Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1, 3-benzoxazine derivatives
- 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
- 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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- 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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Ruthenium complexes with mono-or bis-heterocyclic chelates: DNA/BSA binding, Antioxidant and Anticancer studies
- Maikoo, Sanam, Chakraborty, Abir, Vukea, Nyeleti, Dingle, Laura M K, Samson, William J, de la Mare, Jo-Anne, Edkins, Adrienne L, Booysen, Irvin N
- 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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- 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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Synthetic, characterization and cytotoxic studies of ruthenium complexes with Schiff bases encompassing biologically relevant moieties:
- Maikoo, Sanam, Dingle, Laura M K, Chakraborty, Abir, Xulu, Bheki, Edkins, Adrienne L, Booysen, Irvin N
- 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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- 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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The in vitro antiplasmodial and antiproliferative activity of new ferrocene-based α-aminocresols targeting hemozoin inhibition and DNA interaction:
- 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
- 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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- 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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Use of a non-hepatic cell line highlights limitations associated with cell-based assessment of metabolically induced toxicity:
- Weyers, Carli, Dingle, Laura M K, Wilhelmi, Brendan S, Edkins, Adrienne L, Veale, Clinton G L
- 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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- 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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