A5074208202- Cancer Treatment and Pharmacology
- Microtubule and mitosis dynamics
- Synthetic Organic Chemistry Methods
- 14-3-3 protein interactions
- Microbial Natural Products and Biosynthesis
- Marine Sponges and Natural Products
- X-ray Diffraction in Crystallography
- Chemical synthesis and alkaloids
- Crystallization and Solubility Studies
- Metal complexes synthesis and properties
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Synthesis and Catalytic Reactions
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Ubiquitin and proteasome pathways
- Plant and fungal interactions
- Phytochemistry and Bioactive Compounds
- Magnetism in coordination complexes
- Viral Infectious Diseases and Gene Expression in Insects
- Cyclopropane Reaction Mechanisms
- Synthesis and biological activity
- Cancer therapeutics and mechanisms
- Seaweed-derived Bioactive Compounds
Amgen (United States)
2023-2024
Victoria University of Wellington
2009-2019
Seagen (Canada)
2016
Seagen (United States)
2014-2016
Victoria University
2014-2015
Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite importance MSAs medical applications and basic research, their molecular mechanisms action on tubulin microtubules remain elusive. We determined high-resolution crystal structures αβ-tubulin in complex with two unrelated MSAs, zampanolide epothilone A. Both compounds were bound to taxane pocket β-tubulin respective side chains induce structuring M-loop into a short...
Zampanolide (1), a 20-membered macrolide from Tongan marine sponge, stabilizes microtubules and blocks cells in G2/M of the cell cycle. is cytotoxic low nanomolar range induces microtubule bundles cells. It leads to tubulin assembly purified preparations not substrate for P-glycoprotein drug efflux pump. Zampanolide, with only four stereogenic centers, may be amenable large-scale synthetic preparation.
The NMR-directed investigation of the New Zealand marine sponge Hamigera tarangaensis has afforded ten new compounds hamigeran family, and a 13-epi-verrucosane congener. Notably, F (6) possesses an unusual carbon–carbon bond between C-12 C-13, creating unprecedented skeleton within this class. In particular, structural features 6, H (10) J (12) imply diterpenoid origin, which allowed putative biogenesis three carbon skeletons to be proposed based on geranyl pyrophosphate. All hamigerans...
The NMR-directed isolation and structure elucidation of nine new nitrogenous hamigeran diterpenoids from the New Zealand marine sponge Hamigera tarangaensis are described. Featured in this set oxazole-containing M (4) eight compounds (5a-6a 7a-8c) related to constitutional D (1). Moderate cytotoxicity low-micromolar range against HL-60 promyeloid leukemic cell line is reported for seven compounds. structural nature these suggests that their adducts derived an amino acid source has allowed...
An unusual tetrahalogenated indole with the exceptionally rare inclusion of three halogens bromine, chlorine, and iodine was found using mass spectrometry within a fraction semipurified extract obtained from red alga Rhodophyllis membranacea. We report herein isolation structure elucidation, combination NMR spectroscopy spectrometry, 11 new indoles (1–11), including four bromochloroiodoindoles (5–7, 10). Several were evaluated for cytotoxic antifungal activities against HL-60 promyelocytic...
The marine natural product zampanolide and analogues thereof constitute a new chemotype of taxoid site microtubule-stabilizing agents with covalent mechanism action. Zampanolide-ligated tubulin has the switch-activation loop (M-loop) in assembly prone form and, thus, represents an activated state protein. In this study, we have characterized biochemical properties covalently modified, dimer, determined effect on association binding ligands at other sites. Tubulin activation by does not...
Shell Chemical Company Nonidet P-40 has been used for decades in many biochemical assays as a nonionic, nondenaturing detergent; however, no longer manufactures this product. Four commercially available substitutes were investigated and their activities titrated an intracellular tubulin polymerization assay. Although claimed by the supply companies to be identical P-40, all four about 10-fold more potent needed diluted accordingly. As microtubule targeting drugs are major class of anticancer...
Pateamine A is a naturally occurring metabolite extracted from the marine sponge Mycale hentscheli. It exhibits potent cytotoxicity towards cancer cell lines and has been shown to target protein translation initiation via inhibition of function eukaryotic factor 4A proteins. We have synthesised simplified analogue pateamine A, consisting skeletal core natural product but with thiazole heterocycle replaced by triazole. The convergent design synthesis features base-induced opening...
Abstract The fungal metabolite TAN‐2483B has a 2,6‐ trans ‐relationship across the pyran ring of its furo[3,4‐ b ]pyran‐5‐one core, which thwarted previous attempts at synthesis. We have now developed chiral pool approach to this core and prepared side‐chain analogues TAN‐2483B. synthesis relies on expansion reactive furan ring‐fused dibromocyclopropane alkynylation resulting pyran. is constructed by palladium‐catalysed carbonylative lactonisation. Various side‐chains are appended through...
Abstract Fucosylation is the process of adding a fucose sugar to glycan chain. The analog, 2-fluorofucose (2FF), has been shown inhibit cellular fucosylation by depletion substrate, GDP-fucose, as well direct inhibition fucosyltransferases. 2FF promising activity in number tumor models. For example enhanced protective effect lymphoma vaccine (Okeley et al, PNAS 110, 2013), and this protection was determined be immune dependent since CD4 CD8 T-Cells reduced 2FF/vaccine activity. Due complex...
A new peloruside congener, E (5), has been isolated in sub-milligram quantities from a specimen of the New Zealand marine sponge Mycale hentscheli. The structure 5 differs parent compound (1) by replacement C-10 gem-dimethyl moiety with monomethyl substituent and represents first structural deviation pelorusane scaffold. Peloruside (5) is potently antiproliferative (HL-60, IC50 90 nM, cf. 1, 19 nM) polymerizes purified tubulin, albeit at rate lower than that 1.
Abstract ICVB-1042 is an oncolytic adenovirus containing modifications to enhance replication, lysis, and viral spreading in tumor cells. The anti-tumor activity, immune activation, tropism, selectivity, mechanism of action were evaluated preparation for a first-in-human study. was at least 100-fold more cytotoxic A549 cells than normal primary tested, demonstrating its high selectivity low likelihood targeting tissues. administered mice intravenously or intratumorally effective reducing...
Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8 + T cell anti-tumor immunity thus, a target of high interest for cancer immunotherapy. Type I interferon (IFN) is potent inducer cross-presentation, but, unfortunately, shows only modest results the clinic given short half-life toxicity current IFN therapies, which limit exposure tumor. dependent on signaling cDC1s preclinical studies suggest targeting directly to may be sufficient drive...
Abstract 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 data demonstrated superior a acid the para position. most potent compound ( 3 ) had IC 50 growth inhibition low micromolar range, caused cells...