Wong

Beilstein J. Org. Chem. 2019, 15, 955–962, doi:10.3762/bjoc.15.92

• Chi-Tung Yeung Wesley Ting Kwok Chan Wai-Sum Lo Ga-Lai Law Wing-Tak Wong The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, PR China State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong

• 1–6.a Supporting Information Supporting Information File 396: Experimental data. Acknowledgements The authors gratefully acknowledge the fundings from the Basic Research Program of Shenzhen (No. JCYJ20160531184120814), State Key Laboratory of Chemical Biology and Drug Discovery, and The Hong Kong

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• production, and reduced energy consumption [1][2][3][4][5][6][7][8][9]. So, the design of novel MCRs with facile and green processes has fascinated considerable attention in the fields of drug discovery, organic synthesis of natural products, and materials sciences [10]. Undoubtedly, one of the most

Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety

• Iteng Ng-Choi,
• Àngel Oliveras,
• Lidia Feliu and
• Marta Planas

Beilstein J. Org. Chem. 2019, 15, 761–768, doi:10.3762/bjoc.15.72

• ; cross-coupling; cyclization; macrocycles; solid-phase synthesis; Introduction Monocyclic and bicyclic peptides are acquiring a relevant interest in current drug discovery. They display improved biological properties over their acyclic counterparts and, at the same time, they are suitable to modulate

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• (NPRP6-065-3-012) and to (TAH) by Grant UMO-2014/12/W/NZ1/00457 from the National Science Centre, Poland. Moreover funding was received through ITN “Accelerated Early stage drug dIScovery” (AEGIS, grant agreement No 675555) and COFUND ALERT (grant agreement No 665250), Hartstichting (ESCAPE-HF, 2018B012

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• tremendous impact in organic synthesis, enabling a variety of applications in polymer chemistry, drug discovery and chemical biology. Although challenging, the possibility to perform aqueous metatheses has become an attractive alternative, not only because water is a more sustainable medium, but also to

• different research fields spanning polymer chemistry [11][12] to drug discovery [13][14][15]. Scheme 1 displays the most common metathesis reactions. The metathesis reaction mechanism, proposed by Chauvin in 1971, suggests that the reaction proceeds via the reversible formation of a metallacyclobutane

• performing catalysis in a more sustainable medium, it still remains challenging to achieve due to the detrimental effect of water. Despite this limitation, olefin metathesis widely contributes to polymer chemistry, drug discovery and biocatalysis. Several technologies relying on aqueous metathesis have been

Annulation of 1H-pyrrole-2,3-diones by thioacetamide: an approach to 5-azaisatins

• Aleksandr I. Kobelev,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2019, 15, 364–370, doi:10.3762/bjoc.15.32

• heterocycles; thioamides; Introduction Omnipresent among natural compounds and drugs, the indole core is a privileged scaffold for library design and drug discovery [1]. Its dioxo derivative, isatin (1H-indole-2,3-dione), is an important building block for the construction of diverse indole-based compounds

Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• interesting approaches towards the imidazo[1,2-a]pyridine core are being published nowadays [25][26][27][28][29][30], this molecular entity is still a pursued synthetic target and novel routes to diverse imidazopyridines are of value. Another privileged scaffold for drug discovery is 2-aminochromene, which

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• -benzyloxyacylamide and a range of terminal alkenes. The products include hydroxamic acid derivatives with a long alkyl chain, aromatic and heteroaromatic cores, halogen residue, carboxylic acid moiety at the terminal relevant position for drug discovery. Moreover, an alternate preparation of the amino acid component

Copper(I)-catalyzed tandem reaction: synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and alkynes

• Muhammad Israr,
• Changqing Ye,
• Munira Taj Muhammad,
• Yajun Li and
• Hongli Bao

Beilstein J. Org. Chem. 2018, 14, 2916–2922, doi:10.3762/bjoc.14.270

• research and synthesis of functionalized compounds that have applications in medicinal chemistry, drug discovery, materials chemistry, and as well as in bioconjugates [2][3][4][5][6][7][8][9][10][11][12]. The copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction [13][14][15][16][17][18][19][20][21

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• interface in both Gram-negative and Gram-positive microorganisms. In order to encourage prospective drug discovery endeavours in this field, this study focuses on four examples of bacterial PPIs for which inhibitors with promising activities have been reported. For each of the targets the structural

• inhibition of the catalytic activity of the enzyme [23]. All these drug discovery successes have validated PPIs as a target and, in conjunction with the elucidation and reconstruction of protein–protein interaction networks in bacteria, have paved the way towards the development of novel and promising

• regulation of gene expression, DNA replication, signal transduction, virulence, etc. and therefore represent potential fruitful targets for antibacterial drug discovery. Recently, scientific efforts have helped towards the understanding and the deciphering of the protein-interaction networks (PINs) that

Synthesis of a tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell liquid

• Jacqueline Pollini,
• Valentina Bragoni and
• Lukas J. Gooßen

Beilstein J. Org. Chem. 2018, 14, 2737–2744, doi:10.3762/bjoc.14.252

• found that the tridecanyl substituted derivative ginkgolic acid (13:0, 3) exhibits the most promising inhibitory activity. While this modular approach is very appealing for drug-discovery, the use of expensive γ-resorcylic acid as the substrate basis and the low overall yield over several reaction steps

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• features of these studies are the use of readily available and easily accessible starting materials towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug discovery. Since their ring C–C double bond offers a number of possible chemical

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• salicylaldehydes are used. Complementary to this the one-pot three-component reaction gave better results for liquid salicylaldehydes. In order to show the utility of the developed methodologies towards possible drug discovery, the scalability of the reactions was explored (Scheme 4). Both developed methodologies