Cytotoxic Cu(II) Complexes with a Novel Quinoline Derivative Ligand: Synthesis, Molecular Docking, and Biological Activity Analysis.

The utilization of metallodrugs as a viable alternative to organic molecules has gained significant attention in modern medicine. We hereby report synthesis of new imine quinoline ligand (IQL)-based Cu(II) complexes and evaluation of their potential biological applications. Syntheses of the ligand and complexes were achieved by condensation of 7-chloro-2-hydroxyquinoline-3-carbaldehyde and 2,2'-thiodianiline, followed by complexation with Cu(II) metal ions. The synthesized ligand and complexes were characterized using UV-vis spectroscopy, TGA/DTA, FTIR spectroscopy, 1H and 13C NMR spectroscopy, and pXRD. The pXRD diffractogram analysis revealed that the synthesized ligand and its complexes were polycrystalline systems, with nanolevel average crystallite sizes of 13.28, 31.47, and 11.57 nm for IQL, CuL, and CuL 2 , respectively. The molar conductivity confirmed the nonelectrolyte nature of the Cu(II) complexes. The biological activity of the synthesized ligand and its Cu(II) complexes was evaluated with in vitro assays, to examine anticancer activity against the MCF-7 human breast cancer cell line and antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains. The CuL complex had the highest cytotoxic potency against MCF-7 breast cancer cells, with an IC50 of 43.82 ± 2.351 µg/mL. At 100 µg/mL, CuL induced the largest reduction of cancer cell proliferation by 97%, whereas IQL reduced cell proliferation by 53% and CuL 2 by 28%. The minimum inhibitory concentration for CuL was found to be 12.5 µg/mL against the three tested pathogens. Evaluation of antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl revealed that CuL exhibited the highest antioxidant activity with IC50 of 153.3 ± 1.02 µg/mL. Molecular docking results showed strong binding affinities of CuL to active sites of S. aureus, E. coli, and estrogen receptor alpha, indicating its high biological activity compared to IQL and CuL 2 .

Organic-inorganic hybrid salt and mixed ligand Cr(III) complexes containing the natural flavonoid chrysin: Synthesis, characterization, computational, and biological studies.

Organic-inorganic hybrid salt and mixed ligand Cr(III) complexes (Cr1 and Cr2) containing the natural flavonoid chrysin were synthesized. The metal complexes were characterized using UV-Vis, Fourier-transform infrared, MS, SEM-EDX, XRD, and molar conductance measurements. Based on experimental and DFT/TD-DFT calculations, octahedral geometries for the synthesized complexes were suggested. The powder XRD analysis confirms that the synthesized complexes were polycrystalline, with orthorhombic and monoclinic crystal systems having average crystallite sizes of 21.453 and 19.600 nm, percent crystallinities of 51% and 31.37%, and dislocation densities of 2.324 × 10-3 and 2.603 × 10-3 nm-2 for Cr1 and Cr2, respectively. The complexes were subjected to cytotoxicity, antibacterial, and antioxidant studies. The in vitro biological studies were supported with quantum chemical and molecular docking computational studies. Cr1 showed significant cytotoxicity to the MCF-7 cell line, with an IC50 value of 8.08 µM compared to 30.85 µM for Cr2 and 18.62 µM for cisplatin. Cr2 showed better antibacterial activity than Cr1. The higher E HOMO (-5.959 eV) and dipole moment (10.838 Debye) values of Cr2 obtained from the quantum chemical calculations support the observed in vitro antibacterial activities. The overall results indicated that Cr1 is a promising cytotoxic drug candidate.

Cytotoxicity and Antibacterial Potentials of Mixed Ligand Cu(II) and Zn(II) Complexes: A Combined Experimental and Computational Study.

[Cu(C15H9O4)(C12H8N2)O2C2H3]·3H2O (1) and [Zn(C15H9O4)(C12H8N2)]O2C2H3 (2) have been synthesized and characterized by ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, mass spectrometry, thermogravimetric analysis/differential thermal analysis (TGA/DTA), X-ray diffraction (XRD), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX), and molar conductance, and supported by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. Square pyramidal and tetrahedral geometries are proposed for Cu(II) and Zn(II) complexes, respectively, and the XRD patterns showed the polycrystalline nature of the complexes. Furthermore, in vitro cytotoxic activity of the complexes was evaluated against the human breast cancer cell line (MCF-7). A Cu(II) centered complex with an IC50 value of 4.09 µM was more effective than the Zn(II) centered complex and positive control, cisplatin, which displayed IC50 values of 75.78 and 18.62 µM, respectively. In addition, the newly synthesized complexes experienced the innate antioxidant nature of the metal centers for scavenging the DPPH free radical (up to 81% at 400 ppm). The biological significance of the metal complexes was inferred from the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy band gap, which was found to be 2.784 and 3.333 eV, respectively for 1 and 2, compared to the ligands, 1,10-phenathroline (4.755 eV) and chrysin (4.403 eV). Moreover, the molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) were strongly associated with the in vitro biological activity results (E B and K i are -8.35 kcal/mol and 0.76 µM for 1, -7.52 kcal/mol and 3.07 µM for 2, and -6.32 kcal/mol and 23.42 µM for cisplatin). However, more research on in vivo cytotoxicity is suggested to confirm the promising cytotoxicity results.

Bibliometric analysis of cancer research outputs in Botswana between 2009 and 2021.

INTRODUCTION: Cancer research is critical for cancer control policies; however, the state of cancer research activities in Botswana is largely unknown. The goal of this review was to describe trends and patterns of cancer research outputs in Botswana. METHODS: PubMed, Web of Science, EBSCOhost, African Journals Online, and African Index Medicus databases were systematically searched for peer-reviewed, primary cancer-related research articles published on the Botswana population or by Botswana institutions between January 2009 and June 2021. RESULTS: Of the 86 publications included, 39 (45 %) were about cervical cancer, followed by breast cancer (10 %) and Kaposi sarcoma (7 %). The remainder (27 %) were not focused on any specific cancer type. The research activities were skewed towards three main areas of scientific interest: early detection, diagnosis, and prognosis; cancer control, survivorship, and outcomes; and treatment. Botswana was represented by authors in the first (54 %), last (53 %), and any authorship (53 %) positions. The United States of America had the strongest collaborative partnerships with Botswana, followed by the United Kingdom and South Africa. The majority of funding institutions were American (76 %) and the National Institutes of Health was the most mentioned funding organization, accounting for 33 % of all financial acknowledgments. Only 9 % of the funding acknowledgments came from Botswana. CONCLUSION AND POLICY SUMMARY: Although cancer research in Botswana is expanding because of substantial foreign assistance, it is also hampered by a lack of local funding, minimal participation by Botswana-affiliated researchers, and research that is not aligned with disease burden. Our study highlights the need to strengthen local research capacity in Botswana.

Cervical human papillomavirus genotypes in a high HIV setting: A scoping review of a decade of human papillomavirus epidemiological research in Botswana.

Cervical cancer burden is still high in low- and middle-income countries, including Botswana. Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Accurate knowledge of HPV diversity associated to cervical cancer in sub-Saharan Africa may provide accurate understanding of the natural history of HPV infection in these contexts. The goal of this review was to consolidate existing evidence on cervical HPV infection and to conduct a pooled analysis of data from all eligible Botswana studies. After a successful review of twelve studies on cervical HPV genotypes that met the inclusion criteria, HPV-16 genotype was the most frequently discovered in women with pre-cancerous and cancer lesions, followed by HPV-18. HPV-16 in HIV-positive women with precancerous lesions to cancer is between 45% and 47.7%, and between 4.5% and 26.1% for HPV-18. With reference to other HPV genotypes, the proportion of HPV-35 and HPV-58 (13-16%) seems relatively consistent among the studies, however HPV-58 appears to be more common in HIV-positive subjects compared to HIV-negative women. Indeed, HPV-45 seems to be frequently detected in women with cervical cancer compared to women with precancerous lesions. Regarding the low-risk HPV genotypes, an appropriate breakdown has been provided. In conclusion, the current prophylactic vaccines against HPV-16 and HPV-18, which have demonstrated good immunogenicity in HIV-infected populations, may still prevent infection and ultimately cancer.

Cytotoxic mixed-ligand complexes of Cu(II): A combined experimental and computational study.

Herein, we report the synthesis of mixed-ligand Cu(II) complexes of metformin and ciprofloxacin drugs together with 1,10-phenanthroline as a co-ligand. The synthesized complexes were characterized using different spectroscopic and spectrometric techniques. In vitro cytotoxic activity against human breast adenocarcinoma cancer cell line (MCF-7) as well as antibacterial activity against two gram-negative and two gram-positive bacterial strains were also investigated. The analyses of the experimental results were supported using quantum chemical calculations and molecular docking studies against estrogen receptor alpha (ERα; PDB: 5GS4). The cytotoxicity of the [Cu(II) (metformin) (1,10-phenanthroline)] complex (1), with IC50 of 4.29 µM, and the [Cu(II) (ciprofloxacin) (1,10-phenanthroline)] complex (2), with IC50 of 7.58 µM, were found to be more effective than the referenced drug, cisplatin which has IC50 of 18.62 µM against MCF-7 cell line. The molecular docking analysis is also in good agreement with the experimental results, with binding affinities of -7.35, -8.76 and -6.32 kcal/mol, respectively, for complexes 1, 2 and cisplatin against ERα. Moreover, complex 2 showed significant antibacterial activity against E. coli (inhibition diameter zone, IDZ, = 17.3 mm), P. aeruginosa (IDZ = 17.08 mm), and S. pyogen (IDZ = 17.33 mm), at 25 µg/ml compared to ciprofloxacin (IDZ = 20.0, 20.3, and 21.3 mm), respectively. Our BOILED-egg model indicated that the synthesized metal complexes have potentially minimal neurotoxicity than that of cisplatin.

Glucose Concentration in Cell Culture Medium Influences the BRCA1-Mediated Regulation of the Lipogenic Action of IGF-I in Breast Cancer Cells.

Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0-500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.

Elucidating the novel BRCA1 function as a non-genomic metabolic restraint in ER-positive breast cancer cell lines.

Within populations carrying the same genetic predisposition, the penetrance of BRCA1 mutations has increased over time. Although linked to changes in lifestyle factors associated with energy metabolism, these observations cannot be explained by the established role of BRCA1 in DNA repair alone. We manipulated BRCA1 expression using tetracycline in the UBR60-bcl2 cell line (which has an inducible, tetracycline-regulated BRCA1 expression) and siRNA in oestrogen receptor(ER)-positive MCF7 and T47D breast cancer cells. Cellular responses to BRCA1 silencing and IGF-I actions were investigated using western blotting, 3-H Thymidine incorporation assay, cell fractionation and co-immunoprecipitation. We demonstrated that the loss of BRCA1 resulted in downregulation of a phosphorylated and inactive form of acetyl CoA Carboxylase-α (ACCA), with a concomitant increase in fatty acid synthase (FASN) abundance. BRCA1 was predominantly cytoplasmic in ER-positive breast cancer cells, compatible with the observation that BRCA1 physically associates with phosphorylated ACCA, which is a cytoplasmic protein. We also found that IGF-I induced de-phosphorylation of ACCA by reducing the interaction between BRCA1 and phosphorylated ACCA. BRCA1 deficiency enhanced the non-genomic effects of IGF-I, as well as the proliferative responses of cells to IGF-I. We characterized a novel, non-genomic role for BRCA1 in restraining metabolic activity and IGF-I anabolic actions.

Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer.

OBJECTIVES: To investigate the association between PTEN loss and IGFBP2 expression in a series of triple-negative breast cancers and to relate this expression to basal cytokeratin expression and clinicopathologic features. METHODS: One hundred and one formalin-fixed and paraffin-processed triple-negative breast cancer cases from the University of Malaya Medical Centre were tested immunohistochemically for cytokeratins 5/6 and 14, PTEN, and IGFBP2. The resulting slides were scored for proportion and intensity of staining. RESULTS: Loss of tumor nuclear and cytoplasmic staining for PTEN occurred in 48.3% of cases and was significantly associated with younger age at diagnosis (47 years compared with 57 years in those without PTEN loss; P = .005). Independent predictors of PTEN loss were late stage at presentation (P = .026), cytokeratin 5/6 positivity (P = .028), and IGFBP2 expression (P = .042). High levels of IGFBP2 expression were seen in 32% of cases; an independent predictor of high levels was cytokeratin 14 negativity (P = .005). PTEN loss and high levels of IGFBP2 expression were associated with poorer survival, but neither of these trends was significant. CONCLUSIONS: PTEN loss is a frequent event in triple-negative breast cancers and is significantly associated with younger age at onset of breast cancer, late stage, and IGFBP2 expression.