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Reaction of Perrhenate with Phthalocyanine Derivatives in the Presence of Reducing Agents and Rhenium Oxide Nanoparticles in Biomedical Applications

  • Authors: Ntsimango, Songeziwe , Gandidzanwa, Sendibitiyosi , Joseph, Sinelizwi V , Hosten, Eric C , Randall, Marvin , Edkins, Adrienne L , Khene, Samson M , Mashazi, Philani N , Nyokong, Tebello , Abrahams, Abubak’r , Tshentu, Zenixole R
  • Date: 2022
  • Subjects: To be catalogued
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/300257 , vital:57910 , xlink:href="https://doi.org/10.1002/open.202200037"
  • Description: A novel alternative route to access rhenium(V)−phthalocyanine complexes through direct metalation of metal-free phthalocyanines (H2Pcs) with a rhenium(VII) salt in the presence of various two-electron reducing agents is presented. Direct ion metalation of tetraamino- or tetranitrophthalocyanine with perrhenate (ReO4−) in the presence of triphenylphosphine led to oxidative decomposition of the H2Pcs, giving their respective phthalonitriles. Conversely, treatment of H2Pcs with ReO4− employing sodium metabisulfite yielded the desired ReVO−Pc complex. Finally, reaction of H2Pcs with ReO4− and NaBH4 as reducing agent led to the formation of rhenium oxide (RexOy) nanoparticles (NPs). The NP synthesis was optimised, and the RexOy NPs were capped with folic acid (FA) conjugated with tetraaminophthalocyanine (TAPc) to enhance their cancer cell targeting ability. The cytotoxicity profile of the resultant RexOy−TAPc−FA NPs was assessed and found to be greater than 80 % viability in four cell lines, namely, MDA−MB-231, HCC7, HCC1806 and HEK293T. Non-cytotoxic concentrations were determined and employed in cancer cell localization studies. The particle size effect on localization of NPs was also investigated using confocal fluorescence and transmission electron microscopy. The smaller NPs (≈10 nm) were found to exhibit stronger fluorescence properties than the ≈50 nm NPs and exhibited better cell localization ability than the ≈50 nm NPs.
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  • Date Issued: 2022

Contributions of the pars lateralis, pars basilaris and femur to age estimations of the immature skeleton within a South African forensic setting:

  • Authors: Thornton, Roxanne , Edkins, Adrienne L , Hutchinson, E F
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165451 , vital:41245 , https://0-doi.org.wam.seals.ac.za/10.1007/s00414-019-02143-9
  • Description: Dental development and eruption sequences have prevailed as the gold standard in age estimations of previously unidentified immature individuals within a legal context. However, in the absence of the dentition, skeletal assessments have served as a frequently applied alternative. While various cranial and postcranial skeletal elements have been used in estimating age of the immature skeleton, little is known about the anthropometric value of the pars basilaris, pars lateralis and femur as skeletal age estimation tools. Thus, this study aimed to assess if these bones of the immature human skeleton were useful elements in estimating the age of prenatal and postnatal individuals. These bones were excised from the remains of 74 unclaimed human immature individuals and evaluated using traditional anthropometric methods. The study sample was sourced from the Johannesburg Forensic Pathology Services (JFPS) and the Johannesburg Forensic Paediatric Collection (JFPC), University of the Witwatersrand and subdivided into an early prenatal (younger than 30 gestational weeks); late prenatal (30 to 40 gestational weeks) and postnatal (birth to 7.5 months) age ranges.
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  • Date Issued: 2020

Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay:

  • Authors: Swart, Tarryn , Khan, Farrah D , Ntlantsana, Apelele , Laming, Dustin , Veale, Clinton G L , Przyborski, Jude M , Edkins, Adrienne L , Hoppe, Heinrich C
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165418 , vital:41242 , https://0-doi.org.wam.seals.ac.za/10.1038/s41598-020-61101-3
  • Description: The regulation of human Arf1 GTPase activity by ArfGEFs that stimulate GDP/GTP exchange and ArfGAPs that mediate GTP hydrolysis has attracted attention for the discovery of Arf1 inhibitors as potential anti-cancer agents. The malaria parasite Plasmodium falciparum encodes a Sec7 domain-containing protein - presumably an ArfGEF - and two putative ArfGAPs, as well as an Arf1 homologue (PfArf1) that is essential for blood-stage parasite viability. However, ArfGEF and ArfGAP-mediated activation/deactivation of PfArf1 has not been demonstrated.
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  • Date Issued: 2020

Hop depletion reduces HSF1 levels and activity and coincides with reduced stress resilience:

  • Authors: Chakraborty, Abantika , Edkins, Adrienne L
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165440 , vital:41244 , https://doi.org/10.1016/j.bbrc.2020.04.072
  • Description: Heat-shock factor 1 (HSF1) regulates the transcriptional response to stress and controls expression of molecular chaperones required for cell survival. Here we report that HSF1 is regulated by the abundance of the Hsp70-Hsp90 organizing protein (Hop/STIP1).
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  • Date Issued: 2020

HSP90 interacts with the fibronectin N-terminal domains and increases matrix formation:

  • Authors: Chakraborty, Abir , Boel, Natasha M-E , Edkins, Adrienne L
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165407 , vital:41241 , https://doi.org/10.3390/cells9020272
  • Description: Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly.
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  • Date Issued: 2020

Regulation of Kaposi’s Sarcoma-Associated Herpesvirus Biology by Host Molecular Chaperones:

  • Authors: Kirigin, Elisa , Ruck, Duncan Kyle , Jackson, Zoe , Murphy, James , McDonnell, Euan , Okpara, Michael O , Whitehouse, Adrian , Edkins, Adrienne L
  • Date: 2020
  • Language: English
  • Type: text , book
  • Identifier: http://hdl.handle.net/10962/165385 , vital:41239 , ISBN , https://0-doi.org.wam.seals.ac.za/10.1007/7515_2020_18
  • Description: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with development of the human diseases Kaposi’s sarcoma, Primary Effusion Lymphoma and Multicentric Castleman’s Disease. KSHV establishes a chronic latent infection in hosts, with periods of viral lytic replication, where both latent and lytic virus cycles contribute to malignancy, most often in the immunodeficient host.
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  • Date Issued: 2020

Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1, 3-benzoxazine derivatives

  • Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
  • Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
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  • Date Issued: 2020

Ruthenium complexes with mono-or bis-heterocyclic chelates: DNA/BSA binding, Antioxidant and Anticancer studies

  • Authors: Maikoo, Sanam , Chakraborty, Abir , Vukea, Nyeleti , Dingle, Laura M K , Samson, William J , de la Mare, Jo-Anne , Edkins, Adrienne L , Booysen, Irvin N
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165463 , vital:41246 , DOI: 10.1080/07391102.2020.1775126
  • Description: Deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) binding interactions for a series of ruthenium heterocyclic complexes were monitored using ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence emission spectroscopy and agarose gel electrophoresis. Investigations of the DNA interactions for the metal complexes revealed that they are groove-binders with intrinsic binding constants in the order of 104 – 107 M−1.
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  • Date Issued: 2020

STIP1/HOP regulates the actin cytoskeleton through interactions with actin and changes in actin-binding proteins cofilin and profilin:

  • Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
  • Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
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  • Date Issued: 2020

Synthetic, characterization and cytotoxic studies of ruthenium complexes with Schiff bases encompassing biologically relevant moieties:

  • Authors: Maikoo, Sanam , Dingle, Laura M K , Chakraborty, Abir , Xulu, Bheki , Edkins, Adrienne L , Booysen, Irvin N
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165429 , vital:41243 , https://doi.org/10.1016/j.poly.2020.114569
  • Description: This research study describes the formation and characterization of novel paramagnetic ruthenium complexes, cis-Cl, trans-P-[RuIIICl2(carboim)(PPh3)2] with bidentate chelating carbohydrazide Schiff bases (carboim = bpc for 1, ttc for 2 and tpc for 3). These metal complexes were synthesized by the equimolar coordination reactions of trans-[RuCl2(PPh3)2] with N-[1,3-benzothiazole-2-ylmethylidene]pyridine-2-carbohydrazide (Hbpc), N-((uracil-5-yl)methylene)thiophene-2-carbohydrazide (Httc) and N-[(uracil-5-yl)methylidene]pyridine-2-carbohydrazide (Htpc), respectively. Physicochemical techniques including nuclear magnetic resonance-, electron-spin resonance- and infrared spectroscopy, UV–Vis spectrophotometry, voltammetry as well as molar conductivity measurements provided definitive determinations of the respective ruthenium compounds’ structures.
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  • Date Issued: 2020

The in vitro antiplasmodial and antiproliferative activity of new ferrocene-based α-aminocresols targeting hemozoin inhibition and DNA interaction:

  • Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
  • Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
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  • Date Issued: 2020

Use of a non-hepatic cell line highlights limitations associated with cell-based assessment of metabolically induced toxicity:

  • Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
  • Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
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  • Date Issued: 2020

Anticancer evaluation of ruthenium (III) complexes with N-donor ligands tethered to coumarin or uracil moieties:

  • Authors: Gramni, Larusha , Vukea, Nyeleti , Chakraborty, Abir , Samson, William J , Dingle, Laura M K , Xulu, Bheki , de la Mare, Jo-Anne , Edkins, Adrienne L , Booysen, Irvin N
  • Date: 2019
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/163477 , vital:41041 , DOI: 10.1016/j.ica.2019.04.01
  • Description: In this study, the synthesis and characterization of new paramagnetic ruthenium(III) complexes: cis-[RuCl2(urdpa)] (1) {Hurdpa = 6-((bis(pyridin-2-ylmethyl)amino)methyl)uracil} and fac-[RuCl3(chrdpa)] (2) {chrdpa = 4-((bis(pyridin-2-ylmethyl)amino)methyl)-7-methoxycoumarin} are reported. These metal complexes have been comprehensively characterized by an array of physicochemical techniques and the X-ray solid-state structures of 1 and Hurdpa have been attained.
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  • Date Issued: 2019

In vitro and in vivo toxicity assessment of biologically synthesized silver nanoparticles from Elaeodendron croceum:

  • Authors: Odeyemi, S W , de la Mare, Jo-Anne , Edkins, Adrienne L , Afolayan, A J
  • Date: 2019
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/163488 , vital:41042 , DOI: 10.1515/jcim-2018-0184
  • Description: The cytotoxic properties of nanoparticles have attracted a great deal of attention in the field of nanoscience and nanotechnology due to their small size and ability to penetrate cellular membranes.
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  • Date Issued: 2019

Plaxenone A and B: Cytotoxic halogenated monoterpenes from the South African red seaweed Plocamium maxillosum

  • Authors: Knott, Michael G , de la Mare, Jo-Anne , Edkins, Adrienne L , Zhang, Angel , Stillman, Martin J , Bolton, John J , Antunes, Edith M , Beukes, Denzil R
  • Date: 2019
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/164446 , vital:41119 , https://doi.org/10.1016/j.phytol.2018.12.009
  • Description: The endemic South African red seaweed Plocamium maxillosum (Poiret) Lamouroux produces two unusual isomeric dichlorinated cyclohexenone monoterpenes, plaxenone A and B (1 and 2). The structures of the isolated compounds were determined from spectroscopic data and their absolute configuration was determined by comparison of the experimental and calculated ECD spectra. Compounds 1 and 2 inhibit the growth of MDA-MB-231 breast cancer cells.
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  • Date Issued: 2019

Semi-synthesis and evaluation of sargahydroquinoic acid derivatives as potential antimalarial agents:

  • Authors: Munedzimwe, Tatenda C , van Zyl, Rovyn L , Heslop, Donovan C , Edkins, Adrienne L , Beukes, Denzil R
  • Date: 2019
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/163456 , vital:41040 , DOI: 10.3390/medicines6020047
  • Description: Malaria continues to present a major health problem, especially in developing countries. The development of new antimalarial drugs to counter drug resistance and ensure a steady supply of new treatment options is therefore an important area of research. Meroditerpenes have previously been shown to exhibit antiplasmodial activity against a chloroquinone sensitive strain of Plasmodium falciparum (D10). In this study we explored the antiplasmodial activity of several semi-synthetic analogs of sargahydroquinoic acid.
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  • Date Issued: 2019

Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers:

  • Authors: Lunga, Mayibongwe J , Chisango, Ruramai L , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/164389 , vital:41114 , DOI: 10.1002/cmdc.201800235
  • Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain.
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  • Date Issued: 2018

Heterodimer formation by Oct4 and Smad3 differentially regulates epithelial-to-mesenchymal transition-associated factors in breast cancer progression:

HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature

  • Authors: Mattison, Stacey A , Blatch, Gregory L , Edkins, Adrienne L
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66278 , vital:28928 , https://doi.org/10.1007/s12192-016-0755-8
  • Description: publisher version , The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation.
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  • Date Issued: 2018

Hop/STIP1 depletion alters nuclear structure via depletion of nuclear structural protein emerin:

  • Authors: Kituyi, Sarah N , Edkins, Adrienne L
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/164435 , vital:41118 , https://doi.org/10.1016/j.bbrc.2018.11.073
  • Description: Hop/STIP1 is a co-chaperone of Hsp70 and Hsp90 that regulates a number of cell biology processes via interactions with cellular proteins. Here we report a new relationship between Hop and the nuclear structural protein emerin in maintenance of nuclear morphology. Depletion or overexpression of Hop resulted in the reduction of emerin protein levels via proteasomal and lysosomal pathways.
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  • Date Issued: 2018
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