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International Journal of Molecular... May 2022Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most... (Review)
Review
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.
Topics: Antimitotic Agents; Antineoplastic Agents; Humans; Microtubules; Neoplasms; Vinca Alkaloids
PubMed: 35628467
DOI: 10.3390/ijms23105657 -
Cancer Chemotherapy and Pharmacology Dec 2015Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular... (Review)
Review
Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.
Topics: Antimitotic Agents; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Neoplasms; Taxoids; Vinca Alkaloids
PubMed: 26563258
DOI: 10.1007/s00280-015-2903-8 -
Hematology/oncology Clinics of North... Jun 2012Of the agents available in the treatment of both solid and hematologic cancers, microtubule-targeted agents are among the most widely used and exploiting other... (Review)
Review
Of the agents available in the treatment of both solid and hematologic cancers, microtubule-targeted agents are among the most widely used and exploiting other mechanisms involving the microtubule and its role in mitosis is an area of continued interest. This review will focus on novel microtubule-targeted agents, both recently approved (eg, ixabepilone and eribulin) and in later-stage clinical trials, and kinase inhibitors that aim to directly inhibit the mitotic spindle, such as the aurora kinase, pololike kinase, and kinsein-spindle protein inhibitors.
Topics: Antimitotic Agents; Aurora Kinases; Cell Cycle Proteins; Humans; Kinesins; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Tubulin Modulators; Polo-Like Kinase 1
PubMed: 22520982
DOI: 10.1016/j.hoc.2012.01.007 -
Current Topics in Medicinal Chemistry 2014There is a strong need for new antimitotic drugs that overcome the limitations of the currently used antitubulin compounds, mainly neurotoxicity and the development of... (Review)
Review
There is a strong need for new antimitotic drugs that overcome the limitations of the currently used antitubulin compounds, mainly neurotoxicity and the development of resistance. One of the most promising new targets is kinesin spindle protein (KSP, also known as Eg5), which contributes to the formation of mitotic spindle during cell division and has not been reported to play any other cellular role so far. This review covers KSP inhibitors binding at the allosteric, induced-fit L5 site reported between 2008 and December 2013. Among them, main groups include dihydropyrimidines, STLC derivatives, quinazoline-based compounds and pyrrole/ pyrazole and related agents. Structure-activity relationships are described, as well as the synthesis of representative compounds. They are remarkably selective for KSP and produce G2/M mitotic arrest accompanied by a characteristic monoastral cellular phenotype. Some of them have entered clinical trials, the most advanced being in Phase II. Therefore, KSP inhibitors show great potential as future clinical antimitotic agents, especially due to their activity in taxane-resistant tumors.
Topics: Allosteric Site; Antimitotic Agents; Antineoplastic Agents; Clinical Trials as Topic; G2 Phase Cell Cycle Checkpoints; Humans; Kinesins; Ligands; Mitosis; Neoplasms; Protein Binding; Pyrazoles; Pyrimidines; Quinazolines; Structure-Activity Relationship
PubMed: 25434354
DOI: 10.2174/1568026614666141130095532 -
Current Medicinal Chemistry 2018Phenstatin and their derivatives display remarkable antiproliferative activity toward a wide variety of preclinical tumor models. Structural simplicity and excellent... (Review)
Review
BACKGROUND
Phenstatin and their derivatives display remarkable antiproliferative activity toward a wide variety of preclinical tumor models. Structural simplicity and excellent stability of phenstatins offer a stimulating premise for developing various derivatives with profound antimitotic activity and excellent cytotoxicity.
OBJECTIVE
To do analysis of literature that phenstatins derivatives inhibit tubulin polymerization through their interaction at the colchicine binding site of microtubules and arrest the G2/M phase of the cell cycle. In addition, phenstatin derivatives are undergoing clinical evaluation as vascular targeting/disrupting agents and also exhibit direct antiangiogenic properties.
METHODS
An organised well designed and appropriately managed search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/ exclusion criteria has been done for this article.
CONCLUSION
In this review article, the synthesis and structure-activity relationships of phenstatin and a wide number of their reported analogues with modifications to ring A, ring B, and to the keto position are discussed in the perspective of medicinal chemistry with proper conclusion.
Topics: Antimitotic Agents; Antineoplastic Agents; Benzophenones; Cell Cycle; Cell Proliferation; Humans; Mitosis; Tubulin
PubMed: 29110592
DOI: 10.2174/0929867324666171106162048 -
Clinics (Sao Paulo, Brazil) Dec 2018Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to... (Review)
Review
Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.
Topics: Antimitotic Agents; Antineoplastic Agents; Biological Products; Drug Development; Humans; Mitosis; Neoplasms
PubMed: 30540125
DOI: 10.6061/clinics/2018/e813s -
Current Topics in Medicinal Chemistry 2014Natural products still play an important role in the medicinal chemistry, especially in some therapeutic areas. As example more than 60% of currently-used anticancer... (Review)
Review
Natural products still play an important role in the medicinal chemistry, especially in some therapeutic areas. As example more than 60% of currently-used anticancer agents are derives from natural sources including plants, marine organisms or micro-organism. Thus natural products (NP) are an high-impact source of new "lead compounds" or new potential therapeutic agents despite the large development of biotechnology and combinatorial chemistry in the drug discovery and development. Many examples of anticancer drugs as paclitaxel, combretastatin, bryostatin and discodermolide have shown the importance of NP in the anticancer chemotherapy through many years. Many organisms have been studied as sources of drugs namely plants, micro-organisms and marine organisms and the obtained NP can be considered a group of "privileged chemical structures" evolved in nature to interact with other organisms. For this reason NP are a good starting points for pharmaceutical research and also for library design. Tubulin and microtubules are one of the most studied targets for the search of anticancer compounds. Microtubule targeting agents (MTA) also named antimitotic agents are compounds that are able to perturb mitosis but are also able to arrest cell growing during interphase. The anticancer drugs, taxanes and vinca alkaloids have established tubulin as important target in cancer therapy. More recently the vascular disrupting agents (VDA) combretastatin analogues were studied for their antimitotics properties. This review will consider the anti mitotic NP and their potential impact in the development of new therapeutic agents.
Topics: Antimitotic Agents; Antineoplastic Agents; Bibenzyls; Biological Products; Humans; Ligands; Microtubules; Neoplasms; Paclitaxel; Protein Binding; Structure-Activity Relationship; Tubulin; Vinca Alkaloids
PubMed: 25434355
DOI: 10.2174/1568026614666141130095311 -
British Journal of Clinical Pharmacology Feb 2017Vinca alkaloids have been approved as anticancer drugs for more than 50 years. They have been classified as cytotoxic chemotherapy drugs that act during cellular... (Review)
Review
Vinca alkaloids have been approved as anticancer drugs for more than 50 years. They have been classified as cytotoxic chemotherapy drugs that act during cellular mitosis, enabling them to target fast growing cancer cells. With the evolution of cancer drug development there has been a shift towards new "targeted" therapies to avoid the side effects and general toxicities of "cytotoxic chemotherapies" such as the vinca alkaloids. Due to their original classification, many have overlooked the fact that vinca alkaloids, taxanes and related drugs do have a specific molecular target: tubulin. They continue to be some of the most effective anticancer drugs, perhaps because their actions upon the microtubule network extend far beyond the ability to halt cells in mitosis, and include the induction of apoptosis at all phases of the cell cycle. In this review, we highlight the numerous cellular consequences of disrupting microtubule dynamics, expanding the textbook knowledge of microtubule destabilising agents and providing novel opportunities for their use in cancer therapy.
Topics: Animals; Antimitotic Agents; Antineoplastic Agents; Apoptosis; Humans; Microtubules; Molecular Targeted Therapy; Neoplasms; Tubulin Modulators; Vinca Alkaloids
PubMed: 27620987
DOI: 10.1111/bcp.13126 -
The International Journal of Lower... Sep 2008Scars are a common complication of surgery or burn wound management. Scars occur over the body, affecting people of both sexes and all ages. Scar therapy is a constant... (Review)
Review
Scars are a common complication of surgery or burn wound management. Scars occur over the body, affecting people of both sexes and all ages. Scar therapy is a constant clinical challenge; antimitotic drugs and radiotherapy are used with varying degrees of success. This article examines the success of both these types of treatment modalities.
Topics: Adrenal Cortex Hormones; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antimitotic Agents; Cicatrix, Hypertrophic; Colchicine; Fluorouracil; Humans; Keloid; Keratolytic Agents; Mitomycin; Radiotherapy; Tretinoin; Tubulin Modulators
PubMed: 18757390
DOI: 10.1177/1534734608322099 -
Current Pharmaceutical Design 2018The growing incidence of cancer, the toxic side-effects associated with conventional chemotherapeutic agents and the development of multidrug resistance (MDR) drive the... (Review)
Review
The growing incidence of cancer, the toxic side-effects associated with conventional chemotherapeutic agents and the development of multidrug resistance (MDR) drive the search for novel and more effective drugs with multi-target activity and selectivity towards cancer cells. Stilbenes are a group of naturally occurring phenolic compounds of plant origin derived from the phenylpropanoid pathway that may exist as cis- or trans-isomers. Although the trans-isomer is the more common and stable configuration, resveratrol being a representative compound, cis-stilbenes are potent cytotoxic agents that bind to and inhibit tubulin polymerization, destabilizing microtubules. This review summarizes the chemistry and biological evaluation of cytotoxic stilbenes and their synthetic derivatives as promising antimitotic leads for cancer therapy, focusing on the most potent compounds, the combretastatins. Combretastatins isolated from the South African bushwillow Combretum caffrum are among the most potent antimitotic and vascular disrupting agents (VDAs) of natural origin. Preclinical studies have demonstrated their potent antitumor effects in a wide variety of tumors, both in vitro and in vivo, being currently under evaluation in phase 2 and phase 3 clinical trials for several types of solid tumors. Topics covered herein include synthetic medicinal chemistry, modes of action, structure-activity relationships (SAR), preclinical and clinical studies as VDAs in cancer therapy, either as single agents or in combination with cytotoxic anticancer drugs, antiangiogenic agents, or radiation therapy, and development of appropriate formulations based on nanocarriers (e.g., liposomes, nanoemulsions, polymeric, lipid and ceramic nanoparticles, carbon nanotubes) for improved bioavailability and targeted delivery of combretastatins to the tumor vasculature.
Topics: Animals; Antimitotic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Drug Delivery Systems; Drug Development; Humans; Nanostructures; Neoplasms; Stilbenes; Structure-Activity Relationship
PubMed: 30636588
DOI: 10.2174/1381612825666190111123959