Migrating 1H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding author upon reasonable request.The alkylation of adenine using alkyl halides under basic conditions in dimethyl sulfoxide (DMSO), a common reaction to achieve N9-alkylated adenine derivatives, is often low yielding with unreacted adenine and complicated reaction mixtures. Herein, we report the reaction monitoring of the alkylation of adenine in DMSO in the presence of NaH using benzylic halides via realtime 1H NMR spectroscopy. NMR analysis revealed that under these generally used reaction conditions, the adeninate anion starting material is protonated as the anionic nucleophile abstracts a labile proton from an alkoxy sulfonium ion intermediate formed via the Kornblum oxidation reaction. To prevent the protonation of the adeninate anion, the reaction was performed in the presence of a mop-up base DBU. Simultaneously increasing the concentration of the alkyl halide and the mop-up base in a 1:1 ratio resulted in a complete reaction; however, increasing the temperature of the reaction promoted depletion of the starting material by protonation and hence reduced conversion to products. This result implies that heating of such electrophiles in DMSO should be avoided. The addition of a mop-up base can help resolve the complication of protonation arising from the Kornblum oxidation reaction in alkylation reactions under similar conditions.The National Research Foundation of South Africa and the Scarce Skills Doctoral Scholarship.https://onlinelibrary.wiley.com/journal/19435193am2024ChemistryNon

Coordination sites for sodium and potassium ions in nucleophilic adeninate contact ion-pairs : a molecular-wide and electron density-based (MOWED) perspective

DATA AVAILABILITY STATEMENT : The data presented in this study are openly available in FigShare at https://figshare.com/s/59476a600bad4ba82fc4.SUPPLEMENTARY MATERIAL : TABLE Table S1: CCSD-computed intermolecular diatomic interaction energies between Na+ with the atoms of the adeninate anion for the specified Na-Ade complexes (CIPs). All values in kcal mol1; TABLE S2: CCSD-computed intermolecular diatomic interaction energies between K+ with the atoms of the adeninate anion for the specified K-Ade complexes (CIPs). All values in kcal mol1; TABLE S3: DFT-computed intermolecular diatomic interaction energies between Na+ with the atoms of the adeninate anion for the specified Na-Ade complexes (CIPs). All values in kcal mol1; TABLE S4: DFT-computed intermolecular diatomic interaction energies between K+ with the atoms of the adeninate anion for the specified K-Ade complexes (CIPs). All values in kcal mol1; TABLE S5: DFT-computed changes in the total intramolecular interaction energy of the adeninate anion (DEAde int ), the total CB-interactions (DCBEAde int ) and total LD-interactions (DLDEAde int ) calculated for the indicated Na-Ade and K-Ade complexes. All values are in kcal mol1; TABLE S6: The total change in the exchange-correlation (DCBVAde XC ) and classical (DCBVAde cl ) terms of the interactions between covalently bonded atoms of the adeninate anion, calculated for Na-Ade and K-Ade complexes at the DFT level. All values in kcal mol1; TABLE S7: Net atomic charges of the atoms Q(A) of free Ade, the net molecular charge of Ade Q(Ade), and counter ions Q(Na+) and Q(K+). Relative to free ions, changes in these charges, obtained for each of the CIPs, are also included. All values are in e and are reported at the DFT level of theory (all values in e); FIGURE S1: DFT-optimized structures of the indicated out-of-plane Na- and K-Ade-(DMSO)4 systems and, relative to the lowest energy N-CIP in the main text (Figure 2), the energy difference DENa-Ade between Na-Ade complexes solvated by four DMSO molecules. The energy of formation (Ef) of the Na- and K-Ade-(DMSO)4 molecular systems and, relative to the lowest energy system in the main text (Figure 2), the electronic energy difference between entire molecular systems (DEsystem) are also provided. All values are in kcal mol1; TABLE S8: The total interaction energy EM+,DMSO int and its covalent VM+,DMSO XC and electrostatic VM+,DMSO cl components computed for the for DMSO-1 and DMSO-2 solvent molecules and counter ions Na+ and K+ in the in-plane M-Ade-(DMSO)4 molecular systems. All values in kcal mol1 at the DFT level of theory.; TABLE S9: Intermolecular diatomic interaction energies between the M+ counter ion (Na+ and K+) with the atoms A of the DMSO-3 solvent molecule of the in-plane M-Ade-(DMSO)4 molecular systems at the DFT level of theory. All values in kcal mol1; TABLE S10: Intermolecular diatomic interaction energies between the M+ counter ion (Na+ and K+) with the atoms A of the DMSO-4 solvent molecule of the in-plane M-Ade-(DMSO)4 molecular systems at the DFT level of theory. All values in kcal mol1; TABLE S11: The total interaction energy EAde,DMSO int and its covalent VAde,DMSO XC and electrostatic VAde,DMSO cl components computed for the for DMSO-3 and DMSO-4 solvent molecules and Ade in the in-plane M-Ade-(DMSO)4 molecular systems. All values in kcal mol1 at the DFT level of theory.The adeninate anion (Ade) is a useful nucleophile used in the synthesis of many prodrugs (including those for HIV AIDS treatment). It exists as a contact ion-pair (CIP) with Na+ and K+ (M+) but the site of coordination is not obvious from spectroscopic data. Herein, a molecular-wide and electron density-based (MOWED) computational approach implemented in the implicit solvation model showed a strong preference for bidentate ion coordination at the N3 and N9 atoms. The N3N9-CIP has (i) the strongest inter-ionic interaction, by 30 kcal mol1, with a significant (10–15%) covalent contribution, (ii) the most stabilized bonding framework for Ade, and (iii) displays the largest ion-induced polarization of Ade, rendering the N3 and N9 the most negative and, hence, most nucleophilic atoms. Alkylation of the adeninate anion at these two positions can therefore be readily explained when the metal coordinated complex is considered as the nucleophile. The addition of explicit DMSO solvent molecules did not change the trend in most nucleophilic N-atoms of Ade for the in-plane M-Ade complexes in M-Ade-(DMSO)4 molecular systems. MOWED-based studies of the strength and nature of interactions between DMSO solvent molecules and counter ions and Ade revealed an interesting and unexpected chemistry of intermolecular chemical bonding.The National Research Foundation of South Africa and the University of Pretoria.https://www.mdpi.com/journal/moleculeshttps://figshare.com/s/59476a600bad4ba82fc4am2023Chemistr

A stereoselective synthesis of the urinary metabolite N-acetyl-S-(3,4-dihydroxybutyl)cysteine

On exposure to the potential carcinogen 1,3-butadiene, the major urinary metabolite in humans is N-acetyl-S-(3,4-dihydroxybutyl)cysteine. A novel, stereoselective synthesis of this cysteine–butadiene metabolite has been developed that is suitable for the production of either diastereomer for use in occupational exposure analysis. L-Cysteine and 4-bromo-1-butene are coupled via an SN2 reaction to give the core structure. A Sharpless asymmetric dihydroxylation using the dihydroquinidine (DHQD) ligand provided the terminal 1,2-diol with the 3-hydroxyl group in the R configuration. Supplementary materials are available for this article. Go to the publisher’s online edition of Synthetic Communications1 to view the free supplemental resourceThe National Research Foundation of South Africa and the University of Pretoria.http://www.tandfonline.com/loi/lsyc20hb2017Chemistr

Towards a molecular understanding of cation‐anion interactions and self‐aggregation of adeninate salts in DMSO by NMR and UV spectroscopy and crystallography

Rare anionic forms of nucleic acids play a significant biological role and lead to spontaneous mutations and replication and translational errors. There is a lack of information surrounding the stability and reactivity of these forms. Ion pairs of mono‐sodium and ‐potassium salts of adenine exist in DMSO solution with possible cation coordination sites at the N1, N7 and N9 atoms of the purine ring. At increasing concentrations π‐π stacked dimers are the predominant species of aggregates followed by higher order aggregation governed by coordination to metal cations in which the type of counter ion present has a central role in the aggregate formation.National Research Foundatio

An inquiry-based practical curriculum for organic chemistry as preparation for industry and postgraduate research

This paper describes the development of a new practical curriculum for third-year organic chemistry to replace the recipe-based approach typically used in undergraduate teaching laboratories. The new curriculum consists of an inquiry-based project set in a simulated industrial context preceded by two scaffolding experiments to prepare students for the task. The industrial project requires students to evaluate experimentally three multi-step synthetic routes to a given target based on cost, technical challenge and environmental impact in order to make a recommendation as to which route the ‘company’ should use to synthesize the compound. The project equips students with technical skills suitable for both postgraduate research and industry, and develops metacognition and understanding through the use of the jig-saw cooperative learning strategy and reflection. The students were found to engage with the practical work at a deep intellectual level, demonstrating that contextualized inquiry-based laboratory teaching afforded an improved quality of learning. In addition, the reported practical curriculum made a difficult subject accessible and even popular, to some measure grew the students’ ability in all desired graduate attributes and resulted in the establishment of a professional identity for individual students.Education Innovation grant from the University of Pretoria.http://saci.co.za/journalam201

Development of a mycolic acid-graphene quantum dot probe as a potential tuberculosis biosensor

The development of amine-functionalized graphene quantum dots (GQDs) linked to mycolic acids (MAs) as a potential fluorescent biosensor to detect tuberculosis (TB) biomarkers is described. GQDs have attractive properties: high fluorescence, excellent biocompatibility, good water solubility, and low toxicity. MAs are lipids that are found in the cell wall of Mycobacterium tuberculosis that are antigenic, however, they are soluble only in chloroform and hexane. Chloroform-soluble MAs were covalently linked to synthesized water-soluble GQDs using an amide connection to create a potential fluorescent water-soluble TB biosensor: MA-GQDs. Fluorescence results showed that GQDs had a narrow emission spectrum with the highest emission at 440 nm, while MA-GQDs had a broader spectrum with the highest emission at 470 nm, after exciting at 360 nm. The appearance of the peptide bond (amide linkage) in the Fourier-transform infrared spectrum of MA-GQDs confirmed the successful linking of MAs to GQDs. Powder X-ray diffraction exhibited an increase in the number of peaks for MA-GQDs relative to GQDs, suggesting that linking MAs to GQDs changed the crystal structure thereof. The linked MA-GQDs showed good solubility in water, high fluorescence, and visual flow through a nitrocellulose membrane. These properties are promising for biomedical fluorescence sensing applications.NRF-TWAS scholarship and a postgraduate student bursary from the University of Pretoria.http://wileyonlinelibrary.com/journal/bioam2023Chemistr

Anticancer agents from diverse natural sources

Cancer is one of the major causes of death and the number of new cases, as well as the number of individuals living with cancer, is expanding continuously. Worldwide the alarming rise in mortality rate due to cancer has fuelled the pursuit for effective anticancer agents to combat this disease. Finding novel and efficient compounds of natural origin has been a major point of concern for research in the pharmaceutical sciences. Natural products have been seen to possess the potential to be excellent lead structures and to serve as a basis of promising therapeutic agents for cancer treatment. Many successful anti-cancer drugs currently in use are natural products or their analogues and many more are under clinical trials. This review aims to highlight the invaluable role that natural products have played, and continue to play, in the discovery of anticancer agents and also summarizes the recently launched natural product-derived anticancer drugs and new natural product templates in clinical pipeline.University of Pretoriahttp://www.naturalproduct.us/hb2017ChemistryGenetic

Physico-chemical characterization of polyethylene glycol- conjugated betulinic acid

Betulinic acid (BA) is a naturally occurring plant pentacyclic triterpenoid with activity against cancer and infectious diseases like malaria and AIDS. Its pharmacological activity is limited by low aqueous solubility and bioavailability. Attempts have been made to improve the solubility of BA by conjugation to the water-soluble polymer polyethylene glycol (PEG) but with very limited physico-chemical characterizations. This work presents physico-chemical characterizations of a PEG-BA conjugate using H NMR spectroscopy, electron microscopy, DLS and XRD. The NMR data showed successful conjugation through the formation of an amide bond with a 5% drug loading although the appearance of some chemical shift signals were solvent-dependent. TEM images showed a spherical morphology of the conjugate with average diameter of 59.58±4.47 nm.https://aip.scitation.org/journal/apcpm2021Chemistr

Synthesis, physicochemical characterization, toxicity and efficacy of a PEG conjugate and a hybrid PEG conjugate nanoparticle formulation of the antibiotic moxifloxacin

Antibiotic resistance is increasing at such an alarming rate that it is now one of the greatest global health challenges. Undesirable toxic side-effects of the drugs lead to high rates of non-completion of treatment regimens which in turn leads to the development of drug resistance. We report on the development of delivery systems that enable antibiotics to be toxic against bacterial cells while sparing human cells. The broad-spectrum fluoroquinolone antibiotic moxifloxacin (Mox) was successfully conjugated to poly(ethylene glycol) (PEG) which was further encapsulated into the hydrophobic poly(3- caprolactone) (PCL) nanoparticles (NPs) with high efficiency, average particle size of 241.8 4 nm and negative zeta potential. Toxicity against erythrocytes and MDBK cell lines and drug release in human plasma were evaluated. Hemocompatibility and reduced cytotoxicity of the PEG–Mox and PCL(PEG– Mox) NPs were demonstrated in comparison to free Mox. Antimicrobial activity was assessed against drug sensitive and resistant: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The antibacterial activity of Mox was largely maintained after conjugation. Our data shows that the toxicity of Mox can be effectively attenuated while, in the case of PEG–Mox, retaining significant antibacterial activity. At the conditions employed in this study for antimicrobial activity the encapsulated conjugate (PCL(PEG–Mox) NPs) did not demonstrate, conclusively, significant antibacterial activity. These systems do, however, hold promise if further developed for improved treatment of bacterial infections.The National Research Foundation of South Africa and the Ministry of Higher Education and Scientific Research, Egypt.http://pubs.rsc.org/en/journals/journalissues/raam2021Chemistr

Thiol modified mycolic acids

Patient serum antibodies to mycolic acids have the potential to be surrogate markers of active tuberculosis (TB) when they can be distinguished from the ubiquitously present cross-reactive antibodies to cholesterol. Mycolic acids are known to interact more strongly with antibodies present in the serum of patients with active TB than in patients with latent TB or no TB. Examples of single stereoisomers of mycolic acids with chain lengths corresponding to major homologues of those present in Mycobacterium tuberculosis have now been synthesised with a sulfur substituent on the terminal position of the -chain; initial studies have established that one of these binds to a gold electrode surface, offering the potential to develop second generation sensors for diagnostic patient antibody detection.MMS and ADS wish to acknowledge support from the Government of Iraq through the award of PhD studentships.http://www.elsevier.com/locate/chemphysliphb2017BiochemistryChemistr