Zalcitabine 2-3 -dideoxycytidine, ddc TUD DaMocles SoSe 15

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1 Zalcitabine 2-3 -dideoxycytidine, ddc TUD DaMocles SoSe 15 Nina Drechsler, Christoph Drexler, Robin Dursun, Malte Eckert Graphic 1: Zalcitabine

2 Table of Contents Content Introduction Properties Physical Properties Safety Information Structure Synthesis History Medical Information NRTIs used to treat HIV About Zalcitabine Biological Effects HIV Treatments Sources 8

3 1. Introduction Graphic 2: Zalcitabine. Zalcitabine is a nucleoside analogue reverse transcriptase inhibitor (short: NRTI), which was first synthesized by Jerome Horwitz in , and was used to treat human immunodeficiency virus (HIV) from 1992 until Reverse transcriptase inhibitors prevent the reproduction of HIV by interrupting the process of polymerase. 2. Properties 2.1. Physical Properties Molecular Formula C9H13N3O3 Molecular Weight 211,22 g/mol Melting Point 217 C Zalcitabine is a color- and odorless powder, soluble in water (~80g/L) and DMSO (~100g/L) and only stable for 90 days at room temperature Safety Information Warning Hazard Statements 4 H351 Suspected of causing cancer. H361 Suspected of damaging fertility or the unborn child. Precautionary Statements 5 P281 Use personal protective equipment as required.

4 3. Structure Graphic 3: Structure of Zalcitabine. Graphic 4: Structure of Cytidine. Zalcitabine is an analog of the nucleoside cytidine. The difference is the missing 3 OH-group located on the ribose molecule. Nucleosides consist of a nucleobase and a ribose. Graphic 5: composition of nucleosides (black) and nucleotides (colored). Graphic 6: Desoxyribose. Graphic 7: Cytosine, one out of four nucleobases relevant to the DNA/ RNA. The other three being Adenine, Guanine and Thymine.

5 4. Synthesis Graphic 8: synthesis of Zalcitabine in 6 steps. Source of synthesis: Motawia, Mohammed S.; Pedersen, Erik B., Liebigs Annalen der Chemie Issue 6 Pages Journal 1990 The shown synthesis consists of six steps including the most important ones: Ring closure of 2-deoxy-D-erythro-pentose Substituting the OH-group in position 4 with an H Substituting MeO in position 5 with a propanamide.

6 5. History Zalcitabine was first synthesized in 1966 by Jerome Howitz, Detroit Institute of Cancer Research, Michigan, USA. It was first approved by the Food and Drug Administration (USA) on June 19 th, Zalcitabine, sold as monotherapy medicine named HIVID by Hofmann-LaRoche, was the third antiretroviral released, while Zidovudine was available as Retrovir by GlaxoSmithKline since 1987 and Didanosine was marketed as Videx by Bristol-Myers Squibb since Starting in 1996 Zalcitabine was used combined with Zidovudine to improve effectivity/ lower the progress of the disease even further. 7 In 1997 Zalcitabine was combined with Saquinavir (protease inhibitor, PI) due the combined therapy leading to higher PHS (physical health summary) and MHS (mental health summary) scores. 8 In 2006 Zalcitabine was discontinued by Hofmann-LaRoche and replaced with newer NRTI/PI combinations Medical Information 6.1. NRTIs used to treat HIV Active Ingredient Producer, Drug Approval Emtricitabine, FTC Gilead Sciences, Emtriva Limivudine, 3TC GlaxoSmithKline, Epivir Zidovudine, ZDV Glaxosmithkline, Retrovir enteric coated didanosine, ddi EC Bristol Myers-Squibb, Videx EC dideoxyinosine, ddi Bristol Myers-Squibb, Videx tenofovir disoproxil fumarate, TDF Gilead, Viread stavudine, d4t Bristol Myers-Squibb, Zerit abacavir sulfate, ABC GlaxoSmithKline, Ziagen Apricitabine Avexa Pharmaceuticals in development Table 1: NRTIs used to treat HIV

7 6.2. About Zalcitabine Zalcitabine was indicated as monotherapy if the patient had been intolerant of alternative antiretroviral therapy. It was used in combination with protease inhibitors (PI) if the patient has been treated with other NRTI (e. g. Zidovudine) prior to Zalcitabine. A positive trait of Zalcitabine is it s high oral bioavailability (above 80%) and the short time needed to absorb it (approximately hours). Due to its very short half life time (1-3 hours) it has to be taken in three times per day. 12 The intolerance rate of Zalcitabine is lower than that of other NTRIs but the adverse events range from nausea and headaches to peripheral neuropathy, pancreatitis, oral and oesophageal ulcers. 13 These side effects are common among NRTIs and based on their toxic effect on mitochondria because the NRTI-triphosphates are intervening in the process of mitochondrial reproduction. This leads to decreased mitochondrial energy-generating capacity, constraining the respiratory chain and citric acid cycle and a disequilibrium in energy balance. 7. Biological Effects 7.1. HIV The human immunodeficiency virus (HIV) infects vital parts of the immune system, preferably CD4 + T-cells, in order to replicate itself. 14 The loss of T-cells due to infected cells not functioning as planned and the destruction of infected cells weakens the immune system of the patient which will eventually lead to the death of the host. 15 Graphic 9: Schematic representation of the human immunodeficiency virus. On the outside: glycoproteins of the membrane. Inside: RNA-genome (red) reverse transcriptase enzymes (blue). Source: Stryer,Lubert: Biochemie. 4.Auflage. Spektrum Akademischer Verlag, Heidelberg; Berlin; Oxford, 1996, S. 404.

Graphic 10: The cycle of reproduction of HIV. It infects T-cells, programs them to replicate the virus via reverse transcriptase and lead to the death of the infected cell after finishing reproducing.

Reverse transcriptase: a viral RNA/DNA-polymerase changes the viral RNA into a proviral DNA 2. Integrase: integration of the proviral DNA into the DNA of the host cell.

8 Graphic 10: The cycle of reproduction of HIV. It infects T-cells, programs them to replicate the virus via reverse transcriptase and lead to the death of the infected cell after finishing reproducing. Source: Biologie Oberstufe. Gesamtband. Cornelsen, Berlin: 2001, S HIV has three essential enzymes which are needed to replicate the virus: 1. Reverse transcriptase: a viral RNA/DNA-polymerase changes the viral RNA into a proviral DNA 2. Integrase: integration of the proviral DNA into the DNA of the host cell. Viral polyprotein complexes develop 3. HIV-protease: final stage of reproduction, polyprotein complexes split into singular proteins. The new viruses are able to infect other T-cells Graphic 11: Life cycle of retroviruses. Source: Stryer, Lubert: Biochemie. 4.Auflage. Spektrum Akademischer Verlag, Heidelberg; Berlin; Oxford, 1996, S. 95.

9 7.2. Treatments If left untreated, HIV leaves the person with a life expectancy of 9-11 years. In the final stage of the disease, which is called acquired immunodeficiency syndrome (AIDS), the human body has almost no working immune system left and is susceptible to life-threatening diseases. Zalcitabine and other NRTIs or PIs are not able to eliminate HIV, but these medications lead to a higher life expectancy and better health conditions for the patients by halting the spread of the virus. Nowadays the combined antiretroviral therapy (cart) is used to treat HIV. As the name implies, it uses a combination of different types of medication: 1. NRTI: nucleoside analogue reverse transcriptase inhibitors 2. NNRTI: non-nucleoside reverse-transcriptase inhibitors 3. PI: protease inhibitors 4. FI: entry-inhibitors (or fusion inhibitors) 5. INSTI: integrase strand transfer inhibitors. Zalcitabine belongs to the category of NRTIs. It is a derivate of deoxycytidine. When reaching the target cell, it is activated by being phosphorylated and turned into the active triphosphate (ddcpt). This triphosphate competes as alternate substrate in reverse transcriptase of HIV. When Zalcitabine is used in the transcription process it terminates the process of reproduction, due to missing a 3 -OH-group, which is needed in the next step to build a phosphor-di-ester bond. Without these bonds the replication process will not be able to produce a steady DNA. 16 Graphics 12.1 and 12.2: Comparison of a successful phosphor-di-ester bond to a missing bond. Graphic 13: Guanine (black) and cytidine (red) as part of the RNA.

10 8. Sources 1 J. Horwitz, J. Org. Chem, 32 (1), 1967, abgerufen am abgerufen am abgerufen am abgerufen am E. De Clercq, International Journal of Antimicrobial Agents, 33 (2009), C. Craig, G. Moyle, AIDS, 11, 1997, D. Revicki, Antiviral Therapy, 4, 1999, abgerufen P. Cahn, AIDS, 20 (9), 2006, abgerufen am Instruction leaflet: abgerufen Biologie Oberstufe. Gesamtband. Cornelsen, Berlin: Garg H, Mohl J, Joshi A (Nov 9, 2012). HIV-1 induced bystander apoptosis 16

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