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Recent Advances in Microtubule-Stabilizing Agents

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Recent Advances in Microtubule-Stabilizing Agents Accepted Manuscript Recent advances in microtubule-stabilizing agents Ya-Nan Cao, Ling-Li Zheng, Dan Wang, Xiao-Xia Liang, Feng Gao, Xian-Li Zhou PII: S0223-5234(17)30965-0 DOI: 10.1016/j.ejmech.2017.11.062 Reference: EJMECH 9937 To appear in: European Journal of Medicinal Chemistry Received Date: 23 August 2017 Revised Date: 4 November 2017 Accepted Date: 22 November 2017 Please cite this article as: Y.-N. Cao, L.-L. Zheng, D. Wang, X.-X. Liang, F. Gao, X.-L. Zhou, Recent advances in microtubule-stabilizing agents, European Journal of Medicinal Chemistry (2017), doi: 10.1016/j.ejmech.2017.11.062. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Graphic Abstract MANUSCRIPT ACCEPTED ACCEPTED MANUSCRIPT Recent advances in Microtubule-stabilizing Agents Ya-Nan Cao a,b , Ling-Li Zheng c, Dan Wang d, Xiao-Xia Liang a,* Feng Gao a,b,* and Xian-Li Zhou b a Agronomy College, Sichuan Agriculture University, Chengdu 611130, P. R. China b School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P.R. China c Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, P.R. China d Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, the University of Queensland, Brisbane Qld 4072, Australia * Corresponding Author Email address: [email protected] (F. Gao); [email protected] (X.-X. Liang) MANUSCRIPT ACCEPTED 1 / 55 ACCEPTED MANUSCRIPT Abstract: Highly dynamic mitotic spindle microtubules are superb therapeutic targets for a group of chemically diverse and clinically successful anticancer drugs. Microtubule-targeted drugs disrupt microtubule dynamics in distinct ways, and they are primarily classified into two groups: microtubule destabilizing agents (MDAs), such as vinblastine, colchicine, and combretastatin-A4, and microtubule stabilizing agents (MSAs), such as paclitaxel and epothilones. Systematic discovery and development of new MSAs have been aided by extensive research on paclitaxel, yielding a large number of promising anticancer compounds. This review focuses on the natural sources, structural features, mechanisms of action, structure-activity relationship (SAR) and chemical synthesis of MSAs. These MSAs mainly include paclitaxel, taccalonolides, epothilones, FR182877 (cyclostreptin), dictyostatin, discodermolide, eleutherobin and sarcodictyins, zampanolide, dactylolide, laulimalides, peloruside and ceratamines from natural sources, as well as small molecular microtubule stabilizers obtained via chemical synthesis. Then we discuss the application prospect and development of these anticancer compounds. Keywords: Tubulin; Microtubule-stabilizingMANUSCRIPT agents; Chemotherapy; Paclitaxel; Taccalonolide; Epothilone; Structure-Activity Relationship ACCEPTED 2 / 55 ACCEPTED MANUSCRIPT 1. Introduction Microtubules (MTs) are hollow cylindrical tubes consisting of 13 aligned protofilaments formed from repeating α- and β-tubulin heterodimers [1] . The protofilaments play a central role in pulling apart chromosomes in mitotic cell division. Cancer is a collection of related diseases involving abnormal cell growth with the potential to invade to other parts of the body. The common goal of cancer chemotherapy is to induce the apoptosis of cancer cells. Based on the behavior of tubulins in the cell mitosis, more and more drugs that interact with tubulins have been approved for clinical cancer treatment [2] . MTs have dynamical features of polymerization and de-polymerization in cell division, and they can be easily affected by factors such as low temperature, Ca 2+, and drugs, etc. Anticancer compounds that directly interact with MTs are classified into two main classes: The former, which are represented by vinblastine and colchicine, affect microtubule assembly by preventing tubulin polymerization, whereas, the latter, like paclitaxel and epothilones, promote tubulin polymerization. The former is called microtubule destabilizing agents (MDAs), andMANUSCRIPT the latter is microtubule stabilizing agents (MSAs). This review mainly discusses MSAs. MSAs are antimitotic compounds that can promote the tubulin polymerization. As known so far, the mechanism of action thereof is that MSAs bind to tubulin firstly, then block mitosis in the G 2/M phase in cell cycle by disturbing microtubule dynamics, and induce programmed cell apoptosis eventually [3] . In recent years, the successful development and application of MSAs have made a great contribution in clinical cancer treatment. Meanwhile, with the in-depth research, Swiss scientists have interpreted the crystal structure of those complex compounds formed from zampanolide and epothilone A with tubulin respectively by using X-ray ACCEPTEDdiffraction technique. Their work has also illuminated the mechanism of action of these compounds on tubulin, which provides a new basis for further drug design guided by corresponding structures [4] . As we all know, MSAs mostly derive from natural products or their structure-modified derivatives whose sources are widely ranged from marine organism to terrestrial organism, or from algae to mammal. Besides, there are some 3 / 55 ACCEPTED MANUSCRIPT small molecular compounds came from chemical synthesis that have similar anticancer effects to MSAs. In this review, we introduce the discovery, application and chemical synthesis of the natural MSAs originated from plants, microorganisms, and marine organisms, as well as small molecular compounds prepared by chemical synthesis, and finally make an outlook on the future applications of MSAs with anticancer effects. 2. Natural microtubule stabilizing agents Natural MSAs refer to those compounds generated from natural products and derivatives thereof with the function of stabling the tubulin polymers and preventing microtubule de-polymerization. These compounds are generally direct extracts isolated from natural products or structure-modified derivatives thereof. But these natural MSAs are usually with low contents, and their structures are generally complex, such as diterpenes, steroids, and macrocyclic lactones, etc. The most commonly used classification criterion of these natural MSAs is according to their natural sources, which we employ herein. We classify them into three groups: obtained from plants, microorganisms, and marineMANUSCRIPT organisms, respectively. 2.1. Plants sources 2.1.1. Paclitaxel (Taxol®) Wall ′s laboratory first reported this compound isolated from the stem bark of the western yew, Taxus brevifolia Nutt , named it paclitaxel (1), and identified its diterpene structure with a tetracyclic 17 carbon frame and 11 stereocenters [5] . In bioassay, paclitaxel shows extensive antitumor activity, especially in the treatment of ovarian cancer, breast cancer and non-small cell lung cancer, which makes it a potential broad-spectrum anticancer drug. Schiff et ACCEPTEDal. [6] discovered that paclitaxel can completely inhibit human cervical cancer cell division at low concentrations of the drug (0.25 µM), block human cervical cancer cells in the G2/M phase, but has no apparent effects on DNA, RNA or protein synthesis. Meanwhile, the microtubule polymers induced by paclitaxel could remain stable at a low temperature (4℃) and in the presence of CaCl 2 (4mmol). That is to say, paclitaxel induces cancer cell death by stabilizing microtubules without any effect on 4 / 55 ACCEPTED MANUSCRIPT gene expression. The current studies show that the anticancer mechanism of paclitaxel is completely opposite to vinblastine. Paclitaxel is the first compound with the activity of stabling microtubules, creating a new field of anticancer drug research and making the study of paclitaxel a novel hotspot in natural medicine research in recent 30 years. In 1992, Rao et al. [7] confirmed that the paclitaxel preferentially binds to the β-subunit of tubulin by photo-affinity labeling methods combined with gel electrophoresis. Three years later, Rao [8] and coworkers found that paclitaxel directly assembled in the 31 amino acid residues of β-tubulin N side and the 217-231 amino acid residues of the middle piece, and this position is identified as a microtubule stabilizers binding site in later researches. Their studies of paclitaxel binding site on tubulin play a significant role in clarifying its anticancer mechanism of action. In recent years, some scientists have discussed the mechanism of action that paclitaxel prevents cancer cells proliferation, which provides reference basis for further expounding its mechanism of action. Paclitaxel can inhibit microtubule de-polymerization by binding to β-tubulin, resulting in mitotic arrest and subsequent activation of caspase-dependent apoptosis MANUSCRIPTby Bcl-2 proteins [9]. The unique pharmacological effect of paclitaxel makes it be on a fast development in its clinical research. On December 29, 1992, paclitaxel was formally approved by the US Food and Drug Administration (FDA) and the Canadian government for the treatment of ovarian cancer. Then, it was approved by FDA to be applied in the treatment of breast cancer and non-small cell lung cancer [10]. However,
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