Publications by authors named "William A Denny"

218 Publications

Inhibitors of FF-ATP synthase enzymes for the treatment of tuberculosis and cancer.

Authors:
William A Denny

Future Med Chem 2021 May 13;13(10):911-926. Epub 2021 Apr 13.

Auckland Cancer Society Research Centre, School of Medical Sciences, Private Bag 92019, Auckland, 1142, New Zealand.

The spectacular success of the mycobacterial FF-ATP synthase inhibitor bedaquiline for the treatment of drug-resistant tuberculosis has generated wide interest in the development of other inhibitors of this enzyme. Work in this realm has included close analogues of bedaquiline with better safety profiles and 'bedaquiline-like' compounds, some of which show potent antibacterial activity although none have yet progressed to clinical trials. The search has lately extended to a range of new scaffolds as potential inhibitors, including squaramides, diaminoquinazolines, chloroquinolines, dihydropyrazolo[1,5-a]pyrazin-4-ones, thiazolidinediones, diaminopyrimidines and tetrahydroquinolines. Because of the ubiquitous expression of ATP synthase enzymes, there has also been interest in inhibitors of other bacterial ATP synthases, as well as inhibitors of human mitochondrial ATP synthase for cancer therapy. The latter encompass both complex natural products and simpler small molecules. The review seeks to demonstrate the breadth of the structural types of molecules able to effectively inhibit the function of variants of this intriguing enzyme.
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http://dx.doi.org/10.4155/fmc-2021-0010DOI Listing
May 2021

Novel Linker Variants of Antileishmanial/Antitubercular 7-Substituted 2-Nitroimidazooxazines Offer Enhanced Solubility.

ACS Med Chem Lett 2021 Feb 21;12(2):275-281. Epub 2021 Jan 21.

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Antitubercular 7-substituted 2-nitroimidazo[2,1-][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated and but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that -carbamate offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).
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http://dx.doi.org/10.1021/acsmedchemlett.0c00649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883471PMC
February 2021

Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal.

Eur J Med Chem 2021 Jan 10;209:112914. Epub 2020 Oct 10.

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112914DOI Listing
January 2021

Small-molecule CSF1R kinase inhibitors; review of patents 2015-present.

Expert Opin Ther Pat 2021 Feb 28;31(2):107-117. Epub 2020 Oct 28.

Auckland Cancer Society Research Centre, School of Medical Sciences and Maurice Wilkins Centre, University of Auckland , Auckland, New Zealand.

Introduction: Colony stimulating factor 1 receptor (CSF-1R, also known as c-FMS kinase) is in the class III receptor tyrosine kinase family, along with c-Kit, Flt3 and PDGFRα. CSF-1/CSF-1R signaling promotes the differentiation and survival of myeloid progenitors into populations of monocytes, macrophages, dendritic cells and osteoclasts, as well as microglial cells and also recruits host macrophages to develop into tumor-associated macrophages (TAMs), which promote tumor progression and metastasis.

Areas Covered: In the last 5 years, and recently stimulated by the approval of pexidartinib (Turalio™, Daiichi Sankyo) in 2019 for the treatment of tenosynovial giant cell tumors, there has been a large increase in activity (both journal articles and patent applications) around small molecule inhibitors of CSF1R. Features of this work have been the surprising diversity of chemical classes shown to be potent and selective inhibitors, and the breadth of disease states (cancer, arthritis, and 'cytokine storm' syndromes) covered by CSF1R inhibitors. All these aspects are covered in the following sections.

Expert Opinion: The field has developed rapidly from 2014 to the present, with many different chemotypes proving to be potent inhibitors. The range of potential utilities of CSF1R inhibitors has also expanded to include dementia, ulcerative colitis/Crohn's disease, rheumatoid arthritis inflammation, and fibrosis.
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http://dx.doi.org/10.1080/13543776.2021.1839414DOI Listing
February 2021

Subcellular Location of Tirapazamine Reduction Dramatically Affects Aerobic but Not Anoxic Cytotoxicity.

Molecules 2020 Oct 22;25(21). Epub 2020 Oct 22.

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

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 O 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.
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http://dx.doi.org/10.3390/molecules25214888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660101PMC
October 2020

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy.

Eur J Med Chem 2020 Dec 18;207:112849. Epub 2020 Sep 18.

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.
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http://dx.doi.org/10.1016/j.ejmech.2020.112849DOI Listing
December 2020

Synthesis and structure-activity relationships for tetrahydroisoquinoline-based inhibitors of Mycobacterium tuberculosis.

Bioorg Med Chem 2020 11 24;28(22):115784. Epub 2020 Sep 24.

Auckland Cancer Society Research Centre, School of Medical Sciences, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

A series of 5,8-disubstituted tetrahydroisoquinolines were shown to be effective inhibitors of M. tb in culture and modest inhibitors of M. tb ATP synthase. There was a broad general trend of improved potency with higher lipophilicity. Large substituents (e.g., Bn) at the tetrahydroquinoline 5-position were well-tolerated, while N-methylpiperazine was the preferred 8-substituent. Structure-activity relationships for 7-linked side chains showed that the nature of the 7-linking group was important; -CO- and -COCH- linkers were less effective than -CH- or -CONH- ones. This suggests that the positioning of a terminal aromatic ring is important for target binding. Selected compounds showed much faster rates of microsomal clearance than did the clinical ATP synthase inhibitor bedaquiline, and modest inhibition of mycobacterial ATP synthase.
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http://dx.doi.org/10.1016/j.bmc.2020.115784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721589PMC
November 2020

Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters.

Molecules 2020 Jun 26;25(12). Epub 2020 Jun 26.

Auckland Cancer Society Research Centre, School of Medical Sciences, Auckland 1142, New Zealand.

A series of benzene ring substituted ketamine -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, CF, and OCF, 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 CF and OCF provided fewer effective analogues.
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http://dx.doi.org/10.3390/molecules25122950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356787PMC
June 2020

Heptamethine Cyanine Dye Mediated Drug Delivery: Hype or Hope.

Bioconjug Chem 2020 07 24;31(7):1724-1739. Epub 2020 Jun 24.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

This review covers the application of heptamethine cyanine dye (HMCD) mediated drug delivery. A relatively small number of HMCDs possess tumor targeting abilities, and this has spurred interest from research groups to explore them as drug delivery systems. Their tumor selectivity is primarily attributed to their uptake by certain isoforms of organic anion transporting polypeptides (OATPs) which are overexpressed in cancer tissues, although there are other possible mechanisms for the observed selectivity still under investigation. This specificity is confirmed using various cancer cell lines and is accompanied by moderate cytotoxicity. Their retention in tumor tissue is facilitated by the formation of albumin adducts as revealed by published mechanistic studies. HMCDs are also organelle selective dyes with specificity toward mitochondria and lysosomes, and with absorption and emission in the near-infrared region. This makes them valuable tools for biomedical imaging, especially in the field of fluorescence-guided tumor surgery. Furthermore, conjugating antitumor agents to HMCDs is providing novel drugs that await clinical testing. HMCD development as theranostic agents with dual tumor targeting and treatment capability signals a new approach to overcome drug resistance (mediated through evasion of efflux pumps) and systemic toxicity, the two parameters which have long plagued drug discovery.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00302DOI Listing
July 2020

PARP inhibitor cyanine dye conjugate with enhanced cytotoxic and antiproliferative activity in patient derived glioblastoma cell lines.

Bioorg Med Chem Lett 2020 07 8;30(14):127252. Epub 2020 May 8.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address:

We describe the synthesis and in vitro activity of drug-dye conjugate 1, which is a combination of the PARP inhibitor rucaparib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed strong cytotoxic activity with nanomolar potency (EC: 128 nM), which was a 780 fold improvement over rucaparib itself. We also observe a synergistic effect of 1 with temozolomide (TMZ), the standard drug for treatment for glioblastoma even though these cell lines were resistant to TMZ treatment. We envisage such conjugates to be worth exploring for their utility in the treatment of various brain cancers.
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http://dx.doi.org/10.1016/j.bmcl.2020.127252DOI Listing
July 2020

Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria.

Molecules 2020 May 22;25(10). Epub 2020 May 22.

TenNor Therapeutics Limited, 218 Xinghu Street, Building B2, Suite 711, Suzhou Industrial Park, Suzhou 215123, China.

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) (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.
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http://dx.doi.org/10.3390/molecules25102431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288012PMC
May 2020

Structures and dynamics of DNA complexes of the desmethyl analog of the cytotoxin MLN944: Insights into activity when a methyl isn't futile.

J Mol Recognit 2020 08 6;33(8):e2843. Epub 2020 Apr 6.

Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.

Structure activity relationships for tricyclic-carboxamide topoisomerase II poisons indicate that cytotoxicity is enhanced by the presence of methyl, and other, groups in the position peri to the carboxamide. Linked dimers of phenazine-1-carboxamides are potent cytotoxins and one phenazine dimer, MLN944 (alternatively XR5944), has been in clinical trial. MLN944 is a template inhibitor of transcription, whereas corresponding monomers are not. Nevertheless, its cytotoxic potency is also diminished by removal of its peri methyl groups. Here, we describe NMR and molecular dynamic studies of the interaction of desmethyl MLN944 with d(ATGCAT) , d(TATGCATA) , and d(TACGCGTA) to investigate the influence of the nine-methyl group on the structure of MLN944 complexes. As with MLN944, the carboxamide group hydrogen bonds to the phenazine ring nitrogen, the ligand sandwiches the central GC base pairs in the major groove, and the protonated linker amines hydrogen bond primarily to the O6 atom of the guanines. Molecular dynamics studies reveal that the linker exists in multiple conformations, none of which produce an ideal set of hydrogen bonds. In distinction, however, the carboxamide-to-phenazine ring nitrogen hydrogen bond is weaker, the overall helix winding is less and the NMR resonances are broader in the desmethyl complexes. Exchange between free and complexed DNA, quantified using two-dimensional NOESY spectra, is faster for the desmethyl MLN944 complexes than for MLN944 complexes. Overall, the data suggest that desmethyl MLN944 DNA complexes are "looser" and more unwound at the binding site, leading to faster dissociation rates, which could account for the diminished efficacy of the desmethyl analog.
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http://dx.doi.org/10.1002/jmr.2843DOI Listing
August 2020

Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876-A Less Toxic and More Potent Analogue of Bedaquiline.

Molecules 2020 Mar 20;25(6). Epub 2020 Mar 20.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
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http://dx.doi.org/10.3390/molecules25061423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144385PMC
March 2020

A new selective pharmacological enhancer of the Orai1 Ca channel reveals roles for Orai1 in smooth and skeletal muscle functions.

ACS Pharmacol Transl Sci 2020 Feb 13;3(1):135-147. Epub 2020 Jan 13.

School of Pharmacy, The University of Queensland, Brisbane 4072, Queensland, Australia.

Store operated calcium (Ca) entry is an important homeostatic mechanism in cells, whereby the release of Ca from intracellular endoplasmic reticulum stores triggers the activation of a Ca influx pathway. Mediated by Orai1, this Ca influx has specific and essential roles in biological processes as diverse as lactation to immunity. Although pharmacological inhibitors of this Ca influx mechanism have helped to define the role of store operated Ca entry in many cellular events, the lack of isoform specific modulators and activators of Orai1 has limited our full understanding of these processes. Here we report the identification and synthesis of an Orai1 activity enhancer that concurrently potentiated Orai1 Ca -dependent inactivation (CDI). This unique enhancer of Orai1 had only a modest effect on Orai3 with weak inhibitory effects at high concentrations in intact MCF-7 breast cancer cells. The Orai1 enhancer heightened vascular smooth muscle cell migration induced by platelet-derived growth factor and the unique store operated Ca entry pathway present in skeletal muscle cells. These studies show that IA65 is an exemplar for the translation and development of Orai isoform selective agents. The ability of IA65 to activate CDI demonstrates that agents can be developed that can enhance Orai1-mediated Ca influx but avoid the cytotoxicity associated with sustained Orai1 activation. IA65 and/or future analogues with similar Orai1 and CDI activating properties could be fine tuners of physiological processes important in specific disease states, such as cellular migration and immune cell function.
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http://dx.doi.org/10.1021/acsptsci.9b00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079732PMC
February 2020

Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology.

Bioorg Med Chem 2020 01 26;28(1):115213. Epub 2019 Nov 26.

Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.
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http://dx.doi.org/10.1016/j.bmc.2019.115213DOI Listing
January 2020

Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo.

J Med Chem 2020 03 26;63(5):2229-2239. Epub 2019 Sep 26.

QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia.

Perforin is a key effector protein in the vertebrate immune system and is secreted by cytotoxic T lymphocytes and natural killer cells to help eliminate virus-infected and transformed target cells. The ability to modulate perforin activity in vivo could be extremely useful, especially in the context of bone marrow stem cell transplantation where early rejection of immunologically mismatched grafts is driven by the recipient's natural killer cells, which overwhelmingly use perforin to kill their targets. Bone marrow stem cell transplantation is a potentially curative treatment for both malignant and nonmalignant disorders, but when the body recognizes the graft as foreign, it is rejected by this process, often with fatal consequences. Here we report optimization of a previously identified series of benzenesulfonamide-based perforin inhibitors for their physicochemical and pharmacokinetic properties, resulting in the identification of , the first reported small molecule able to prevent rejection of transplanted bone marrow stem cells in vivo by blocking perforin function.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00881DOI Listing
March 2020

Cyclic Tetrapeptides from Nature and Design: A Review of Synthetic Methodologies, Structure, and Function.

Chem Rev 2019 09 16;119(17):10318-10359. Epub 2019 Aug 16.

Division of Organic Chemistry , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411 008 , India.

Small cyclic peptides possess a wide range of biological properties and unique structures that make them attractive to scientists working in a range of areas from medicinal to materials chemistry. However, cyclic tetrapeptides (CTPs), which are important members of this family, are notoriously difficult to synthesize. Various synthetic methodologies have been developed that enable access to natural product CTPs and their rationally designed synthetic analogues having novel molecular structures. These methodologies include the use of reversible protecting groups such as pseudoprolines that restrict conformational freedom, ring contraction strategies, on-resin cyclization approaches, and optimization of coupling reagents and reaction conditions such as temperature and dilution factors. Several fundamental studies have documented the impacts of amino acid configurations, -alkylation, and steric bulk on both synthetic success and ensuing conformations. Carefully executed retrosynthetic ring dissection and the unique structural features of the linear precursor sequences that result from the ring dissection are crucial for the success of the cyclization step. Other factors that influence the outcome of the cyclization step include reaction temperature, solvent, reagents used as well as dilution levels. The purpose of this review is to highlight the current state of affairs on naturally occurring and rationally designed cyclic tetrapeptides, including strategies investigated for their syntheses in the literature, the conformations adopted by these molecules, and specific examples of their function. Using selected examples from the literature, an in-depth discussion of the synthetic techniques and reaction parameters applied for the successful syntheses of 12-, 13-, and 14-membered natural product CTPs and their novel analogues are presented, with particular focus on the cyclization step. Selected examples of the three-dimensional structures of cyclic tetrapeptides studied by NMR, and X-ray crystallography are also included.
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http://dx.doi.org/10.1021/acs.chemrev.8b00737DOI Listing
September 2019

The synthesis of a novel Crizotinib heptamethine cyanine dye conjugate that potentiates the cytostatic and cytotoxic effects of Crizotinib in patient-derived glioblastoma cell lines.

Bioorg Med Chem Lett 2019 09 29;29(18):2617-2621. Epub 2019 Jul 29.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

We describe the synthesis of drug-dye conjugate 1 between anaplastic lymphoma kinase inhibitor Crizotinib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed potent cytotoxic activity with nanomolar potency (EC: 50.9 nM). We also demonstrate evidence for antiproliferative activity of 1 with single digit nanomolar potency (IC: 4.7 nM). Furthermore, the cytotoxic effects conveyed a dramatic, 110-fold improvement over Crizotinib. This improvement was even more pronounced (492-fold) when 1 was combined with Temozolomide, the standard drug for treatment for glioblastoma. This work lays the foundation for future exploration of similar tyrosine kinase inhibitor drug-dye conjugates for the treatment of glioblastoma.
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http://dx.doi.org/10.1016/j.bmcl.2019.07.051DOI Listing
September 2019

Transcriptional changes in response to ketamine ester-analogs SN 35210 and SN 35563 in the rat brain.

BMC Genomics 2019 Apr 11;20(1):281. Epub 2019 Apr 11.

Waikato District Health Board, Pembroke Street, Hamilton, 3204, New Zealand.

Background: Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared across four relevant target regions of the rat brain.

Results: SN 35563 produced large-scale alteration of gene expression in the Basolateral Amygdala (BLA) and Paraventricular Nucleus of the Thalamus (PVT), in excess of 10x that induced by ketamine and SN 35210. A smaller and quantitatively similar number of gene changes were observed in the Insula (INS) and Nucleus Accumbens (ACB) for all three agents. In the BLA and PVT, SN 35563 caused enrichment for gene pathways related to the function and structure of glutamatergic synapses in respect to: release of neurotransmitter, configuration of postsynaptic AMPA receptors, and the underlying cytoskeletal scaffolding and alignment.

Conclusion: The analgesic ketamine ester analog SN 35563 induces profound large-scale changes in gene expression in key pain-related brain regions reflecting its unique prolonged pharmacodynamic profile.
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http://dx.doi.org/10.1186/s12864-019-5649-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458767PMC
April 2019

Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474.

Bioorg Med Chem 2019 04 25;27(8):1529-1545. Epub 2019 Feb 25.

Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address:

Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.
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http://dx.doi.org/10.1016/j.bmc.2019.02.050DOI Listing
April 2019

3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel.

Bioorg Med Chem 2019 04 15;27(7):1292-1307. Epub 2019 Feb 15.

Auckland Cancer Society Research Centre, School of Medical Sciences, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
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http://dx.doi.org/10.1016/j.bmc.2019.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467547PMC
April 2019

Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain.

Bioorg Med Chem 2019 04 5;27(7):1226-1231. Epub 2019 Feb 5.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, New Zealand.

N-Aliphatic ester analogues of the non-opioid ketamine (1) retain effective anaesthetic/analgesic properties while minimising ketamine's psychomimetic side-effects. We show that the anaesthetic/analgesic properties of these ester analogues depend critically on the length (from 2 to 4 carbons), polarity and steric cross-section of the aliphatic linker chain. More stable amide and ethylsulfone analogues generally showed weaker anaesthetic/analgesic activity. There was no correlation between the anaesthetic/analgesic properties of the compounds and their binding affinities for the N-methyl-d-aspartate (NMDA) receptor.
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http://dx.doi.org/10.1016/j.bmc.2019.02.010DOI Listing
April 2019

Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline.

Bioorg Med Chem 2019 04 15;27(7):1283-1291. Epub 2019 Feb 15.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.
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http://dx.doi.org/10.1016/j.bmc.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467542PMC
April 2019

Synthesis and Evaluation of Imidazo[1,2-a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3-Kinase Inhibitors.

Chem Asian J 2019 Apr 12;14(8):1249-1261. Epub 2019 Mar 12.

Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.
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http://dx.doi.org/10.1002/asia.201801762DOI Listing
April 2019

Synthesis and Microtubule-Destabilizing Activity of N-Cyclopropyl-4-((3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzamide and its Analogs.

Chem Asian J 2019 Apr 14;14(8):1151-1157. Epub 2018 Nov 14.

School of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington, 6140, New Zealand.

While clinically useful, microtubule-targeting agents are limited by factors that include their susceptibility to multidrug resistance. A series of aryl sulfonamides, terminally substituted with an amide or carboxylic acid, was synthesized and assayed for biological activity in two human cancer cell lines. The resulting antiproliferative activity data demonstrated that an amide was superior to a carboxylic acid in the para position. The most potent compound (3) had an IC for growth inhibition in the low micromolar range, caused cells to accumulate in G M of the cell cycle, and led to depolymerization of microtubules. It was also not susceptible to the P-glycoprotein drug efflux pump that underpins the resistance of cells to long-term drug treatment schedules.
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http://dx.doi.org/10.1002/asia.201801313DOI Listing
April 2019

An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay.

Bioorg Med Chem 2018 07 9;26(12):3406-3413. Epub 2018 May 9.

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address:

The proteins Orai1 and STIM1 control store-operated Ca entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
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http://dx.doi.org/10.1016/j.bmc.2018.05.012DOI Listing
July 2018

A mitochondria-selective near-infrared-emitting fluorescent dye for cellular imaging studies.

Bioorg Med Chem Lett 2018 06 3;28(11):2013-2017. Epub 2018 May 3.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address:

This communication details the synthesis, evaluation of photophysical properties, and cellular imaging studies of cyanine chromophore based fluorescent dye 1 as a selective imaging agent for mitochondria.
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http://dx.doi.org/10.1016/j.bmcl.2018.05.001DOI Listing
June 2018

Inhibition of strigolactone receptors by -phenylanthranilic acid derivatives: Structural and functional insights.

J Biol Chem 2018 04 9;293(17):6530-6543. Epub 2018 Mar 9.

From the New Zealand Institute for Plant and Food Research Limited, Private Bag 92169, Auckland 1142, New Zealand,

The strigolactone (SL) family of plant hormones regulates a broad range of physiological processes affecting plant growth and development and also plays essential roles in controlling interactions with parasitic weeds and symbiotic fungi. Recent progress elucidating details of SL biosynthesis, signaling, and transport offers many opportunities for discovering new plant-growth regulators via chemical interference. Here, using high-throughput screening and downstream biochemical assays, we identified -phenylanthranilic acid derivatives as potent inhibitors of the SL receptors from petunia (DAD2), rice (OsD14), and (AtD14). Crystal structures of DAD2 and OsD14 in complex with inhibitors further provided detailed insights into the inhibition mechanism, and modeling of 19 other plant strigolactone receptors suggested that these compounds are active across a large range of plant species. Altogether, these results provide chemical tools for investigating SL signaling and further define a framework for structure-based approaches to design and validate optimized inhibitors of SL receptors for specific plant targets.
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http://dx.doi.org/10.1074/jbc.RA117.001154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925799PMC
April 2018

Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles.

Bioorg Med Chem 2018 05 20;26(8):1797-1809. Epub 2018 Feb 20.

Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MICs) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.
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http://dx.doi.org/10.1016/j.bmc.2018.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933462PMC
May 2018

Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.

J Med Chem 2018 03 6;61(6):2329-2352. Epub 2018 Mar 6.

Auckland Cancer Society Research Centre, School of Medical Sciences , The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand.

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867678PMC
March 2018