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Topoisomerase I inhibitors

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Camptothecin and Derivatives as Anticancer Therapeutics.

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Inhibitors of Topoisomerase I were first based on Camptothecin, which demonstrated evidence of the selective poisoning of Topoisomerase in vitro; however, clinical trials showed limited effectiveness due to toxic effects regarding the pharmacological characteristics. [1][2] Alternatively,  the discovery of Camptothecin led to the synthesis of three currently FDA approved derivatives: topotecan, irinotecan, and Belotecan.[1][3]Topotecan (Hycamtin) is commonly used to treat ovarian and small cell lung cancer (SCLC) while Irinotecan (Campto) is useful in treating colon or rectum cancer.[4][5][1] Commonly, Topotecan (TPT)  is used in conjunction with a combination of drugs such as cyclophosphamide, doxorubicin, and vincristine. [4] It was noted that IV treatment with Topotecan had similar response and survival rates to oral medication.[4]Furthermore, it has been shown that TPT treatment with radiotherapy can improve survival rates of patients with brain metastases. Belotecan is a recent Camptothecin derivative currently used as treatment of small cell lung cancer (SCLC).[6] Serval clinical trials on Camptothecin derivatives such as gimatecan, and silatecan continue to progress.[6] Furthermore, silatecan is in a phase 2 study for the treatment of gliosarcoma in adults who have not had bevacizumab treatment.[7] Despite the clinical success of the many Camptothecin derivatives, they require long-term treatment, have low water solubility, and possess many side effects such as temporary liver dysfunction, severe diarrhea, and bone marrow damage.[2] In addition, Camptothecin is composed of pentacyclic structures with a closed lactone ring.[8] However, the lactone ring has been demonstrated to be unfavorable, promoting the inhibitor to transform into an inactive carboxylate compound.[8]

Non-Camptothecin

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Therefore, three clinically relevant non-Camptothecin inhibitors, indenoisoquinoline, phenanthridines, and indocarbazoles, are currently being considered by the FDA as possibly chemotherapeutics.[1] Clinical trials for these drugs have not been posted. However, studies have shown that non-Camptothecin are chemically stable, remain selective to topoisomerase I, and exhibit greater activity than Camptothecin in mice models[1]

Topoisomerase II Inhibitors

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Antibiotics.

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Aminocoumarins (Coumarins and simocyclioners) and quinolones are the two main classes of topoII inhibitors that function as antibiotics.[9] The Aminocoimaris can be further divided into two groups:

  1. Traditional coumarin
  2. Simocyclioners.

The coumarins group, which includes novobiocin and coumermycin, are natural products from Streptomyces species and target the bacterial enzyme DNA gyrase (Type II topoisomerase).[10][9] Mechanistically,  the inhibitor binds in the B subunit of the gyrase (gyB) and prevents ATPase activity.[11] [10][9] This is attributed to the drug creating a stable conformation of the enzyme, which exhibits a low affinity for the ATP that is needed for DNA supercoiling.[10] It’s proposed that the drug functions as a competitive inhibitor, thus, at low concentration of inhibitor, the mechanism is reversed.[10] One limitation of traditional coumarin is their inducing of antibiotic resistance due mutation in gyrB, which decreases the inhibitor’s ability to bind and induce apoptosis.[9][12]

Simocycliones also target bacterial DNA gyrase but differ from aminocoumarins in that 1) it's composed of both aminocoumarins and a polyketide elements 2) inhibits gyrase ability to bind to DNA instead of inhibiting ATPase activity.[9] Furthermore, Simocycliones bind to both E. coli topo IV and human topo II, effectively inhibiting their functions.[9]

The most common antibiotics used to treat bacterial infections in humans are quinolones, which treat illness such as urinary infections, skin infections, sexually transmitted diseases, and tuberculosis.[13] The effectiveness of Quinolones against infectious agents is proposed to be from chromosome fragments, which initiate the accumulation of reactive oxygen species that leads to apoptosis. [13] Quinolones can be divided into four generations:

  1. First Generation: Nalidixic acid**
  2. Second Generation: Cinoxacin, Norfloxacin, Ciprofloxacin, and Ofloxacin**
  3. Third Generation: Levofloxacin, Sparfloxacin**
  4. Fourth Generation: Moxifloxacin**

The old-generation (one and two) include quinolones such as Cinoxacin, Norfloxacin, Ciprofloxacin, and Ofloxacin.* The newer generation (three and four) include Levofloxacin, Sparfloxacin, and Moxifloxacin drugs.**New generations drugs are classified as fluoroquinolones due to the addition of a fluorine and a methyl-piperazine, allowing for improved gyrase targeting. However, topo IV can also be targeted based on 1) the organisms 2) type of quinolone 3) mutations in GyrA and GyrB that promotes quinolone resistance.* Furthermore, Fluoroquinolones are promising in fighting anthrax infections and used against agents of bioterrorism.** Currently, the  U.S. Food and Drug Administration (FDA) has approved eight new-generation fluoroquinolones: Mmoxifloxacin, delafloxacin, ciprofloxacin, ciprofloxacin extended-release, Gemifloxacin, levofloxacin, and ofloxacin.[14] Despite these quinolones success as antibiotics, their effectiveness are limited due to accumulation of small mutations and multidrug efflux mechanisms, which pumps out unwanted drugs out of the cell through through a general TolC channel. In particular, smaller quinolones have shown to bind with high affinity to AcrB of the multidrug efflux pump in Escherichia coli and Staphylococcus aureus.[15][16] [17]Furthermore, the FDA has updated safety labels to include the following side effects: hypoglycemia, high blood pressure, and mental health  effects such as agitation, nervousness, memory impairment and delirium.[18][19]

Intercalating Poisons as Anticancer therapeutics

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Topo II inhibitors have two main identification: poisons and catalytic inhibitors.** Topo 2 poisons are characterized by their ability to create irreversible covalent bonds with DNA.**Furthermore, topo 2 poisons are classified as intercalating or non-intercalating poisons.**One strength of intercalating poisons are their ability to treat a variety of cancer due to the diverse drug derivations such as doxorubicin and anthracyclines available .* However, it has been shown that interaction poisons have a few limitations including 1) little inhibitor success of small compounds 2) anthracyclines’ adverse effects such as membrane damage and secondary cancers due to oxygen-free radical generation **4) congestive heart failure.**

  1. ^ a b c d e Li, Fengzhi; Jiang, Tao; Li, Qingyong; Ling, Xiang (2017-12-01). "Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?". American Journal of Cancer Research. 7 (12): 2350–2394. ISSN 2156-6976. PMC 5752681. PMID 29312794.
  2. ^ a b Cunha, Kênya Silva; Reguly, Maria Luíza; Graf, Ulrich; Rodrigues de Andrade, Heloisa Helena (2002-03-01). "Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination". Mutagenesis. 17 (2): 141–147. doi:10.1093/mutage/17.2.141. ISSN 0267-8357.
  3. ^ HOPKINS, R. P. (1983-12-01). "Principles of Biochemistry, Seventh Edition (two volumes): General Aspects, Mammalian Biochemistry". Biochemical Society Transactions. 11 (6): 829–830. doi:10.1042/bst0110829a. ISSN 0300-5127.
  4. ^ a b c Lynch, T (1996-12-01). "Topotecan today". Journal of Clinical Oncology. 14 (12): 3053–3055. doi:10.1200/JCO.1996.14.12.3053. ISSN 0732-183X.
  5. ^ Li, Fengzhi; Jiang, Tao; Li, Qingyong; Ling, Xiang (2017-12-01). "Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?". American Journal of Cancer Research. 7 (12): 2350–2394. ISSN 2156-6976. PMC 5752681. PMID 29312794.
  6. ^ a b Hu, Guohua; Zekria, David; Cai, Xun; Ni, Xiaoling (2015-06). "Current status of CPT and its analogues in the treatment of malignancies". Phytochemistry Reviews. 14 (3): 429–441. doi:10.1007/s11101-015-9397-1. ISSN 1568-7767. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Arno Therapeutics (2014-12-08). "A Phase 2 Study of AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin) in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma". {{cite journal}}: Cite journal requires |journal= (help)
  8. ^ a b Cunha, Kênya Silva; Reguly, Maria Luíza; Graf, Ulrich; Rodrigues de Andrade, Heloisa Helena (2002-03-01). "Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination". Mutagenesis. 17 (2): 141–147. doi:10.1093/mutage/17.2.141. ISSN 0267-8357.
  9. ^ a b c d e f Hevener, KirkE.; Verstak, Tatsiana A.; Lutat, Katie E.; Riggsbee, Daniel L.; Mooney, Jeremiah W. (2018-10). "Recent developments in topoisomerase-targeted cancer chemotherapy". Acta Pharmaceutica Sinica. B. 8 (6): 844–861. doi:10.1016/j.apsb.2018.07.008. ISSN 2211-3835. PMC 6251812. PMID 30505655. {{cite journal}}: Check date values in: |date= (help)
  10. ^ a b c d Kampranis, Sotirios C.; Gormley, Niall A.; Tranter, Rebecca; Orphanides, George; Maxwell, Anthony (1999-02-01). "Probing the Binding of Coumarins and Cyclothialidines to DNA Gyrase". Biochemistry. 38 (7): 1967–1976. doi:10.1021/bi982320p. ISSN 0006-2960.
  11. ^ Lewis, R J; Singh, O M; Smith, C V; Skarzynski, T; Maxwell, A; Wonacott, A J; Wigley, D B (1996-03-15). "The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography". The EMBO Journal. 15 (6): 1412–1420. ISSN 0261-4189. PMID 8635474.
  12. ^ Anderson, V. E.; Osheroff, N. (2001-03). "Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde". Current Pharmaceutical Design. 7 (5): 337–353. doi:10.2174/1381612013398013. ISSN 1381-6128. PMID 11254893. {{cite journal}}: Check date values in: |date= (help)
  13. ^ a b Anderson, V. E.; Osheroff, N. (2001-03). "Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde". Current Pharmaceutical Design. 7 (5): 337–353. doi:10.2174/1381612013398013. ISSN 1381-6128. PMID 11254893. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Research, Center for Drug Evaluation and (2019-04-15). "FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes". FDA.
  15. ^ Collin, Frédéric; Karkare, Shantanu; Maxwell, Anthony (2011-11). "Exploiting bacterial DNA gyrase as a drug target: current state and perspectives". Applied Microbiology and Biotechnology. 92 (3): 479–497. doi:10.1007/s00253-011-3557-z. ISSN 0175-7598. PMC 3189412. PMID 21904817. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Drlica, Karl; Hiasa, Hiroshi; Kerns, Robert; Malik, Muhammad; Mustaev, Arkady; Zhao, Xilin (2009-8). "Quinolones: Action and Resistance Updated". Current Topics in Medicinal Chemistry. 9 (11): 981–998. doi:10.2174/156802609789630947. ISSN 1568-0266. PMC 3182077. PMID 19747119. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Li, Fengzhi; Jiang, Tao; Li, Qingyong; Ling, Xiang (2017-12-01). "Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?". American Journal of Cancer Research. 7 (12): 2350–2394. ISSN 2156-6976. PMC 5752681. PMID 29312794.
  18. ^ Wolfson, John S.; Hooper, David C. (1991-12-30). "Overview of fluoroquinolone safety". The American Journal of Medicine. Fluoroquinolones in the Treatment of Human Infection: The Role of Temafloxacin. 91 (6, Supplement 1): S153–S161. doi:10.1016/0002-9343(91)90330-Z. ISSN 0002-9343.
  19. ^ Research, Center for Drug Evaluation and (2019-04-15). "FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes". FDA.
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