Term Paper Medicinal Chemistry
Term Paper Medicinal Chemistry 4000
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Chem 1220(Chemistry, Dr. Clark, General Chemistry)
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This 14 page Bundle was uploaded by Maryna Gregulich on Sunday February 14, 2016. The Bundle belongs to 4000 at 1 MDSS-SGSLM-Langley AFB Advanced Education in General Dentistry 12 Months taught by Dr. Dunlap in Winter 2016. Since its upload, it has received 24 views. For similar materials see Medicinal Chemistry in Chemistry at 1 MDSS-SGSLM-Langley AFB Advanced Education in General Dentistry 12 Months.
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Date Created: 02/14/16
Tubulin Polymerization and Depolymerization as a Chemotherapeutic Approach Combating Cancer By: Maryna Gregulich Chemistry 4000 December 1, 2015 Introduction Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers that associate to form a hollow cylindrical structures which involved in cell movement, intracellular organelle trafficking, and mitosis (10). In the context of oncologic diseases, the tubulin family of proteins is well-known as the target of the tubulin-binding chemotherapeutics, which suppress the dynamics of the mitotic spindle causing mitotic arrest and cell death by apoptosis. Importantly, the different shifts in microtubule stability as well as post-translational modifications caused by targeting drugs have been reported for a wide range of cancers (10). This paper will focus on the mechanism of action chemotherapeutics on microtubule dynamics as an effective approach for the treatment of cancer. Tubulin-Binding Drugs Generally, microtubule-binding drugs are categorized into two subgroups: microtubule stabilizers, including taxanes and epothilones, and microtubule destabilizers, including a variety of vinca alkaloids. It is widely appreciated that all microtubule-binding drugs, administered at low nano-molar concentrations, act to reduce microtubule dynamicity rather than altering net polymer mass; thus, these drugs could be referred as the “suppressors of dynamic instability” (11). Nevertheless, they occupy different sites on their cellular target and factually are categorized based upon their binding sites on microtubules rather than their mode of action. For example, the taxane binding site exists on β-tubulin within the microtubular lumen; on the other hand, the vinca domain is surrounding the GTP binding site on β-tubulin (11). I. Assembly-Demoters: “Destabilizing” Drugs In this class of antimitotic drugs, the chemotherapeutic agents generally bind to the vinca domain or colchicine domain of tubulin and act to destabilize the microtubule structure by interacting with various β-tubulin binding sites (2). However, due to colchicine’s severe toxicity to healthy tissues at doses required for antitumor effects, it have not been successful as a chemotherapeutic agent, and for this review only the vinca domain binders would be discussed. Furthermore, as with the polymerizing drugs, they are generally dosed at much lower concentrations clinically, and they act by disrupting microtubule dynamics vs. merely reducing polymerization which blocks dividing cells in mitosis, eventually leading to apoptosis (2). A. Vinca Domain Binders The vinca alkaloids are a subset of drugs derived from the Madagascar periwinkle plant. They were discovered in the 1950’s by Canadian scientists, Robert Noble, and Charles Beer. Vinca alkaloids have been used to treat diabetes, hypertension, and it even been used as disinfectants. However, the vinca alkaloids are most famous for being cancer combatants (12). In this review, the three major vinca alkaloids in today’s clinical use: vinblastine, vinorelbine, vincristine, would be discussed. The vinca alkaloid’s mechanism is characterized by occupying tubulin’s building block structure, and prevent cancer cells from successfully dividing. At low concentrations, vincas bind to the plus (+) ends of microtubules, reducing the dynamics and further leading to mitotic arrest. For this reason, they are also referred to as “end poisons” (12). The following are the examples of several vinca alkaloids that are used in present day for oncologic treatment. 1. Vinblastine & Vincristine – are plant derived natural products, originally isolated in trace quantities from the Catharanthus roseus. Its biological properties were among the first to exhibit the action of perturbation in microtubule dynamics that led to inhibition of mitosis (7). i. Lead development- The great effort required to isolate the needed natural product quantity suggested that an efficient synthetic approach might offer a better and cheaper alternative to produce the chemotherapeutic agent (7). As a consequence, a method for coupling the lower half of the plant, vindoline, with the appropriate precursors to the upper velbanamine subunit, have been defined (6).It was achieved by Dale L. Boger’s group, though the coupling of catharanthine and vindoline to provide vinblastine and in a few more steps ,vincristine. This one pot procedure, combined an initial FeCl – 3 promoted vindoline/ catharanthine coupling reaction with a subsequent Fe2(ox)3-NaBH /4ir concomitant oxidation of C3’-C4’ double bond and reduction of the iminium intermediate (7). Figure 1. Natural product Figure 2. Oxidation of vinblastine to structures vincristine ii. Pharmacology. The treatment with vinblastine causes the arrest of M phase cell cycle, during which division takes place, by disrupting the microtubule assembly and proper formation of the mitotic spindle and the kinetochore, all of which are necessary for the separation of chromosomes during anaphase of mitosis (7). iv. Mechanism of action. The dynamic instability of microtubules is the consequence of GTP hydrolysis on the β-subunit, that followed by tubulin polymerization and then the exchange of GDP to GTP to regenerate GTP- tubulin. And so, vinblastine and vincristine act by binding near the hydrolyzable GTP site in order to alter the dimer conformation, inhibiting the tubulin-dependent GTP hydrolysis and preventing GDP–GTP exchange (11). Even by present medicinal standards, both vinblastine and vincristine are efficacious clinical drugs and are used in combination therapies for treatment of Hodgkin’s disease, testicular cancer, ovarian cancer, breast cancer, head and neck cancer, as well as in non-Hodgkin’s lymphoma(7). nd 2. Vinorelbine- (Navelbine) represent the first 2 generation semi-synthetic vinca-alkaloid, developed by Pierre Fabre in France in the 1980s (5). i. lead development- Anhydrovinblastine Nb-oxide, an important key intermediate in the biosynthesis of vinblastine, shown in figure below, is used as a starting material for the semi- synthesis of vinorelbine in just two steps (5). Figure 3. Semi-Synthesis of Vindoline + Catharantine Anhydrovinblastine Vinorelb ine ii. Pharmacology. Vinorelbine has similar antitumor activity to the first generation vinca alkaloids inhibiting cell mitosis through the interaction with tubulin. However, preclinical studies have showed that vinorelbine is more potent against non-small cell lung carcinoma NSCLC than vinblastine, and vincristine (8). iii Mechanism of action-In addition to the inhibition of mitosis at metaphase through its interaction with tubulin, vinorelbine may also interfere with amino acids, cyclic AMP, and glutathione; metabolism, calmodulin-dependent Ca 2+- transport ATPase activity; cellular respiration, and nucleic acid and lipid biosynthesis (8). Furthermore, vinorelbine was approved as single agent and in combination therapy for the treatment of both hematological and solid tumors, including lung cancer, breast cancer, and gynecological tumors (2). II. Assembly Promoters: Stabilizing Drugs These microtubule-binding drugs target specific sites within the lumen of polymerized microtubules. They act by binding to GDP-bound β-tubulin molecules and stabilizing them by changing their conformation to the more stable GTP-bound β-tubulin structure. This alteration aligns the dimer's biological vector with the vector of microtubule growth (figure 4), increasing the incorporation into the microtubule and its subsequent stabilization (3). Figure 4. Taxane bound to a straight protofilament of a A. Taxane Domain Binders Taxane history begins in 1962, when bark from the Pacific yew tree, Taxus brevifolia, was collected as part of the U.S National Cancer Institute (NCI) natural products screening program. Later on, adverse publicity regarding the large amounts of Pacific yews that were being destroyed to produce taxanes led to production of the compound using the needles of the more common European yew, Taxus baccata, to produce docetaxel and avoid conflict with environmental groups (11).Throughout time, they have been widely used as cytotoxic agents targeting a wide range of tumors. Their cytotoxic effects are evidently attributed to their ability to stabilize protofilaments leading to microtubule over-polymerization, protecting it from disassembly and preventing chromosomes from achieving the metaphase spindle configuration. This blocks progression of mitosis, and the continued stimulation of the mitotic barrier triggers apoptosis or setback to the G phase of the cell cycle without cell division (10). The taxanes paclitaxel and docetaxel were the first antimicrotubule agents approved for use in solid tumors. 1. Paclitaxel (Taxol) –1 generation of taxanes) shown to promote tubulin assembly based on the natural product Taxus brevifolia (Yew tree bark) (3). i. pharmacology- For decades it has been the backbone of therapy for several solid tumors including breast, ovarian, and prostate cancers (3). ii. Mechanism of action. Paclitaxel enables tubulin assembly under all reaction conditions including low protein concentrations, lower temperature, absence of MAPs, and absence of GTP, resulting in highly resistant tubulin polymers with shorter and highly polymerized microtubules. It is thought that paclitaxel reaches its binding site through small openings on the microtubule surface or due to dynamic oscillations in microtubule structure. Paclitaxel's attachment to its binding site, on the inner side of the microtubule, tends to stabilize the microtubule lattice, thus increasing polymerization. This can happen due to the conformational change in paxlitaxel-bound tubulin that maintains a straight biological vector in the dimer, which aligns with the biological vector of the growing microtubule, and thus enhances its affinity to the surrounding tubulin molecules (3). 2. Docetaxel (Taxotere) - To improve on the pharmacology of paclitaxel, its semi-synthetic analog, docetaxel, was introduced as a second-generation taxane based on the Taxus baccata (3). i. Pharmacology. Docetaxel is more water-soluble than paclitaxel and turns out to be more active than its analog against cancer cell proliferation; thus it is presently being employed in chemotherapeutic routines to treat breast and prostate malignances (11). The major factor influencing the further clinical development of these polymerizing drugs is tumor resistance. One of the mechanisms explaining tumor resistance is the intrinsic expression of multidrug resistance proteins like P-glycoprotein (Pgp), which is an ATP-binding cassette transporter. Due to its expression, these transporters act as drug efflux pumps causing diffusion of drugs out of tumor cells (11). B. Epothilones- Overcoming Texane Resistance The epothilones are a novel class of microtubule-stabilizing anticancer drugs and have been used in treating taxane-resistant cancers. They were originally isolated from the mycobacterium Sorangium cellulosum (3) and thought to occupy the same binding site on β-tubulin; however structural evidence suggest that epothilones do not share a common pharmacophore with taxanes but rather that each ligand occupies the tubulin-binding pocket in exclusive and independent way (4). For one thing, an uncommon 16- member ring is a core characteristic of the epothilones but not the taxanes. In addition, the epothilone structure is flexible, as demonstrated by the 180° rotation about a number of bonds in the 16-member ring (4). Epothilone Ixabepilon B Ixabepilone- is the first epothilone FDA approved drug that can be used as a monotherapy or in combination, for treatment of locally advanced or metastatic breast cancer (3). i. Lead development- Ixabepilone is a semi-synthetic analog of epothilone B, developed to overcome its narrow therapeutic index and is thought to have higher metabolic stability (9). ii. Mechanism of action. Compared with Taxol, ixabepilone showed analogous antitumor activity in paclitaxel-sensitive tumors and significantly higher activity in paclitaxel-resistant tumors that overexpress P-glycoprotein or contain a tubulin mutation (4). Conclusion After reviewing both the tubulin polymerization and depolymerization chemotherapeutic approaches, several definite trends are being revealed, a portion of which include the drug interactions with tubulin, specifically the mode of binding and the binding site, the mechanisms of action, and subsequent microtubule dynamics. Hence; those trends point out to the obvious correlation in biological responses, between the two classes of microtubules, with respect to their binding sites. Taxol binds at the luminal side of β-tubulin, and doesn’t affect the conformation of the dimer nor the GTP hydrolysis or exchange rate of the dimer; thus supporting microtubule growth and stability. On the other hand, vinca drugs bind to the dimer, resulting in conformational changes of the monomers, altering the interaction between neighboring heterodimers; thus creating a twist in the biological vector so it no longer aligns with the straight microtubule axis. Both of these approaches have proved to be successful in combating cancer and saving many people lives’ worldwide. Work Cited 1. Bryan, Jenny. “How Bark From the Pacific Yew Tree Improved the Treatment of Breast Cancer” The Pharmaceutical Journal. Sep. 2011. Web 2. Daniele Fanale, Giuseppe Bronte, Francesco Passiglia, et al., “Stabilizing Versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?” Analytical Cellular Pathology, vol. 2015, Article ID 690916, 19 pages, 2015. Web 3. Donovan, D., Vahdat, L. T. “Epothilones: Clinical Update and Future Directions”. Cancer Network home for the Journal ONCOLOGY. April 15, 2008. UBM medical network. Web. 02 Nov. 2015 4. Fojo, T., & Menefee, M.. “Mechanisms of multidrug resistance: The potential role of microtubule-stabilizing agents”. Annals of Oncology, V3-V8. (2007). Web 5. Gordon M. Cragg, David G. I. Kingston, David J. Newman. “Anticancer Agents from Natural Products, Second Edition”. (182-188). CRC Press, Oct 10, 2011. Print 6. Ishikawa H, Colby DA, Boger DL. Direct Coupling of Catharanthine and Vindoline to Provide Vinblastine: Total Synthesis of (+)- and ent-(−)- Vinblastine. Journal of the American Chemical Society. 2008;130(2):420- 421. 7. Justin E. Sears and Dale L. Boger. “Total Synthesis of Vinblastine, Related Natural Products, and Key Analogues and Development of Inspired Methodology Suitable for the Systematic Study of Their Structure–Function Properties”. Accounts of Chemical Research. ASC. 2015 48 (3), 653-662 8. Kazuya Fukuoka et al, “Mechanism of the Radiosensitization Induced By vinorelbine in Human Non-Small Cell Lung Cancer Cells”. Pharmacology Division, National Cancer Center Research Institute. Lung Cancer Vol. 34, Issue 3, Dec. 2001, Pages 451–460. Tokyo, Japan. Web 9. Loong HH, Yeo W. “Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma” .Dovepress. Volume 2014:7 Pages 575—585. 2014. Web 10. Parker, Amelia L., Maria Kavallaris, and Joshua A. McCarroll. “Microtubules and Their Role in Cellular Stress in Cancer.” Frontiers in Oncology 4 (2014): 153. PMC. Web. 02 Nov. 2015. 11. Stanton, R. A., Gernert, K. M., Nettles, J. H., & Aneja, R. “Drugs That Target Dynamic Microtubules: A New Molecular Perspective”. Medicinal Research Reviews, 31(3), 443– 481.2011 Web. 02 Nov. 2015. 12. Moudi, M., Go, R., Yien, C. Y. S., & Nazre, M. (2013). “Vinca Alkaloids”. International Journal of Preventive Medicine, 4(11), 1231–1235.Web
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