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Special Issue "Cancer and Tuberculosis Drug Discovery: A Theme Issue in Honor of Prof. William A. Denny"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 11508

Special Issue Editors

Prof. Dr. Larry Wakelin
E-Mail Website
Guest Editor
University of New South Wales (UNSW) Australia, Sydney, Australia
Interests: medicinal chemistry; cancer drug discovery; DNA-targeted cytotoxins; DNA–ligand interactions
Prof. Dr. Sandra Gemma
E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: medicinal chemistry; small molecules; drug discovery; structure-activity relationships; anti-infective agents; parasitic diseases; chemotherapeutics; synthesis of biologically active compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Professor William (Bill) Denny was born in Malvern, UK, and has a PhD in organic chemistry from the University of Auckland, New Zealand. In addition to brief periods at Oxford University and at UC San Diego, he has worked at the University of Auckland in the Auckland Cancer Society Research Centre (ACSRC), where he has been Director from 1981 to today. He has mentored 80-plus PhD candidates and post-doctoral scientists in his laboratory and, to date, has published with them 720 scientific papers and more than 130 patent applications.

With the primary goal of developing novel drugs for cancer therapy and infectious diseases, Professor Denny has endeavoured, with colleagues, to develop a group in the ACSRC that covers the necessary skills (computer modelling, medicinal chemistry, pharmacology, cancer and radiation biology, immunology and clinical oncology) for drug design and development. He sought in particular to build commercial collaborations, with both existing pharma companies, and via new start-up companies, out of the ACSRC’s research. He has been a scientific co-founder of Proacta Inc (San Diego), Pathway Therapeutics Ltd (San Francisco) and KEA Therapeutics (Auckland). So far, this has resulted in 18 drugs from the ACSRC being taken to clinical trial.

Professor Denny’s own areas of research have included topoisomerase poisons, DNA-targeted alkylating agents, DNA methyltransferase inhibitors, kinase inhibitors (EGFR, PI3K, CSF1R), and hypoxia-activated prodrugs for cancer therapy and inhibitors of deazaflavin-dependent nitroreductase and ATP synthase for tuberculosis. Professor Denny’s awards include the UK Royal Society of Chemistry’s Lectureship (1999) and Adrien Albert Medal (2005), the University of Auckland Vice-Chancellor’s Commercialisation Medal (2012) and the American Chemical Society Biennial Medicinal Chemistry Award (2014). He is currently an associate editor of the Journal of Medicinal Chemistry (American Chemical Society) and of Anti-Cancer Agents in Medicinal Chemistry (Bentham).

Professor Denny, through his outstanding leadership in the medicinal chemistry of a wide range of classes of cancer drugs, as well as drugs for tuberculosis, and by his skills in chaperoning lead compounds to clinical candidates, has developed the ACSRC into a world-renowned academic centre for drug discovery and development. By his extraordinary efforts, and those of his senior colleagues, he has provided a paradigm for how academic research groups can make a material contribution to the treatment of the most serious human diseases. He is an inspiration to all, and on the occasion of his retirement as ACSRC director, we are pleased to invite you to submit a publication for this Special Issue.

Prof. Larry Wakelin
Prof. Dr. Sandra Gemma
Guest Editors

Manuscript Submission Information

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Keywords

  • DNA-targeted cytotoxins
  • Kinase inhibitors as cancer drugs
  • Hypoxia-activated pro-drugs for cancer therapy
  • Nitroreductase and ATP synthase inhibitors for tuberculosis

Published Papers (9 papers)

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Research

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Article
Impact of the Metal Center and Leaving Group on the Anticancer Activity of Organometallic Complexes of Pyridine-2-carbothioamide
Molecules 2021, 26(4), 833; https://doi.org/10.3390/molecules26040833 - 05 Feb 2021
Cited by 2 | Viewed by 959
Abstract
RuII(cym)Cl (cym = η6-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal [...] Read more.
RuII(cym)Cl (cym = η6-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal center on the anticancer activity and their physicochemical properties, the Os(cym), Rh- and Ir(Cp*) (Cp* = pentamethylcyclopentadienyl) analogues of the most promising and orally active compound plecstatin 2 were prepared and characterized by spectroscopic techniques and X-ray diffraction analysis. Dissolution in aqueous medium results in quick ligand exchange reactions; however, over time no further changes in the 1H NMR spectra were observed. The Rh- and Ir(Cp*) complexes were investigated for their reactions with amino acids, and while they reacted with Cys, no reaction with His was observed. Studies on the in vitro anticancer activity identified the Ru derivatives as the most potent, independent of their halido leaving group, while the Rh derivative was more active than the Ir analogue. This demonstrates that the metal center has a significant impact on the anticancer activity of the compound class. Full article
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Article
Unravelling the Allosteric Targeting of PHGDH at the ACT-Binding Domain with a Photoactivatable Diazirine Probe and Mass Spectrometry Experiments
Molecules 2021, 26(2), 477; https://doi.org/10.3390/molecules26020477 - 18 Jan 2021
Cited by 4 | Viewed by 1238
Abstract
The serine biosynthetic pathway is a key element contributing to tumor proliferation. In recent years, targeting of phosphoglycerate dehydrogenase (PHGDH), the first enzyme of this pathway, intensified and revealed to be a promising strategy to develop new anticancer drugs. Among attractive PHGDH inhibitors [...] Read more.
The serine biosynthetic pathway is a key element contributing to tumor proliferation. In recent years, targeting of phosphoglycerate dehydrogenase (PHGDH), the first enzyme of this pathway, intensified and revealed to be a promising strategy to develop new anticancer drugs. Among attractive PHGDH inhibitors are the α-ketothioamides. In previous work, we have demonstrated their efficacy in the inhibition of PHGDH in vitro and in cellulo. However, the precise site of action of this series, which would help the rational design of new inhibitors, remained undefined. In the present study, the detailed mechanism-of-action of a representative α-ketothioamide inhibitor is reported using several complementary experimental techniques. Strikingly, our work led to the identification of an allosteric site on PHGDH that can be targeted for drug development. Using mass spectrometry experiments and an original α-ketothioamide diazirine-based photoaffinity probe, we identified the 523Q-533F sequence on the ACT regulatory domain of PHGDH as the binding site of α-ketothioamides. Mutagenesis experiments further documented the specificity of our compound at this allosteric site. Our results thus pave the way for the development of new anticancer drugs using a completely novel mechanism-of-action. Full article
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Article
A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells
Molecules 2020, 25(22), 5407; https://doi.org/10.3390/molecules25225407 - 19 Nov 2020
Cited by 4 | Viewed by 1367
Abstract
The stabilisation of G-quadruplexes (G4s) by small-molecule compounds is an effective approach for causing cell growth arrest, followed by cell death. Some of these compounds are currently being developed for the treatment of human cancers. We have previously developed a substituted naphthalene diimide [...] Read more.
The stabilisation of G-quadruplexes (G4s) by small-molecule compounds is an effective approach for causing cell growth arrest, followed by cell death. Some of these compounds are currently being developed for the treatment of human cancers. We have previously developed a substituted naphthalene diimide G4-binding molecule (CM03) with selective potency for pancreatic cancer cells, including gemcitabine-resistant cells. We report here that CM03 and the histone deacetylase (HDAC) inhibitor SAHA (suberanilohydroxamic acid) have synergistic effects at concentrations close to and below their individual GI50 values, in both gemcitabine-sensitive and resistant pancreatic cancer cell lines. Immunoblot analysis showed elevated levels of γ-H2AX and cleaved PARP proteins upon drug combination treatment, indicating increased levels of DNA damage (double-strand break events: DSBs) and apoptosis induction, respectively. We propose that the mechanism of synergy involves SAHA relaxing condensed chromatin, resulting in higher levels of G4 formation. In turn, CM03 can stabilise a greater number of G4s, leading to the downregulation of more G4-containing genes as well as a higher incidence of DSBs due to torsional strain on DNA and chromatin structure. Full article
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Article
Subcellular Location of Tirapazamine Reduction Dramatically Affects Aerobic but Not Anoxic Cytotoxicity
Molecules 2020, 25(21), 4888; https://doi.org/10.3390/molecules25214888 - 22 Oct 2020
Cited by 3 | Viewed by 1268
Abstract
Hypoxia is an adverse prognostic feature of solid cancers that may be overcome with hypoxia-activated prodrugs (HAPs). Tirapazamine (TPZ) is a HAP which has undergone extensive clinical evaluation in this context and stimulated development of optimized analogues. However the subcellular localization of the [...] Read more.
Hypoxia is an adverse prognostic feature of solid cancers that may be overcome with hypoxia-activated prodrugs (HAPs). Tirapazamine (TPZ) is a HAP which has undergone extensive clinical evaluation in this context and stimulated development of optimized analogues. However the subcellular localization of the oxidoreductases responsible for mediating TPZ-dependent DNA damage remains unclear. Some studies conclude only nuclear-localized oxidoreductases can give rise to radical-mediated DNA damage and thus cytotoxicity, whereas others identify a broader role for endoplasmic reticulum and cytosolic oxidoreductases, indicating the subcellular location of TPZ radical formation is not a critical requirement for DNA damage. To explore this question in intact cells we engineered MDA-231 breast cancer cells to express the TPZ reductase human NADPH: cytochrome P450 oxidoreductase (POR) harboring various subcellular localization sequences to guide this flavoenzyme to the nucleus, endoplasmic reticulum, cytosol or inner surface of the plasma membrane. We show that all POR variants are functional, with differences in rates of metabolism reflecting enzyme expression levels rather than intracellular TPZ concentration gradients. Under anoxic conditions, POR expression in all subcellular compartments increased the sensitivity of the cells to TPZ, but with a fall in cytotoxicity per unit of metabolism (termed ‘metabolic efficiency’) when POR is expressed further from the nucleus. However, under aerobic conditions a much larger increase in cytotoxicity was observed when POR was directed to the nucleus, indicating very high metabolic efficiency. Consequently, nuclear metabolism results in collapse of hypoxic selectivity of TPZ, which was further magnified to the point of reversing O2 dependence (oxic > hypoxic sensitivity) by employing a DNA-affinic TPZ analogue. This aerobic hypersensitivity phenotype was partially rescued by cellular copper depletion, suggesting the possible involvement of Fenton-like chemistry in generating short-range effects mediated by the hydroxyl radical. In addition, the data suggest that under aerobic conditions reoxidation strictly limits the TPZ radical diffusion range resulting in site-specific cytotoxicity. Collectively these novel findings challenge the purported role of intra-nuclear reductases in orchestrating the hypoxia selectivity of TPZ. Full article
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Article
Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters
Molecules 2020, 25(12), 2950; https://doi.org/10.3390/molecules25122950 - 26 Jun 2020
Cited by 1 | Viewed by 1486
Abstract
A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of [...] Read more.
A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of these norketamines via the Neber (oxime to α-aminoketone) rearrangement of readily available substituted 2-phenycyclohexanones. We explored the use of the substituents Cl, Me, OMe, CF3, and OCF3, with a wide range of lipophilic and electronic properties, at all available benzene ring positions. The 2- and 3-substituted compounds were generally more active than 4-substituted compounds. The most generally acceptable substituent was Cl, while the powerful electron-withdrawing substituents CF3 and OCF3 provided fewer effective analogues. Full article
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Article
Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria
Molecules 2020, 25(10), 2431; https://doi.org/10.3390/molecules25102431 - 22 May 2020
Cited by 4 | Viewed by 1401
Abstract
The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen [...] Read more.
The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections. Full article
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Review

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Review
Novel DNA Bis-Intercalator XR5944 as a Potent Anticancer Drug—Design and Mechanism of Action
Molecules 2021, 26(14), 4132; https://doi.org/10.3390/molecules26144132 - 07 Jul 2021
Cited by 1 | Viewed by 894
Abstract
This review is dedicated to Professor William A. Denny’s discovery of XR5944 (also known as MLN944). XR5944 is a DNA-targeted agent with exceptionally potent antitumor activity and a novel DNA binding mode, bis-intercalation and major groove binding, as well as a novel mechanism [...] Read more.
This review is dedicated to Professor William A. Denny’s discovery of XR5944 (also known as MLN944). XR5944 is a DNA-targeted agent with exceptionally potent antitumor activity and a novel DNA binding mode, bis-intercalation and major groove binding, as well as a novel mechanism of action, transcription inhibition. This novel anticancer compound represents a remarkable accomplishment resulting from two decades of drug discovery by Professor Denny and coworkers. Here, we review our work on the structural study of the DNA binding mode of XR5944 and mechanistic study of XR5944 action. Full article
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Review
DNA-Binding Anticancer Drugs: One Target, Two Actions
Molecules 2021, 26(3), 552; https://doi.org/10.3390/molecules26030552 - 21 Jan 2021
Cited by 7 | Viewed by 1135
Abstract
Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA [...] Read more.
Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, N-[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs. Full article
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Review
Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases
Molecules 2020, 25(18), 4137; https://doi.org/10.3390/molecules25184137 - 10 Sep 2020
Cited by 4 | Viewed by 1123
Abstract
Nitroimidazole drugs have a long history as therapeutic agents to treat bacterial and parasitic diseases. The discovery in 1989 of a bicyclic nitroimidazole lead, displaying in vitro and in vivo antitubercular activity, spurred intensive exploration of this and related scaffolds, which led to [...] Read more.
Nitroimidazole drugs have a long history as therapeutic agents to treat bacterial and parasitic diseases. The discovery in 1989 of a bicyclic nitroimidazole lead, displaying in vitro and in vivo antitubercular activity, spurred intensive exploration of this and related scaffolds, which led to the regulatory approval of pretomanid and delamanid as a new class of tuberculosis drugs. Much of the discovery work related to this took place over a 20-year period ending in 2010, which is covered in a number of cited reviews. This review highlights subsequent research published over the 2011–August 2020 timeframe, and captures detailed structure–activity relationship studies and synthetic strategies directed towards uncovering newer generation drugs for both tuberculosis and selected neglected tropical diseases. Additionally, this review presents in silico calculations relating to the drug-like properties of lead compounds and clinical agents, as well as chemical development and manufacturing processes toward providing bulk drug supplies. Full article
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