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1.
Chem Sci ; 15(28): 10918-10925, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39027309

ABSTRACT

Bridged bicycloalkanes such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.1.1]heptanes (BCHeps) are important motifs in contemporary drug design due to their potential to act as bioisosteres of disubstituted benzene rings, often resulting in compounds with improved physicochemical and pharmacokinetic properties. Access to such motifs with proximal nitrogen atoms (i.e. α-amino/amido bicycloalkanes) is highly desirable for drug discovery applications, but their synthesis is challenging. Here we report an approach to α-amino BCPs and BCHeps through the visible-light enabled addition of α-amino radicals to the interbridgehead C-C bonds of [1.1.1] and [3.1.1]propellane respectively. The reaction proceeds under exceptionally mild conditions and displays broad substrate scope, providing access to an array of medicinally-relevant BCP and BCHep products. Experimental and computational mechanistic studies provide evidence for a radical chain pathway which depends critically on the stability of the α-amino radical, as well as effective catalyst turnover.

2.
Sci Adv ; 10(2): eadj9695, 2024 Jan 12.
Article in English | MEDLINE | ID: mdl-38215201

ABSTRACT

Prediction of the outcome of ring opening of small organic rings under cationic conditions can be challenging due to the intermediacy of nonclassical carbocations. For example, the solvolysis of cyclobutyl or cyclopropylmethyl derivatives generates up to four products on nucleophilic capture or elimination via cyclopropylcarbinyl and bicyclobutonium ions. Here, we show that such reaction outcomes can be controlled by subtle changes to the structure of nonclassical carbocation. Using bicyclo[1.1.0]butanes as cation precursors, the regio- and stereochemistry of ring opening is shown to depend on the degree and nature of the substituents on the cationic intermediates. Reaction outcomes are rationalized using computational models, resulting in a flowchart to predict product formation from a given cation precursor.

3.
Nature ; 611(7937): 721-726, 2022 11.
Article in English | MEDLINE | ID: mdl-36108675

ABSTRACT

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.


Subject(s)
Bridged Bicyclo Compounds , Drug Design , Heptanes , Anions/chemistry , Benzene/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Drug Discovery , Heptanes/chemical synthesis , Heptanes/chemistry , Pentanes/chemical synthesis , Pentanes/chemistry , Solubility
4.
J Am Chem Soc ; 144(22): 10017-10024, 2022 06 08.
Article in English | MEDLINE | ID: mdl-35609003

ABSTRACT

Thiophene S,S-dioxides are underutilized tools for the de novo construction of benzene rings in organic synthesis. We report a collective synthesis of nine illudalane sesquiterpenes using bicyclic thiophene S,S-dioxides as generalized precursors to the indane core of the natural products. Exploiting furans as unusual dienophiles in this inverse electron demand Diels-Alder cascade, this concise and convergent approach enables the synthesis of these targets in as little as five steps. Theoretical studies rationalize the reactivity of thiophene S,S-dioxides with both electron-poor and electron-rich dienophiles and reveal reaction pathways involving either nonpolar pericyclic or bifurcating ambimodal cycloadditions. Overall, this work demonstrates the wider potential of thiophene S,S-dioxides as convenient and flexible precursors to polysubstituted arenes.


Subject(s)
Electrons , Sesquiterpenes , Cycloaddition Reaction , Polycyclic Sesquiterpenes , Thiophenes
5.
Org Lett ; 23(21): 8628-8633, 2021 Nov 05.
Article in English | MEDLINE | ID: mdl-34699248

ABSTRACT

Bicyclo[1.1.1]pentanes (BCPs) are important in drug design as sp3-rich bioisosteres of arenes and tert-butyl groups; however, the preparation of BCPs with adjacent quaternary carbons is barely known. We report a facile synthesis of α-quaternary BCPs using organophotoredox and hydrogen atom transfer catalysis in which α-keto radicals, generated through oxidation of ß-ketocarbonyls, undergo efficient addition to [1.1.1]propellane. The BCP products can be transformed into a variety of useful derivatives, including enantioenriched BCPs featuring α-quaternary stereocenters.

6.
Org Lett ; 22(14): 5671-5674, 2020 07 17.
Article in English | MEDLINE | ID: mdl-32640160

ABSTRACT

We report a nucleophilic substitution reaction of five-membered hetarylsulfonium salts that results in a change of the substitution pattern on the arene. The products of these cine-substitutions are hard to access synthetically otherwise. The sulfonium salts that serve as starting materials are generated by a highly site-selective C-H functionalization reaction.

7.
Nature ; 567(7747): 223-228, 2019 03.
Article in English | MEDLINE | ID: mdl-30867606

ABSTRACT

Direct C-H functionalization can quickly increase useful structural and functional molecular complexity1-3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns1-4-in the absence of such functionality, most aromatic C-H functionalization reactions provide more than one product isomer for most substrates1,4,5. Development of a C-H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C-H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C-H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.

8.
ACS Synth Biol ; 6(12): 2260-2272, 2017 12 15.
Article in English | MEDLINE | ID: mdl-29136368

ABSTRACT

Trans-signaling of the major pro- and anti-inflammatory cytokines Interleukin (IL)-6 and IL-11 has the unique feature to virtually activate all cells of the body and is critically involved in chronic inflammation and regeneration. Hyper-IL-6 and Hyper-IL-11 are single chain designer trans-signaling cytokines, in which the cytokine and soluble receptor units are trapped in one complex via a flexible peptide linker. Albeit, Hyper-cytokines are essential tools to study trans-signaling in vitro and in vivo, the superior potency of these designer cytokines are accompanied by undesirable stress responses. To enable tailor-made generation of Hyper-cytokines, we developed inactive split-cytokine-precursors adapted for posttranslational reassembly by split-intein mediated protein trans-splicing (PTS). We identified cutting sites within IL-6 (E134/S135) and IL-11 (G116/S117) and obtained inactive split-Hyper-IL-6 and split-Hyper-IL-11 cytokine precursors. After fusion with split-inteins, PTS resulted in reconstitution of active Hyper-cytokines, which were efficiently secreted from transfected cells. Our strategy comprises the development of a background-free cytokine signaling system from reversibly inactivated precursor cytokines.


Subject(s)
Immunoglobulin Constant Regions , Interleukin-11 , Interleukin-6 , Recombinant Fusion Proteins , Trans-Splicing , Animals , COS Cells , Chlorocebus aethiops , HEK293 Cells , Humans , Immunoglobulin Constant Regions/biosynthesis , Immunoglobulin Constant Regions/genetics , Interleukin-11/biosynthesis , Interleukin-11/genetics , Interleukin-6/biosynthesis , Interleukin-6/genetics , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics
9.
Infect Immun ; 74(7): 3845-52, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16790756

ABSTRACT

Maintaining metal homeostasis is crucial for the adaptation of Helicobacter pylori to the gastric environment. Iron, copper, and nickel homeostasis has recently been demonstrated to be required for the establishment of H. pylori infection in animal models. Here we demonstrate that the HP0969-0971 gene cluster encoding the Czc-type metal export pump homologs HP0969, HP0970, and the H. pylori-specific protein HP0971 forms part of a novel H. pylori metal resistance determinant, which is required for gastric colonization and for the modulation of urease activity. Insertional mutagenesis of the HP0971, HP0970, or HP0969 genes in H. pylori reference strain 26695 resulted in increased sensitivity to cadmium, zinc, and nickel (czn), suggesting that the encoded proteins constitute a metal-specific export pump. Accordingly, the genes were designated cznC (HP0971), cznB (HP0970), and cznA (HP0969). The CznC and CznA proteins play a predominant role in nickel homeostasis, since only the cznC and cznA mutants but not the cznB mutant displayed an 8- to 10-fold increase in urease activity. Nickel-specific affinity chromatography demonstrated that recombinant versions of CznC and CznB can bind to nickel and that the purified CznB protein interacted with cadmium and zinc, since both metals competitively inhibited nickel binding. Finally, single cznA, cznB, and cznC mutants did not colonize the stomach in a Mongolian gerbil-based animal model. This demonstrates that the metal export functions of H. pylori cznABC are essential for gastric colonization and underlines the extraordinary importance of metal ion homeostasis for the survival of H. pylori in the gastric environment.


Subject(s)
Bacterial Proteins/physiology , Cadmium/metabolism , Cation Transport Proteins/physiology , Gastric Mucosa/microbiology , Helicobacter pylori/metabolism , Nickel/metabolism , Urease/metabolism , Zinc/metabolism , Animals , Bacterial Proteins/genetics , Cation Transport Proteins/genetics , Gerbillinae , Helicobacter Infections/metabolism , Helicobacter Infections/microbiology , Helicobacter pylori/enzymology , Helicobacter pylori/growth & development , Helicobacter pylori/pathogenicity , Mutation
10.
J Bacteriol ; 187(13): 4683-8, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15968080

ABSTRACT

Here we describe that the Helicobacter pylori sensor kinase produced by HP1364 and the response regulator produced by HP1365 and designated CrdS and CrdR, respectively, are both required for transcriptional induction of the H. pylori copper resistance determinant CrdA by copper ions. CrdRS-deficient mutants lacked copper induction of crdA expression and were copper sensitive. A direct role of CrdR in transcriptional regulation of crdA was confirmed by in vitro binding of CrdR to the crdA upstream region. A 21-nucleotide sequence located near the crdA promoter was shown to be required for CrdR binding.


Subject(s)
Bacterial Proteins/genetics , Copper/pharmacology , Genes, Bacterial/genetics , Helicobacter pylori/drug effects , Protein Kinases/genetics , Trans-Activators/genetics , Base Sequence , Binding Sites/genetics , Drug Resistance, Bacterial/genetics , Helicobacter pylori/genetics , Molecular Sequence Data , Promoter Regions, Genetic , Protein Kinases/metabolism , Transcription, Genetic
11.
FEMS Immunol Med Microbiol ; 44(2): 183-9, 2005 May 01.
Article in English | MEDLINE | ID: mdl-15866214

ABSTRACT

In the gastric microenvironment, Helicobacter pylori is exposed to bicarbonate, urea and acid. Here it is demonstrated that both H. pylori carbonic anhydrases (CAs) are required for maintaining urease activity and therefore influence H. pylori urea resistance at neutral pH. Furthermore, the beta-CA is required for acid resistance as indicated by a growth defect of the corresponding mutant at low pH. The alpha- and beta-CA mutants as well as the double mutant were more resistant to bicarbonate, indicating that both enzymes are involved in bicarbonate metabolism. These phenotypes support important CA-functions in H. pylori urea and bicarbonate metabolism and acid resistance. Thus, both CA enzymes might be required for survival in the gastric niche.


Subject(s)
Carbonic Anhydrases/genetics , Carbonic Anhydrases/metabolism , Helicobacter pylori/enzymology , Mutation , Bicarbonates/metabolism , Bicarbonates/pharmacology , Culture Media , Drug Resistance, Bacterial , Helicobacter pylori/genetics , Helicobacter pylori/growth & development , Humans , Hydrogen-Ion Concentration , Urea/metabolism , Urea/pharmacology , Urease/metabolism
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