Antitubulin Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Halichondrin B, a large polyether macrolide with a molecular weight of 1,110 (Figure 4.9), is a natural product originally isolated from the marine sponge Halichondria okadai (Lissodendoryx sp.) by Hirata and Uemura in the 1980s working at the National Cancer Center Research Institute in Tokyo (Japan). It was shown to be a potent mitotic inhibitor with a unique mechanism of action and to have significant cytotoxicity toward murine tumor cells in culture and antitumor activity in in vivo studies. Halichondrin B was prioritized for development as a novel anticancer agent by the NCI (NSC-707389), and in 1991, it became the first cytotoxic agent to have its mechanism of action (in this case, tubulin-targeted mitotic inhibition) identified through the NCI’s new (at the time) “60-cell line screen”. Structure of halichondrin B, showing the pharmacophore that provides the basis of the structure of eribulin (HavalenTM).
Advanced Formulation Techniques Including Innovative Materials
Heather A.E. Benson, Michael S. Roberts, Vânia Rodrigues Leite-Silva, Kenneth A. Walters in Cosmetic Formulation, 2019
Among the drugs that have been loaded in TyroSpheres, a significant effort has been made to develop and characterize paclitaxel-TyroSphere formulations aimed at treating skin disorders such as psoriasis. Paclitaxel is a mitotic inhibitor drug and is marketed for cancer therapy. Paclitaxel also prevents cellular over-proliferation and therefore can potentially be used to treat psoriasis. However, the poor solubility of paclitaxel and its toxicity limits the medical applications of this drug. TyroSpheres were able to load paclitaxel with up to 8.4% w/w loading efficiency and provided substantial enhancement of its solubility (1160 µg/mL). In a 72-hour in vitro drug release study using dialysis cassettes, a sustained release pattern was observed with paclitaxel-TyroSpheres. In 72 h about 44 and 58% of the drug was released from the paclitaxel-TyroSpheres with 5.0 and 8.4 wt% drug loading, respectively, while no burst release was observed. A viscous formulation of paclitaxel-TyroSpheres was prepared by adding 1% HPMC to the formulation, which showed a similar drug release profile to the TyroSphere liquid formulation. Following a skin permeation study using human cadaver skin, paclitaxel–TyroSpheres in both aqueous dispersion and gel-like formulation delivered significant amounts of the drug to the epidermis, and the delivery to the receptor compartment – representing the systemic circulation – was minimal (Kilfoyle et al., 2012).
Warts
Nilton Di Chiacchio, Antonella Tosti in Therapies for Nail Disorders, 2020
Bleomycin is an antimitotic agent that has been reported to be safe and effective in treating periungual warts with a success rate as high as 92%–96%.14,42,43 The study reporting a 94% cure rate for periungual warts used up to two intralesional injections to achieve cure.44 Application includes placing 1 mg/mL bleomycin onto the target lesion and then pricking the wart with a needle to allow penetration of the treatment. Superficial intralesional bleomycin at 0.5–1 mg/cc is also used successfully.45 In this case, bleomycin is injected into the epidermal–dermal junction to create a blanching (Figures 25.1 and 25.3). The technique of bleomycin delivery is important and bifurcated needles may provide better results.46
Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors
Published in Expert Opinion on Investigational Drugs, 2018
Susanne Liewer, Ashley Huddleston
Alisertib (MLN8237) is an orally administered selective AAK inhibitor which was developed as an enhancement over its predecessor, MLN8054. MLN8054, also an AAK inhibitor, was terminated in Phase I studies secondary to central nervous system (CNS) effects, including dose-limiting somnolence. These off-target CNS effects were attributed to GABAA binding of MLN8054, creating undesirable benzodiazepine-like effects [2]. In pre-clinical studies, alisertib demonstrated minimal effects related to GABAA binding, making it favorable as a less toxic alternative to MLN8054. Alisertib significantly impairs mitotic progression through activation of the mitotic checkpoint, causing abnormal spindle formation, mitotic defects, and ultimately cell death [9]. It may also have the ability to induce in vivo tumor regression [10]. Alisertib possesses selectivity of AAK over aurora B in in vitro kinase activity studies, although preclinical studies have suggested that both aurora A and aurora B kinases may be inhibited at therapeutic doses [8,11]. This newer antimitotic agent could provide advantages over traditional antimitotic drugs including more simple and convenient dosing and administration, more manageable toxicities and potentially improved outcomes for patients over a variety of malignancy types.
Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Delia Preti, Romeo Romagnoli, Riccardo Rondanin, Barbara Cacciari, Ernest Hamel, Jan Balzarini, Sandra Liekens, Dominique Schols, Francisco Estévez-Sarmiento, José Quintana, Francisco Estévez
Chalcones (1,3-diphenyl-3-propen-1-ones) are antitumor agents characterized by the presence of two aromatic rings linked by a three-carbon α,β-unsaturated system (Figure 1). A large number of synthetic chalcones have been shown to have potent antiproliferative activity against cancer cell lines, exhibiting antimitotic properties caused by inhibition of tubulin assembly through binding to the colchicine site14,15. Considering structure–activity relationship studies, derivatives that contain a 3′,4′,5′-trimethoxyphenyl ring as one of the aryl rings is thought to be of great interest for anticancer activity16. From the wide number of synthetic chalcones tested for their cell growth inhibitory activity, Ducki et al.18 discovered compound 117 possessing the same aromatic substitution pattern as the naturally occurring stilbene derivative combretastatin A-4 (CA-4, 2). This derivative showed antiproliferative effects against various cancer cell lines by acting as an antimitotic agent by the disruption of microtubule polymerisation.
Methods in marine natural product drug discovery: what’s new?
Published in Expert Opinion on Drug Discovery, 2023
Jehad Almaliti, William H. Gerwick
Rapid progress is being made with synthetic biology approaches to meet compound supply challenges. Total chemical synthesis or semi-synthesis is another technique by which to solve the supply problem of low abundance NPs. Another issue with drugs from the sea is that many are of a peptidic nature which due to metabolism issues, do not necessarily make for ideal drug agents. However, synthetic medicinal chemical approaches can modify these peptidic characteristics to improve on their pharmacological and pharmacokinetic (ADME) properties. Another successful application of medicinal chemistry to the development of marine NP drugs has been the production of Antibody Drug Conjugates (ADCs) to deliver potent cytotoxic payloads directly to cancer cells. For example, dolastatin 10 (6), an antimitotic agent of picomolar potency, had previously been evaluated for its anticancer properties, but was found to be too toxic as a stand-alone agent. It was subsequently tethered to various antibodies such that there are now six approved ADC-type anticancer drugs which utilize an analog of this marine cyanobacterial metabolite as the warhead component [16,17].