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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Some types of cancer cells appear to be more susceptible to mitotic inhibitors such as colchicine and the Vinca and taxol alkaloids than healthy cells, and it has been suggested that this may be due, in part, to the ability of certain cancer cell types to divide more rapidly than normal cells. However, colchicine was found to have only a narrow range of effectiveness as an anticancer agent in humans, and so was not extensively developed, although it is still occasionally used in veterinary medicine to treat tumors in some animal species. The main clinical use of colchicine today is for the treatment of gout (e.g., ColBenemidTM), in which case it is thought to work by binding to tubulin in white cells (leukocytes), inhibiting their migration into inflamed areas and leading to a reduction in pain and inflammation. Colchicine is also used as an antimitotic agent to treat cell cultures in biomedical research.
Respiratory, endocrine, cardiac, and renal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Vinca alkaloids bind to tubulin and prevent the constitution of the mitotic spindle necessary for the migration of the chromosomes during the course of the metaphase and mitosis. These drugs are called spindle poisons and constitute the true antimitotic agent with anticancer therapeutic armantarium.
Warts
Published in Nilton Di Chiacchio, Antonella Tosti, Therapies for Nail Disorders, 2020
Sonali Nanda, Rachel Fayne, Martin N. Zaiac
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
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].
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.