Purinyl N-directed aroylation of 6-arylpurine ribo- and 2'-deoxyribonucleosides, and mechanistic insights.

The purinyl ring contains four embedded nitrogen atoms of varying basicities. Selective utilization of these ring nitrogen atoms can lead to relatively facile remote functionalization, yielding modified purinyl motifs that are otherwise not easily obtained. Herein, we report previously undescribed N-directed aroylation of 6-arylpurine ribo and the more labile 2'-deoxyribonucleosides. Kinetic isotope analysis as well as reaction with a well-defined dimeric, palladated 9-benzyl 6-arylpurine provided evidence for N-directed cyclometallation as a key step, with a plausible rate-limiting C-H bond cleavage. Radical inhibition experiments indicate the likely intermediacy of aroyl radicals. The chemistry surmounts difficulties often posed in the functionalization of polynitrogenated and polyoxygenated nucleosidic structures that possess complex reactivities and a labile glycosidic bond that is more sensitive in the 2'-deoxy substrates.

ProPhos: A Ligand for Promoting Nickel-Catalyzed Suzuki-Miyaura Coupling Inspired by Mechanistic Insights into Transmetalation.

Nickel-catalyzed Suzuki-Miyaura coupling (Ni-SMC) offers the potential to reduce the cost of pharmaceutical process synthesis. However, its application has been restricted by challenges such as slow reaction rates, high catalyst loading, and a limited scope of heterocycles. Despite recent investigations, the mechanism of transmetalation in Ni-SMC, often viewed as the turnover-limiting step, remains insufficiently understood. We elucidate the "Ni-oxo" transmetalation pathway, applying PPh2Me as the ligand, and identify the formation of a nickel-oxo intermediate as the turnover-limiting step. Building on this insight, we develop a scaffolding ligand, ProPhos, featuring a pendant hydroxyl group connected to the phosphine via a linker. The design preorganizes both the nucleophile and the nickel catalyst, thereby facilitating transmetalation. This catalyst exhibits fast kinetics and robust activity across a wide range of heteroarenes, with a catalyst loading of 0.5-3 mol %. For arene substrates, the catalyst loading can be further reduced to 0.1 mol %.

Crystal structures of two formamidinium hexa-fluorido-phosphate salts, one with batch-dependent disorder.

Syntheses of the acyclic amidinium salts, morpholino-formamidinium hexa-fluorido-phosphate [OC4H8N-CH=NH2]PF6 or C5H11N2O+·PF6 -, 1, and pyrrolidinoformamidinium hexa-fluorido-phosphate [C4H8N-CH= NH2]PF6 or C5H11N2 +·PF6 -, 2, were carried out by heating either morpholine or pyrrolidine with triethyl orthoformate and ammonium hexa-fluorido-phosphate. Crystals of 1 obtained directly from the reaction mixture contain one cation and one anion in the asymmetric unit. The structure involves cations linked in chains parallel to the b axis by N-H⋯O hydrogen bonds in space group Pbca, with glide-related chains pointing in opposite directions. Crystals of 1 obtained by recrystallization from ethanol, however, showed a similar unit cell and the same basic structure, but unexpectedly, there was positional disorder [occupancy ratio 0.639 (4):0.361 (4)] in one of the cation chains, which lowered the crystal symmetry to the non-centrosymmetric space group Pca21, with two cations and anions in the asymmetric unit. In the pyrrolidino compound, 2, cations and anions are ordered and are stacked separately, with zigzag N-H⋯F hydrogen-bonding between stacks, forming ribbons parallel to (101), extended along the b-axis direction. Slight differences in the delocalized C=N distances between the two cations may reflect the inductive effect of the oxygen atom in the morpholino compound.

Two short approaches to the COVID-19 drug ß-D-N4-hydroxycytidine and its prodrug molnupiravir.

Molnupiravir, the prodrug for ß-D-N4-hydroxycytidine (NHC), is marketed by Merck as Lagevrio™ against mild-moderate COVID-19, under FDA emergency use authorization. It is the first oral drug against the disease. This work describes two synthetic approaches to NHC and molnupiravir by amide activation in uridine with a peptide-coupling agent and with a 4-chloropyrimidinone nucleoside intermediate.

5-Nitrofuryl-Containing Thiosemicarbazone Gold(I) Compounds: Synthesis, Stability Studies, and Anticancer Activity.

Invited for this month's cover are the collaborating groups of Esteban Rodríguez-Arce from the University of Chile and María Contel from The City University of New York Brooklyn College. The cover picture shows "Supergold" a very powerful gender neutral warrior with superpowers who fights against cancer! The warrior's golden armor and sword represent the pharmacological power of the gold atom. Engraved on the shield, the gold-thiosemicarbazone molecules are the warrior's coat of arms. Supergold selectively destroys different cancer cells. More information can be found in the Research Article by Esteban Rodríguez-Arce, María Contel, and co-workers.

Ligand Redox Activity of Organonickel Radical Complexes Governed by the Geometry.

Nickel-catalyzed cross-coupling reactions often employ bidentate π-acceptor N-ligands to facilitate radical pathways. This report presents the synthesis and characterization of a series of organonickel radical complexes supported by bidentate N-ligands, including bpy, phen, and pyrox, which are commonly proposed and observed intermediates in catalytic reactions. Through a comparison of relevant analogues, we have established an empirical rule governing the electronic structures of these nickel radical complexes. The N-ligands exhibit redox activity in four-coordinate, square-planar nickel radical complexes, leading to the observation of ligand-centered radicals. In contrast, these ligands do not display redox activity when supporting three-coordinate, trigonal planar nickel radical complexes, which are better described as nickel-centered radicals. This trend holds true irrespective of the nature of the actor ligands. These results provide insights into the beneficial effect of coordinating salt additives and solvents in stabilizing nickel radical intermediates during catalytic reactions by modulating the redox activity of the ligands. Understanding the electronic structures of these active intermediates can contribute to the development and optimization of nickel catalysts for cross-coupling reactions.

Homoleptic octahedral CoII complexes as precatalysts for regioselective hydroboration of alkenes with high turnover frequencies.

Homoleptic complexes adopting octahedral coordination modes are usually less active in catalysis due to the saturated coordination around metal centers that prevents substrate activation in a catalytic event. In this work, we demonstrated that a homoleptic octahedral cobalt complex (1) of 4'-pyridyl-2,2';6',2''-terpyridine that experienced monoprotonation at the non-coordinating pyridyl moiety upon crystallization could serve as a highly efficient precatalyst for the hydroboration of styrene derivatives with Markovnikov selectivity. The solid-state structure of this precatalyst along with relevant homoleptic CoII and FeII complexes has been characterized by X-ray crystallography. In the solid state, 1 features one-dimensional hydrogen-bonded chains that are further stacked by interchain π⋯π interactions. The newly synthesized complexes (1-3) along with several known analogues (4-6) were examined as precatalysts for the hydroboration of alkenes. The best-performing system, 1/KOtBu was found to promote Markovnikov hydroboration of substituted styrenes with high turnover frequencies (TOFs) up to ∼47 000 h-1, comparable to the most efficient polymeric catalyst [Co(pytpy)Cl2]n reported to date. Although some limitations in substrate scope as well as functional group tolerance exist, the catalyst shows good promise for several relevant hydrofunctionaliation reactions.

Nitrene C-H Bond Insertion Approach to Carbazolones and Indolones, and a Reactivity Departure for 7-Membered Analogues.

A modular platform for facile access to 1,2,3,9-tetrahydro-4H-carbazol-4-ones (H4 -carbazolones) and 3,4-dihydrocyclopenta[b]indol-1(2H)-ones (H2 -indolones) is described. The requisite 6- and 5-membered 2-arylcycloalkane-1,3-dione precursors were readily obtained through a Cu-catalyzed arylation of 1,3-cyclohexanediones or by a ring expansion of aryl succinoin derivatives. Enolization of one carbonyl group in the diones, conversion to a leaving group, and subsequent azidation gave 2-aryl-3-azidocycloalk-2-en-1-ones. This two-step, one-pot azidation is highly regioselective with unsymmetrically substituted 2-arylcyclohexane-1,3-diones. The regioselectivity, which is important for access to single isomers of 3,3-disubstituted carbazolones, was analyzed mechanistically and computationally. Finally, a Rh-catalyzed nitrene/nitrenoid insertion into the ortho C-H bond of the aryl moiety gave the H4 -carbazolones and H2 -indolones. One carbazolone was elaborated to an intermediate reported in the total synthesis of N-decarbomethoxychanofruticosinate, (-)-aspidospermidine, (+)-kopsihainanine A. With 2-phenylcycloheptane-1,3-dione, prepared from cyclohexanone and benzaldehyde, the azidation reaction was readily accomplished. However, the Rh-catalyzed reaction unexpectedly led to a labile but characterizable azirine rather than the indole derivative. Computations were performed to understand the differences in reactivities of the 5- and 6-membered 2-aryl-3-azidocycloalk-2-en-1-ones in comparison to the 7-membered analogue, and to support the structural assignment of the azirine.

Vanadium-catalysed regioselective hydroboration of epoxides for synthesis of secondary alcohols.

Regioselective epoxide ring-opening through hydroboration catalysed by a vanadium(III) dialkyl complex supported by a redox-active terpyridine ligand is reported. Secondary alcohols were obtained in high yields via effective Markovnikov hydroboration of terminal epoxides, showcasing a new catalytic application of an earth-abundant vanadium(III) complex.

5-Nitrofuryl-Containing Thiosemicarbazone Gold(I) Compounds: Synthesis, Stability Studies, and Anticancer Activity.

This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5-nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2 ]± , and/or dimeric species. Neutral [{Au(TSC)}2 ] species were obtained from one of the compounds in dichlomethane/n-hexane solution and characterized by X-ray crystallography revealing a Au-Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki-1) demonstrated its relevant antimigratory and anti-angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis.

An ionic Fe-based metal-organic-framework with 4'-pyridyl-2,2':6',2''-terpyridine for catalytic hydroboration of alkynes.

An ionic metal-organic-framework (MOF) containing nanoscale channels was readily assembled from ditopic 4'-pyridyl-2,2':6',2''-terpyridine (pytpy) and a simple iron(ii) salt. X-ray structural analysis revealed a two-dimensional grid-like framework assembled by classic octahedral (pytpy)2FeII cations as linkers (with pytpy as a new ditopic pyridyl ligand) and octa-coordinate FeCl2 centers as nodes. The layer-by-layer assembly of the 2-D framework resulted in the formation of 3-D porous materials consisting of nano-scale channels. The charges of the cationic framework were balanced with anionic Cl3FeOFeCl3 in its void channels. The new Fe-based MOF material was employed as a precatalyst for syn-selective hydroboration of alkynes under mild, solvent-free conditions in the presence of an activator, leading to the synthesis of a range of trans-alkenylboronates in good yields. The larger scale applicability and recyclability of the new MOF catalyst was further explored. This represents a rare example of an ionic MOF material that can be utilized in hydroboration catalysis.

Sc-HOPO: A Potential Construct for Use in Radioscandium-Based Radiopharmaceuticals.

Three isotopes of scandium─43Sc, 44Sc, and 47Sc─have attracted increasing attention as potential candidates for use in imaging and therapy, respectively, as well as for possible theranostic use as an elementally matched pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO), an effective chelator for hard cations, as a potential ligand for use in radioscandium constructs with simple radiolabeling under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully characterized, both experimentally and theoretically. [47Sc]Sc-HOPO exhibited good stability in chemical and biological challenges over 7 days. In healthy mice, [43,47Sc]Sc-HOPO cleared the body rapidly with no signs of demetalation. HOPO is a strong candidate for use in radioscandium-based radiopharmaceuticals.

Markovnikov alcohols via epoxide hydroboration by molecular alkali metal catalysts.

Synthesis of branched "Markovnikov" alcohols is crucial to various chemical industries. The catalytic reduction of substituted epoxides under mild conditions is a highly attractive method for preparing such alcohols. Classical methods based on heterogeneous or homogeneous transition metal-catalyzed hydrogenation, hydroboration, or hydrosilylation usually suffer from poor selectivity, reverse regioselectivity, limited functional group compatibility, high cost, and/or low availability of the catalysts. Here we report the discovery of highly regioselective hydroboration of nonsymmetrical epoxides catalyzed by ligated archetypal reductants in organic chemistry ‒ alkali metal triethylborohydrides. The chemoselectivity and turnover efficiencies of the present catalytic approach are excellent. Thus, terminal and internal epoxides with ene, yne, aryl, and halo groups were selectively and quantitatively reduced under a substrate-to-catalyst ratio (S/C) of up to 1000. Mechanistic investigations point to a mechanism reminiscent of frustrated Lewis pair action on substrates in which a nucleophile and Lewis acid act cooperatively on the substrate.

Diplumbane-catalysed solvent- and additive-free hydroboration of ketones and aldehydes.

A new diplumbane, namely [Pb(CH2SiMe3)3]2, was synthesized and structurally characterized. This group 14 element compound was found to catalyse the hydroboration of ketones and aldehydes under mild conditions without the use of additives and solvents, leading to the synthesis of a range of alcohols in high yields after hydrolysis.

Intracellular Localization Studies of the Luminescent Analogue of an Anticancer Ruthenium Iminophosphorane with High Efficacy in a Triple-Negative Breast Cancer Mouse Model.

The potential of ruthenium(II) compounds as an alternative to platinum-based clinical anticancer agents has been unveiled after extensive research for over 2 decades. As opposed to cisplatin, ruthenium(II) compounds have distinct mechanisms of action that do not rely solely on interactions with DNA. In a previous report from our group, we described the synthesis, characterization, and biological evaluation of a cationic, water-soluble, organometallic ruthenium(II) iminophosphorane (IM) complex of p-cymene, ([(η6-p-cymene)Ru{(Ph3P═N-CO-2N-C5H4)-κ-N,O}Cl]Cl (1 or Ru-IM), that was found to be highly cytotoxic against a panel of cell lines resistant to cisplatin, including triple-negative breast cancer (TNBC) MDA-MB-231, through canonical or caspase-dependent apoptosis. Studies on a MDA-MB-231 xenograft mice model (after 28 days of treatment) afforded an excellent tumor reduction of 56%, with almost negligible systemic toxicity, and a favored ruthenium tumor accumulation compared to other organs. 1 is known to only interact weakly with DNA, but its intracellular distribution and ultimate targets remain unknown. To gain insight on potential mechanisms for this highly efficacious ruthenium compound, we have developed two luminescent analogues containing the BOPIPY fluorophore (or a modification) in the IM scaffold with the general structure of [(η6-p-cymene)Ru{(BODIPY-Ph2P═N-CO-2-NC5H4)-κ-N,O}Cl]Cl {BODIPY-Ph2P = 8-[(4-diphenylphosphino)phenyl]-4,4-dimethyl-1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3a) and 4,4-difluoro-8-[4-[[2-[4-(diphenylphosphino)benzamido]ethyl]carbamoyl]phenyl]-1,3,5,7-tetramethyl,2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3b)}. We report on the synthesis, characterization, lipophilicity, stability, luminescence properties, and cell viability studies in the TNBC cell line MDA-MB-231, nonmalignant breast cells (MCF10a), and lung fibroblasts (IMR-90) of the new compounds. The ruthenium derivative 3b was studied by fluorescence confocal microscopy. These studies point to a preferential accumulation of the compound in the endoplasmic reticulum, mitochondria, and lysosomes. Inductively coupled plasma optical emission spectrometry (ICP-OES) analysis also confirms a greater ruthenium accumulation in the cytoplasmic fraction, including endoplasmic reticulum and lysosomes, and a smaller percentage of accumulation in mitochondria and the nucleus. ICP-OES analysis of the parent compound 1 indicates that it accumulates preferentially in the mitochondria and cytoplasm. Subsequent experiments in 1-treated MDA-MB-231 cells demonstrate significant reactive oxygen species generation.

Targeting the pregnane X receptor using microbial metabolite mimicry.

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

1-D manganese(ii)-terpyridine coordination polymers as precatalysts for hydrofunctionalisation of carbonyl compounds.

Reductive catalysis with earth-abundant metals is currently of increasing importance and shows potential in replacing precious metal catalysis. In this work, we revealed catalytic hydroboration and hydrosilylation of ketones and aldehydes achieved by a structurally defined manganese(ii) coordination polymer (CP) as a precatalyst under mild conditions. The manganese-catalysed methodology can be applied to a range of functionalized aldehydes and ketones with turnover numbers (TON) of up to 990. Preliminary results on the regioselective catalytic hydrofunctionalization of styrenes by the Mn-CP catalyst are also presented.

Redox-Noninnocent Ligand-Supported Vanadium Catalysts for the Chemoselective Reduction of C═X (X = O, N) Functionalities.

Catalysis is the second largest application for V after its use as an additive to improve steel production. Molecular complexes of vanadium(V) are particularly useful and efficient catalysts for oxidation processes; however, their ability to catalyze reductive transformations has yet to be fully explored. Here we report the first examples of polar organic functionality reduction mediated by V. Open-shell VIII complexes that feature a π-radical monoanionic 2,2':6',2″-terpyridine ligand (Rtpy•)- functionalized at the 4'-position (R = (CH3)3SiCH2, C6H5) catalyze mild and chemoselective hydroboration and hydrosilylation of functionalized ketones, aldehydes, imines, esters, and carboxamides with turnover numbers (TONs) of up to ∼1000 and turnover frequencies (TOFs) of up to ∼500 h-1. Computational evaluation of the precatalyst synthesis and activation has revealed underappreciated complexity associated with the redox-active tpy chelate.

Synthesis, characterization and biological studies of rhenium, technetium-99m and rhenium-188 pentapeptides.

A pentapeptide macrocyclic ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for SPECT imaging and therapeutic in vivo agents. This study shows the synthesis and characterization of KYCAR complexes containing nonradioactive rhenium, 99mTc, or 188Re. The metal complexes were also biologically evaluated to determine in vivo distribution in healthy mice. The overall goals of this project were (1) to synthesize the Tc/Re pentapeptide complexes, (2) to identify spectroscopic methods for characterization of syn versus anti rhenium peptide complexes, (3) to analyze the ex vivo stability, and (4) to assess the biological properties of the [99mTc]TcO-KYCAR and [188Re]ReO-KYCAR complexes in vivo. Details on these efforts are provided below. METHODS: NatRe/99mTc/188ReO-KYCAR complexes were synthesized, and macroscopic species were characterized via HPLC, IR, NMR, and CD. These characterization data were compared to the crystallographic data of ReO-KYC to assist in the assignment of diastereomers and to aid in the determination of the structure of the complex. RESULTS: The radiometal complexes were synthesized with high purity (>95%). HPLC, IR, NMR and CD data on the macroscopic natReO-KYCAR complexes confirm the successful complexation as well as the presence of two diastereomers in syn and anticonformations. Tracer level complexes show favorable stabilities ex vivo for 2+ h. CONCLUSION: Macroscopic metal complexes form diastereomers with the KYCAR ligand; however, this phenomenon is not readily observed on the tracer level due to the rapid interconversion. It was determined through pKa measurements that the macroscopic natReO-KYCAR complex is 0 at physiological pH. The [99mTc]TcO-KYCAR is stable in vitro while the [188Re]ReO-KYCAR shows 50% decomposition in PBS and serum. Biologically, the tracer level complexes clear through the hepatobiliary pathway. Some decomposition of both tracers is evident by uptake in the thyroid and stomach.