Synthesis and evaluation of benzoylbenzofurans and isoflavone derivatives as sirtuin 1 inhibitors with antiproliferative effects on cancer cells.

Isoflavone derivatives were prepared from benzoylbenzofuran precursors. The synthesized compounds were analyzed by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS) to confirm their structures. The benzoylbenzofuran and isoflavone analogues were evaluated for inhibition of sirtuin 1 (SIRT1) and cell proliferation in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Several isoflavone and benzoylbenzofuran derivatives exhibited potent antiproliferative effects against the MDA-MB-231 cancer cell line. Most of the isoflavone derivatives attenuated SIRT1 activity to below 50%. The most active compounds were the isoflavone quinones 38, 39, and 40, at IC50 values of 5.58 ± 0.373, 1.62 ± 0.0720, and 7.24 ± 0.823 µM, respectively. Importantly, the most active compound, 6-methoxy-4',6'-dimethylisoflavone-2',5'-quinone (39) displayed SIRT1 inhibitory activity comparable to that of the reference compound, suramin. The in silico docking simulations in the active site of SIRT1 further substantiated the experimental results and explored the binding orientations of potent compounds in the active site of the target.

Phytochemical Profiling and Isolation of Bioactive Compounds from Leucosidea sericea (Rosaceae).

In the study, ultraperformance liquid chromatography-quadrupole time-of-flight-mass spectrometry analysis of Leucosidea sericea leaf and stem extracts led to the identification of various classes of compounds. Further chromatographic purifications resulted in the isolation of 22 compounds that consisted of a new triterpenoid named leucosidic acid A (1), an acetophenone derivative 2, a phloroglucinol derivative 3, three chromones 4-6, seven pentacyclic triterpenoids 7-13, a phytosterol glucoside 14, a flavonoid 15, and seven flavonoid glycosides 16-22. Nineteen of these compounds including the previously undescribed triterpenoid 1 are isolated for the first time from L. sericea. The structures of the isolated compounds were assigned based on their high-resolution mass spectrometry and nuclear magnetic resonance data. Some of the isolated triterpenoids were evaluated for inhibitory activity against α-amylase, α-glucosidase, and pancreatic lipase. Of the tested compounds, 1-hydroxy-2-oxopomolic acid (7) and pomolic acid (13) showed higher potency on α-glucosidase than acarbose, which is used as a positive control in this study. The two compounds inhibited α-glucosidase with IC50 values of 192.1 ± 13.81 and 85.5 ± 6.87 µM, respectively.

Synthesis, anti-microbial, toxicity and molecular docking studies of N-nitroso-N-phenylhydroxylamine (cupferron) and its derivatives.

Bacterial resistance to antimicrobial agents is increasing at an alarming rate globally and requires new lead compounds for antibiotics. In this study, N-phenyl-N-nitroso hydroxylamine (cupferron) and its derivatives have been synthesised using readily available starting materials. The compounds were obtained in high yield and purity. They show activity towards a range of Gram-positive and Gram-negative pathogenic bacteria, with minimum inhibitory concentration (MIC) values as low as 2 µg.mL-1 against the tested organisms, especially for Gram-positive species. Toxicity studies on the lead compound 3b indicate insignificant effects on healthy cell lines. Molecular docking studies on the lead compound identify possible binding modes of the compound, and the results obtained correlate with those of in vitro and MIC studies. The lead compound shows excellent drug-likeness properties.

Flavonoids from the Genus Euphorbia: Isolation, Structure, Pharmacological Activities and Structure-Activity Relationships.

Plants of the genus Euphorbia are widely distributed across temperate, tropical and subtropical regions of South America, Asia and Africa with established Ayurvedic, Chinese and Malay ethnomedical records. The present review reports the isolation, occurrence, phytochemistry, biological properties, therapeutic potential and structure-activity relationship of Euphorbia flavonoids for the period covering 2000-2020, while identifying potential areas for future studies aimed at development of new therapeutic agents from these plants. The findings suggest that the extracts and isolated flavonoids possess anticancer, antiproliferative, antimalarial, antibacterial, anti-venom, anti-inflammatory, anti-hepatitis and antioxidant properties and have different mechanisms of action against cancer cells. Of the investigated species, over 80 different types of flavonoids have been isolated to date. Most of the isolated flavonoids were flavonols and comprised simple O-substitution patterns, C-methylation and prenylation. Others had a glycoside, glycosidic linkages and a carbohydrate attached at either C-3 or C-7, and were designated as d-glucose, l-rhamnose or glucorhamnose. The structure-activity relationship studies showed that methylation of the hydroxyl groups on C-3 or C-7 reduces the activities while glycosylation loses the activity and that the parent skeletal structure is essential in retaining the activity. These constituents can therefore offer potential alternative scaffolds towards development of new Euphorbia-based therapeutic agents.

Bioactive Lignans from Hypoestes aristata.

Phytochemical investigation of extracts of the stems of Hypoestes aristata led to the isolation of nine lignans that included four known compounds, namely, hinokinin (1), savinin (2), medioresinol (3), and two cubebins (8a,b), three new butyrolactone lignans (4-6), and butyrolactol lignans 7a-c. The structures of the new compounds were established using 1D and 2D NMR and HRESIMS data. The absolute configurations of the new lignans were determined from their ECD data and the Mosher's ester method. This is the first unequivocal assignment of the absolute configuration at C-7 and C-7' of 7- and 7'-hydroxybutyrolactone lignans. The compounds were screened for inhibition of an HIV-1 protease enzyme, and compounds 1 and 6 exhibited moderate activity in this regard.

Synthesis and Antifungal Activity of Chromones and Benzoxepines from the Leaves of Ptaeroxylon obliquum.

This study reports the first total synthesis of the bioactive oxepinochromones 12-O-acetyleranthin (8) (angular isomer) and 12-O-acetylptaeroxylinol (9) (linear isomer). The antifungal activity of these compounds and their derivatives was determined against Candida albicans and Cryptococcus neoformans. Most compounds had good selectivity between the two fungi and showed moderate to good activity. 12-O-Acetyleranthin (8) had the highest activity against C. albicans, with an MIC value of 9.9 µM, while 12-O-acetylptaeroxylinol (9), the compound present in Ptaeroxylon obliquum, had the highest activity against C. neoformans, with an MIC value of 4.9 µM.

Synthesis of Isoflavones by Tandem Demethylation and Ring-Opening/Cyclization of Methoxybenzoylbenzofurans.

The unexpected conversion of benzoylbenzofurans into isoflavones through an intramolecular cascade that involves deprotection and ring-opening/cyclization is described. This was discovered in an investigation of the possible transformation of benzoylbenzofurans into coumaronochromones. This route affords isoflavones in two major steps from acetophenones and benzoquinones. The transformation was validated by synthesizing differently substituted isoflavone derivatives and further applied to a concise synthesis of a potential anticancer lead compound, glaziovianin A (1).

Carbon-14 radiolabeling and tissue distribution evaluation of MMV390048.

The antimalarial compound MMV390048 ([14 C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon-14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [14 C]-11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all-time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([14 C]-11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound.

Carbon-14 radiolabelling and tissue distribution evaluation of a potential anti-TB compound.

This paper describes a five-step synthesis of a carbon-14-labelled pyrazole compound (11). A total of 2.96 MBq of 11 was obtained with the specific activity of 2242.4 MBq/mmol. The radiochemical purity was >99%, and the overall radiochemical yield was 60% based on the [(14) C6 ] 4-bromoaniline starting material. Biodistribution results showed that the radiotracer (administrated orally) has a high accumulation in the small intestine, large intestine and liver of both non-infected and tuberculosis (TB)-infected mice. Therefore, this suggests that compound 11 undergoes hepatobiliary clearance. The compound under investigation has been found to be slowly released from the liver between 2 and 8 h. The study revealed that 11 has no affinity for TB cells.

Dual radiolabeling as a technique to track nanocarriers: the case of gold nanoparticles.

Gold nanoparticles (AuNPs) have shown great potential for use in nanomedicine and nanotechnologies due to their ease of synthesis and functionalization. However, their apparent biocompatibility and biodistribution is still a matter of intense debate due to the lack of clear safety data. To investigate the biodistribution of AuNPs, monodisperse 14-nm dual-radiolabeled [14C]citrate-coated [198Au]AuNPs were synthesized and their physico-chemical characteristics compared to those of non-radiolabeled AuNPs synthesized by the same method. The dual-radiolabeled AuNPs were administered to rats by oral or intravenous routes. After 24 h, the amounts of Au core and citrate surface coating were quantified using gamma spectroscopy for 198Au and liquid scintillation for the 14C. The Au core and citrate surface coating had different biodistribution profiles in the organs/tissues analyzed, and no oral absorption was observed. We conclude that the different components of the AuNPs system, in this case the Au core and citrate surface coating, did not remain intact, resulting in the different distribution profiles observed. A better understanding of the biodistribution profiles of other surface attachments or cargo of AuNPs in relation to the Au core is required to successfully use AuNPs as drug delivery vehicles.

Carbon-14 radiolabeling and in vivo biodistribution of a potential anti-TB compound.

A potential anti-TB compound bearing a nitroimidazole moiety from iThemba Pharmaceuticals TB chemical library exhibits promising in vitro activity in the microplate almar blue assay (MABA) with a minimum inhibitory concentration (MIC) value of 3 µg/mL. It is equipotent to the front-line drug Isoniazid, but the compound is less toxic with an IC50 of >100 µg/mL. Therefore, this potential iThemba nitroimidazole, 4-([1,1'-[(14)C6]biphenyl]-4-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1,3,6]oxadiazocine, was radiolabeled with the C-14 isotope. The synthesis of the (14)C-labeled nitroimidazole was accomplished in seven steps from diethanolamine with a final specific radioactivity of 3.552 GBq/mmol, a radiochemical yield of 87%, and a radiochemical purity of ≥96%. The source of the C-14 radiolabel was bromobenzene which was introduced by the Suzuki-Miyaura reaction. Tissue distribution results showed that the radiotracer has a high accumulation in the lungs of TB-infected mice, statistically significantly higher than in healthy mice. However, the clearance (for both TB-infected and non-TB-infected mice) from all organs (except the small intestine) from 1 to 2 h as well as the low percentage of injected dose per gram values achieved indicates breakdown of the compound in vivo and subsequent clearance from the body. The latter suggests that the compound might not be useful as an anti-TB drug in humans.