Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry

May 31, 2015, 12:22 pm

≫ Next: Synthesis and functionalization of bicyclic N,O-acetal scaffolds from furfural

≪ Previous: Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Andrew Nortcliffe , Christopher J. Moody

Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction.

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Synthesis and functionalization of bicyclic N,O-acetal scaffolds from furfural

May 31, 2015, 12:22 pm

≫ Next: Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries

≪ Previous: Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Ferdi van der Pijl , Floris L. van Delft , Floris P.J.T. Rutjes

We have synthesized biologically relevant 6-aza-8-oxa[3.2.1]bicyclooctane scaffolds in a five-step procedure starting from furfural. Besides showing that these scaffolds are amenable to decoration via standard functional group interconversions, we also describe investigations for further functionalization via Lewis acid-mediated N,O-acetal opening, followed by nucleophilic trapping of the resulting intermediate cation. By using different nucleophiles, we have successfully prepared a modest library of 2,6-trans-disubstituted pyrans in good yields and in a highly diastereoselective manner.

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Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries

May 31, 2015, 12:22 pm

≫ Next: MCR synthesis of a tetracyclic tetrazole scaffold

≪ Previous: Synthesis and functionalization of bicyclic N,O-acetal scaffolds from furfural

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Raquel Ortega , Jorge Sanchez-Quesada , Christoph Lorenz , Grzegorg Dolega , Anna Karawajczyk , Miguel Sanz , Graham Showell , Fabrizio Giordanetto

The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug discovery-relevant chemical matter, the design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries is described.

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MCR synthesis of a tetracyclic tetrazole scaffold

May 31, 2015, 12:22 pm

≫ Next: Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction

≪ Previous: Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Pravin Patil , Kareem Khoury , Eberhardt Herdtweck , Alexander Dömling

Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.

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Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction

May 31, 2015, 12:22 pm

≫ Next: Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

≪ Previous: MCR synthesis of a tetracyclic tetrazole scaffold

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Michael Åxman Petersen , Michael A. Mortensen , A. Emil Cohrt , Rico Petersen , Peng Wu , Nicolas Fleury-Brégeot , Rémy Morgentin , Claude Lardy , Thomas E. Nielsen , Mads H. Clausen

A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds.

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Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

May 31, 2015, 12:22 pm

≫ Next: Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis

≪ Previous: Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Monique Lüthy , Mary C. Wheldon , Chehasnah Haji-Cheteh , Masakazu Atobe , Paul S. Bond , Peter O’Brien , Roderick E. Hubbard , Ian J.S. Fairlamb

Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) −1⩽ A log P ⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å². The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space.

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Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis

May 31, 2015, 12:22 pm

≫ Next: Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery

≪ Previous: Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Michelle S. Frei , Matthew K. Bilyard , Thomas A. Alanine , Warren R.J.D. Galloway , Jamie E. Stokes , David R. Spring

Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods. The azabicyclic compounds synthesized in this study reside in attractive regions of heterocyclic chemical space that are underexploited in current drug and agrochemical discovery efforts.

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Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery

May 31, 2015, 12:22 pm

≫ Next: Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence

≪ Previous: Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Jalindar D. Padwal , Dmitri V. Filippov , Bharat D. Narhe , Sjoerd Aertssen , Remmelt Jan Beuving , Jorg C.J. Benningshof , Gijsbert A. van der Marel , Herman S. Overkleeft , Mario van der Stelt

A concise and efficient synthesis of cyclopentitols as a scaffold for a two-dimensional compound library for drug discovery is described. Starting from d-mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp³-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared.

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Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence

May 31, 2015, 12:22 pm

≫ Next: Synthesis of a hexahydropyrrolo indole (HPI) compound library

≪ Previous: Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Rico Petersen , A. Emil Cohrt , Michael Åxman Petersen , Peng Wu , Mads H. Clausen , Thomas E. Nielsen

Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet–Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.

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Synthesis of a hexahydropyrrolo indole (HPI) compound library

May 31, 2015, 12:22 pm

≫ Next: Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

≪ Previous: Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Sabrina Nickel , Philipp Nickel , Marco Hellmert , Silvia Ernst , Robert Jewell , Christopher A. Pearce , Geraint Jones , Daniel Hamza , Markus Kaiser

Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library.

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Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

May 31, 2015, 12:22 pm

≫ Next: Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

≪ Previous: Synthesis of a hexahydropyrrolo indole (HPI) compound library

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Philip Craven , Anthony Aimon , Mark Dow , Nicolas Fleury-Bregeot , Rachel Guilleux , Remy Morgentin , Didier Roche , Tuomo Kalliokoski , Richard Foster , Stephen P. Marsden , Adam Nelson

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.

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Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

May 31, 2015, 12:22 pm

≫ Next: Innovative approaches to the design and synthesis of small molecule libraries

≪ Previous: Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Thomas E. Storr , Sarah J. Cully , Michael J. Rawling , William Lewis , Daniel Hamza , Geraint Jones , Robert A. Stockman

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp³-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp³-rich natural product-like library.

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Innovative approaches to the design and synthesis of small molecule libraries

May 31, 2015, 12:22 pm

≫ Next: Graphical contents list

≪ Previous: Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Adam Nelson , Didier Roche

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Graphical contents list

May 31, 2015, 12:22 pm

≫ Next: Editorial board

≪ Previous: Innovative approaches to the design and synthesis of small molecule libraries

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11

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Editorial board

May 31, 2015, 12:22 pm

≫ Next: Developing new chemical tools for DNA methyltransferase 1 (DNMT 1): A small-molecule activity-based probe and novel tetrazole-containing inhibitors

≪ Previous: Graphical contents list

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11

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Developing new chemical tools for DNA methyltransferase 1 (DNMT 1): A small-molecule activity-based probe and novel tetrazole-containing inhibitors

May 31, 2015, 12:22 pm

≫ Next: Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines

≪ Previous: Editorial board

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Biwei Zhu , Jingyan Ge , Shao Q. Yao

DNA methylation is an important epigenetic modification catalyzed by DNA methyltransferases (DNMTs). Abnormal expression of endogenous DNMTs in human causes alterations in the genome methylation patterns which subsequently lead to the development of cancers. Thus detection of endogenous DNMT activities and efficient inhibition of DNMTs have important therapeutic significance. In this work, a small molecule activity-based probe (ABP) of DNA methyltransferase 1 (DNMT1), T1, was developed. The probe was a clickable analog of tryptophan and was able to covalently label endogenous DNMT1 and inhibit its enzymatic activity more effectively than previously known DNMT1 inhibitors (RG108 and its maleimide analog 1149). In addition, we also discovered a new type of small molecule DNMT inhibitors based on tetrazole-containing compounds which were analogs of 1149. Among these compounds, which we called Gn, one of them (G6) possessed reasonable inhibitory activity against DNMT1 in both in vitro enzymatic assays and cell growth proliferation experiments. Both T1 and G6 showed effective labeling of endogenous DNMT1 from mammalian cells by using in vitro competitive pull-down and live-cell bioimaging experiments.

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Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines

May 31, 2015, 12:22 pm

≫ Next: Native chemical ligation between asparagine and valine: Application and limitations for the synthesis of tri-phosphorylated C-terminal tau

≪ Previous: Developing new chemical tools for DNA methyltransferase 1 (DNMT 1): A small-molecule activity-based probe and novel tetrazole-containing inhibitors

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Marco Potowski , Christopher Golz , Carsten Strohmann , Andrey P. Antonchick , Herbert Waldmann

A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal 1,3-dipolar cycloaddition of coumarins with α-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-substituted diastereomer with respect to the 1,3-dipole and shows a broad substrate scope.

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Native chemical ligation between asparagine and valine: Application and limitations for the synthesis of tri-phosphorylated C-terminal tau

May 31, 2015, 12:22 pm

≫ Next: Semisynthesis and initial characterization of sortase A mutants containing selenocysteine and homocysteine

≪ Previous: Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Oliver Reimann , Maria Glanz , Christian P.R. Hackenberger

We present the successful native chemical ligation (NCL) at an Asn-Val site employing β-mercaptovaline and subsequent desulfurization in the synthesis of native phosphorylated C-terminal tau, relevant for Alzheimer’s disease related research. Despite recent progress in the field of NCL we illustrate limitations of this ligation site that stem from thioester hydrolysis and predominantly aspartimide formation. We systematically investigated the influence of pH, temperature, peptide concentration and thiol additives on the outcome of this ligation and identified conditions under which the ligation can be driven toward complete conversion, which required the deployment of a high surplus of thioester. Application of the optimized conditions allowed us to gain access to challenging tri-phosphorylated C-terminal tau peptide in practical yields.

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Semisynthesis and initial characterization of sortase A mutants containing selenocysteine and homocysteine

May 31, 2015, 12:22 pm

≫ Next: Reversible chemical dimerizer-induced recovery of PIP2 levels moves clathrin to the plasma membrane

≪ Previous: Native chemical ligation between asparagine and valine: Application and limitations for the synthesis of tri-phosphorylated C-terminal tau

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Lena Schmohl , Felix Roman Wagner , Michael Schümann , Eberhard Krause , Dirk Schwarzer

The bacterial transpeptidase sortase A is a well-established tool in protein chemistry and catalyzes the chemoselective ligation of peptides and proteins. During catalysis sortase A cleaves the conserved Leu-Pro-X-Thr-Gly sorting motif at the Thr residue under concomitant thioester formation at active site Cys184. We have used expressed protein ligation (EPL) to generate sortase mutants with Cys184 replaced by selenocysteine (Sec) and homocysteine (Hcy). Sec-sortase showed a moderate 2–3-fold reduction in catalytic activity in contrast to Hcy-sortase which is a poor catalyst with less than 1% of wild-type activity. The sensitivity of the active site nucleophiles towards an alkylation reagent correlated with the pK a values of the mutated residues. Furthermore, the pH-profile of Sec-sortase was shifted to more acidic conditions when compared to the wild-type enzyme. These observations provide information on sortase catalysis and the semisynthetic enzymes might represent useful tools for further biochemical investigations and engineering approaches of sortases A.

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Reversible chemical dimerizer-induced recovery of PIP2 levels moves clathrin to the plasma membrane

May 31, 2015, 12:22 pm

≫ Next: Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites

≪ Previous: Semisynthesis and initial characterization of sortase A mutants containing selenocysteine and homocysteine

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Martina Schifferer , Suihan Feng , Frank Stein , Christian Tischer , Carsten Schultz

Chemical dimerizers are powerful non-invasive tools for bringing molecules together inside intact cells. We recently introduced a rapidly reversible chemical dimerizer system which enables transient translocation of enzymes to and from the plasma membrane (PM). Here we have applied this system to transiently activate phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown at the PM via translocation of phosphoinositide 5-phosphatase (5Ptase). We found that the PIP2 sensor phospholipase C-δ PH domain (PLCδ-PH) is released from the PM upon addition of the reversible chemical dimerizer rCD1. By outcompeting rCD1, rapid release of the 5Ptase from the PM is followed by PIP2 recovery. This permits the observation of the PIP2-dependent clathrin assembly at the PM.

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