Azido derivatives of sesquiterpene lactones: Synthesis, anticancer proliferation, and chemistry of nitrogen-centered radicals.

Sesquiterpene lactones (SLs) such as parthenolide (PTL) and dehydroleucodine (DhL) selectively kill cancer cells without exerting normal tissue toxicity, potentially due to presence of α-methylene-γ-lactone (αMγL) fragment. We hypothesize that the addition of an azido group to the αMγL fragment of PTL or DhL further augments their anticancer properties as well as radiation sensitivity of cancer cells. Azido-SLs containing the azido group at the C14 methyl position of PTL (i.

Nitrogen-Centered Radicals Derived from Azidonucleosides.

Azido-modified nucleosides have been extensively explored as substrates for click chemistry and the metabolic labeling of DNA and RNA. These compounds are also of interest as precursors for further synthetic elaboration and as therapeutic agents. This review discusses the chemistry of azidonucleosides related to the generation of nitrogen-centered radicals (NCRs) from the azido groups that are selectively inserted into the nucleoside frame along with the subsequent chemistry and biological implications of NCRs.

6-azido and 6-azidomethyl uracil nucleosides.

Azido nucleosides have been utilized for click reactions, metabolic incorporation into cellular DNA, and fluorescent imaging of live cells. Two classes of 6-azido modified uracil nucleosides; one with azido group directly attached to uracil ring and second with azido group attached methylene linker are described. The 6-azido-2'-deoxyuridine (6-AdU) was prepared in 55% overall yield by lithiation-based regioselective C6-iodination of silyl protected 2'-deoxyuridine followed by treatment with sodium azide and deprotection with TBAF.

Gas-Phase Synthesis of Coronene through Stepwise Directed Ring Annulation.

Molecular beam experiments together with electronic structure calculations provide the first evidence of a complex network of elementary gas-phase reactions culminating in the bottom-up preparation of the 24π aromatic coronene (CH) molecule─a representative peri-fused polycyclic aromatic hydrocarbon (PAH) central to the complex chemistry of combustion systems and circumstellar envelopes of carbon stars. The gas-phase synthesis of coronene proceeds via aryl radical-mediated ring annulations through benzo[]pyrene (CH) and benzo[]perylene (CH) involving armchair-, zigzag-, and arm-zig-edged aromatic intermediates, highlighting the chemical diversity of molecular mass growth processes to polycyclic aromatic hydrocarbons. The isomer-selective identification of five- to six-ringed aromatics culminating with the detection of coronene is accomplished through photoionization and is based upon photoionization efficiency curves along with photoion mass-selected threshold photoelectron spectra, providing a versatile concept of molecular mass growth processes via aromatic and resonantly stabilized free radical intermediates to two-dimensional carbonaceous nanostructures.

Construction of quaternary stereocenters at carbon 2' of nucleosides.

The non-natural nucleosides with a quaternary stereogenic center at C2' are crucial to drug discovery. They have become a cornerstone for the treatment of cancer and various viral infections as exemplified by gemcitabine and sofosbuvir. Major research effort has been expended to gain synthetic access to these nucleoside analogues with a significant steric bulk at C2' in the furanoside ring.

Gas phase synthesis of the C40 nano bowl CH.

Nanobowls represent vital molecular building blocks of end-capped nanotubes and fullerenes detected in combustion systems and in deep space such as toward the planetary nebula TC-1, but their fundamental formation mechanisms have remained elusive. By merging molecular beam experiments with electronic structure calculations, we reveal a complex chain of reactions initiated through the gas-phase preparation of benzocorannulene (CH) via ring annulation of the corannulenyl radical (CH) by vinylacetylene (CH) as identified isomer-selectively in situ via photoionization efficiency curves and photoion mass-selected threshold photoelectron spectra. In silico studies provided compelling evidence that the benzannulation mechanism can be expanded to pentabenzocorannulene (CH) followed by successive cyclodehydrogenation to the C40 nanobowl (CH) - a fundamental building block of buckminsterfullerene (C).

Pathways of the Dissociative Electron Attachment Observed in 5- and 6-Azidomethyluracil Nucleosides: Nitrogen (N) Elimination vs Azide Anion (N) Elimination.

5-Azidomethyl-2'-deoxyuridine (5-AmdU, ) has been successfully employed for the metabolic labeling of DNA and fluorescent imaging of live cells. 5-AmdU also demonstrated significant radiosensitization in breast cancer cells via site-specific nitrogen-centered radical (π-aminyl (U-5-CH-NH), , and σ-iminyl (U-5-CH═N), ) formation. This work shows that these nitrogen-centered radicals are not formed via the reduction of the azido group in 6-azidomethyluridine (6-AmU, ).

Exotic Reaction Dynamics in the Gas-Phase Preparation of Anthracene (CH) via Spiroaromatic Radical Transients in the Indenyl-Cyclopentadienyl Radical-Radical Reaction.

The gas-phase reaction between the 1-indenyl (CH) radical and the cyclopentadienyl (CH) radical has been investigated for the first time using synchrotron-based mass spectrometry coupled with a pyrolytic reactor. Soft photoionization with tunable vacuum ultraviolet photons afforded for the isomer-selective identification of the production of phenanthrene, anthracene, and benzofulvalene (CH). The classical theory prevalent in the literature proposing that radicals combine only at their specific radical centers is challenged by our discovery of an unusual reaction pathway that involves a barrierless combination of a resonantly stabilized hydrocarbon radical with an aromatic radical at the carbon atom adjacent to the traditional C1 radical center; this unconventional addition is followed by substantial isomerization into phenanthrene and anthracene via a category of exotic spiroaromatic intermediates.

Chemical synthesis of the organoarsenical antibiotic arsinothricin.

We report two routes of chemical synthesis of arsinothricin (AST), the novel organoarsenical antibiotic. One is by condensation of the 2-chloroethyl(methyl)arsinic acid with acetamidomalonate, and the second involves reduction of the -acetyl protected derivative of hydroxyarsinothricin (AST-OH) and subsequent methylation of a trivalent arsenic intermediate with methyl iodide. The enzyme AST -acetyltransferase (ArsN1) was utilized to purify l-AST from racemic AST.

A molecular beam and computational study on the barrierless gas phase formation of (iso)quinoline in low temperature extraterrestrial environments.

Despite remarkable progress toward the understanding of the formation pathways leading to polycyclic aromatic hydrocarbons (PAHs) in combustion systems and in deep space, the complex reaction pathways leading to nitrogen-substituted PAHs (NPAHs) at low temperatures of molecular clouds and hydrocarbon-rich, nitrogen-containing atmospheres of planets and their moons like Titan have remained largely obscure. Here, we demonstrate through laboratory experiments and computations that the simplest prototype of NPAHs - quinoline and isoquinoline (CHN) - can be synthesized via rapid and de-facto barrier-less reactions involving o-, m- and p-pyridinyl radicals (CHN˙) with vinylacetylene (CH) under low-temperature conditions.

Gas-phase synthesis of corannulene - a molecular building block of fullerenes.

Fullerenes (C, C) detected in planetary nebulae and carbonaceous chondrites have been implicated to play a key role in the astrochemical evolution of the interstellar medium. However, the formation mechanism of even their simplest molecular building block-the corannulene molecule (CH)-has remained elusive. Here we demonstrate via a combined molecular beams and ab initio investigation that corannulene can be synthesized in the gas phase through the reactions of 7-fluoranthenyl (CH˙) and benzo[ghi]fluoranthen-5-yl (CH˙) radicals with acetylene (CH) mimicking conditions in carbon-rich circumstellar envelopes.

Site of Azido Substitution in the Sugar Moiety of Azidopyrimidine Nucleosides Influences the Reactivity of Aminyl Radicals Formed by Dissociative Electron Attachment.

In this work, electron-induced site-specific formation of neutral π-type aminyl radicals (RNH·) and their reactions with pyrimidine nucleoside analogs azidolabeled at various positions in the sugar moiety, e.g., at 2'-, 3'-, 4'-, and 5'- sites along with a model compound 3-azido-1-propanol (3AZPrOH), were investigated.

Gas phase formation of cyclopentanaphthalene (benzindene) isomers reactions of 5- and 6-indenyl radicals with vinylacetylene.

The tricyclic polycyclic aromatic hydrocarbons (PAHs) 3H-cyclopenta[a]naphthalene (C13H10), 1H-cyclopenta[b]naphthalene (C13H10) and 1H-cyclopenta[a]naphthalene (C13H10) along with their indene-based bicyclic isomers (E)-5-(but-1-en-3-yn-1-yl)-1H-indene, (E)-6-(but-1-en-3-yn-1-yl)-1H-indene, 5-(but-3-ene-1-yn-1-yl)-1H-in-dene, and 6-(but-3-ene-1-yn-1-yl)-1H-indene were formed via a "directed synthesis" in a high-temperature chemical micro reactor at the temperature of 1300 ± 10 K through the reactions of the 5- and 6-indenyl radicals (C9H7˙) with vinylacetylene (C4H4). The isomer distributions were probed utilizing tunable vacuum ultraviolet light by recording the photoionization efficiency curves at mass-to-charge of m/z = 166 (C13H10) and 167 (13CC12H10) of the products in a supersonic molecular beam. The underlying reaction mechanisms involve the initial formation of van-der-Waals complexes followed by addition of the 5- and 6-indenyl radicals to vinylacetylene via submerged barriers, followed by isomerization (hydrogen shifts, ring closures), and termination via atomic hydrogen elimination accompanied by aromatization.

Semisynthesis of the Organoarsenical Antibiotic Arsinothricin.

Arsinothricin [AST ()], a new broad-spectrum organoarsenical antibiotic, is a nonproteinogenic analogue of glutamate that effectively inhibits glutamine synthetase. We report the chemical synthesis of an intermediate in the pathway to , hydroxyarsinothricin [AST-OH ()], which can be converted to by enzymatic methylation catalyzed by the ArsM As(III) -adenosylmethionine methyltransferase. This is the first report of semisynthesis of , providing a source of this novel antibiotic that will be required for future clinical trials.

Gas phase formation of phenalene via 10π-aromatic, resonantly stabilized free radical intermediates.

For the last few decades, the Hydrogen-Abstraction/aCetylene-Addition (HACA) mechanism has been fundamental in aiding our understanding of the source of polycyclic aromatic hydrocarbons (PAHs) in combustion processes and in circumstellar envelopes of carbon rich stars. However, the reaction mechanisms driving high temperature molecular mass growth beyond triphenylene (CH) along with the link between PAHs and graphene-type nanostructures as identified in carbonaceous meteorites such as in Murchison and Allende has remained elusive. By exploring the reaction of the 1-naphthyl radical (CH˙) with methylacetylene (CHCCH) and allene (HCCCH) under conditions prevalent in carbon-rich circumstellar environments and combustion systems, we provide compelling evidence on a facile formation of 1H-phenalene (CH) - the central molecular building block of graphene-type nanostructures.

Model Substrate/Inactivation Reactions for MoaA and Ribonucleotide Reductases: Loss of Bromo, Chloro, or Tosylate Groups from C2 of 1,5-Dideoxyhomoribofuranoses upon Generation of an α-Oxy Radical at C3.

We report studies on radical-initiated fragmentations of model 1,5-dideoxyhomoribofuranose derivatives with bromo, chloro, and tosyloxy substituents on C2. The effects of stereochemical inversion at C2 were probed with the corresponding arabino epimers. In all cases, the elimination of bromide, chloride, and tosylate anions occurred when the 3-hydroxyl group was unprotected.

Molecular mass growth through ring expansion in polycyclic aromatic hydrocarbons via radical-radical reactions.

Polycyclic aromatic hydrocarbons (PAHs) represent key molecular building blocks leading to carbonaceous nanoparticles identified in combustion systems and extraterrestrial environments. However, the understanding of their formation and growth in these high temperature environments has remained elusive. We present a mechanism through laboratory experiments and computations revealing how the prototype PAH-naphthalene-can be efficiently formed via a rapid 1-indenyl radical-methyl radical reaction.

How to add a five-membered ring to polycyclic aromatic hydrocarbons (PAHs) - molecular mass growth of the 2-naphthyl radical (CH) to benzindenes (CH) as a case study.

The three-ring polycyclic aromatic hydrocarbons (PAHs) 3H-benz[e]indene (CH) and 1H-benz[f]indene (CH) along with their naphthalene-based isomers 2-(prop-2-yn-1-yl)naphthalene (CH), 2-(prop-1-yn-1-yl)naphthalene (CH), and 2-(propa-1,2-dien-1-yl)naphthalene (CH) were formed through a "directed synthesis"via a high temperature chemical micro reactor under combustion-like conditions (1300 ± 35 K) through the reactions of the 2-naphthyl isomer (CH˙) with allene (CH) and methylacetylene (CH). The isomer distributions were probed utilizing tunable vacuum ultraviolet radiation from the Advanced Light Source (ALS) by recording the photoionization efficiency curves at mass-to-charge of m/z = 166 (CH) and 167 (CCH) of the products in a supersonic molecular beam. Complemented by electronic structure calculations, our study reveals critical mass growth processes via annulation of a five-membered ring from the reaction between aryl radicals and distinct CH isomers at elevated temperatures as present in combustion processes and in circumstellar envelopes of carbon stars.

Gas phase synthesis of [4]-helicene.

A synthetic route to racemic helicenes via a vinylacetylene mediated gas phase chemistry involving elementary reactions with aryl radicals is presented. In contrast to traditional synthetic routes involving solution chemistry and ionic reaction intermediates, the gas phase synthesis involves a targeted ring annulation involving free radical intermediates. Exploiting the simplest helicene as a benchmark, we show that the gas phase reaction of the 4-phenanthrenyl radical ([CH]) with vinylacetylene (CH) yields [4]-helicene (CH) along with atomic hydrogen via a low-barrier mechanism through a resonance-stabilized free radical intermediate (CH).

Reactivity of the Indenyl Radical (C H ) with Acetylene (C H ) and Vinylacetylene (C H ).

The reactions of the indenyl radicals with acetylene (C H ) and vinylacetylene (C H ) is studied in a hot chemical reactor coupled to synchrotron based vacuum ultraviolet ionization mass spectrometry. These experimental results are combined with theory to reveal that the resonantly stabilized and thermodynamically most stable 1-indenyl radical (C H ) is always formed in the pyrolysis of 1-, 2-, 6-, and 7-bromoindenes at 1500 K. The 1-indenyl radical reacts with acetylene yielding 1-ethynylindene plus atomic hydrogen, rather than adding a second acetylene molecule and leading to ring closure and formation of fluorene as observed in other reaction mechanisms such as the hydrogen abstraction acetylene addition or hydrogen abstraction vinylacetylene addition pathways.

Fluorescent 5-Pyrimidine and 8-Purine Nucleosides Modified with an N-Unsubstituted 1,2,3-Triazol-4-yl Moiety.

The Cu(I)- or Ag(I)-catalyzed cycloaddition between 8-ethynyladenine or guanine nucleosides and TMSN gave 8-(1- H-1,2,3-triazol-4-yl) nucleosides in good yields. On the other hand, reactions of 5-ethynyluracil or cytosine nucleosides with TMSN led to the chemoselective formation of triazoles via Cu(I)-catalyzed cycloaddition or vinyl azides via Ag(I)-catalyzed hydroazidation. These nucleosides with a minimalistic triazolyl modification showed excellent fluorescent properties with 8-(1- H-1,2,3-triazol-4-yl)-2'-deoxyadenosine (8-TrzdA), exhibiting a quantum yield of 44%.

Gas-Phase Synthesis of Triphenylene (C H ).

For the last decades, the hydrogen-abstraction-acetylene-addition (HACA) mechanism has been widely invoked to rationalize the high-temperature synthesis of PAHs as detected in carbonaceous meteorites (CM) and proposed to exist in the interstellar medium (ISM). By unravelling the chemistry of the 9-phenanthrenyl radical ([C H ] ) with vinylacetylene (C H ), we present the first compelling evidence of a barrier-less pathway leading to a prototype tetracyclic PAH - triphenylene (C H ) - via an unconventional hydrogen abstraction-vinylacetylene addition (HAVA) mechanism operational at temperatures as low as 10 K. The barrier-less, exoergic nature of the reaction reveals HAVA as a versatile reaction mechanism that may drive molecular mass growth processes to PAHs and even two-dimensional, graphene-type nanostructures in cold environments in deep space thus leading to a better understanding of the carbon chemistry in our universe through the untangling of elementary reactions on the most fundamental level.

Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells.

Two classes of azido-modified pyrimidine nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2'-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2'-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells.

4-N-Alkanoyl and 4-N-alkyl gemcitabine analogues with NOTA chelators for 68-gallium labelling.

The conjugation of 4-N-(3-aminopropanyl)-2'-deoxy-2',2'-difluorocytidine with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) ligand in 0.1 M NaCO buffer (pH 11) at ambient temperature provided 4-N-alkylgemcitabine-NOTA chelator. Incubation of latter with excess of gallium(III) chloride (GaCl) (0.