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Chemistry

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Also known as: Dideoxycytidine, 7481-89-2, 2',3'-dideoxycytidine, Ddcyd, Hivid, Cytidine, 2',3'-dideoxy-
Molecular Formula
C9H13N3O3
Molecular Weight
211.22  g/mol
InChI Key
WREGKURFCTUGRC-POYBYMJQSA-N
FDA UNII
6L3XT8CB3I

Zalcitabine
A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chain-terminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy.
1 2D Structure

Zalcitabine

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
4-amino-1-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
2.1.2 InChI
InChI=1S/C9H13N3O3/c10-7-3-4-12(9(14)11-7)8-2-1-6(5-13)15-8/h3-4,6,8,13H,1-2,5H2,(H2,10,11,14)/t6-,8+/m0/s1
2.1.3 InChI Key
WREGKURFCTUGRC-POYBYMJQSA-N
2.1.4 Canonical SMILES
C1CC(OC1CO)N2C=CC(=NC2=O)N
2.1.5 Isomeric SMILES
C1C[C@@H](O[C@@H]1CO)N2C=CC(=NC2=O)N
2.2 Other Identifiers
2.2.1 UNII
6L3XT8CB3I
2.3 Synonyms
2.3.1 MeSH Synonyms

1. 2',3' Dideoxycytidine

2. 2',3'-dideoxycytidine

3. Ddc (antiviral)

4. Dideoxycytidine

5. Hivid

6. Hivid Roche

7. Nsc 606170

8. Nsc-606170

9. Nsc606170

2.3.2 Depositor-Supplied Synonyms

1. Dideoxycytidine

2. 7481-89-2

3. 2',3'-dideoxycytidine

4. Ddcyd

5. Hivid

6. Cytidine, 2',3'-dideoxy-

7. Ddc

8. Zalcitibine

9. 4-amino-1-((2r,5s)-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1h)-one

10. Nsc 606170

11. Ro 24-2027/000

12. Ro-24-2027/000

13. Nsc-606170

14. Chembl853

15. 6l3xt8cb3i

16. 4-amino-1-[(2r,5s)-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2(1h)-one

17. Chebi:10101

18. Ncgc00090705-08

19. Ro-242027000

20. Ro-24-2027000

21. Dsstox_cid_3747

22. 4-amino-1-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one

23. Dsstox_rid_77182

24. Dsstox_gsid_23747

25. 2,3-dideoxycytidine

26. Nsc606170

27. 4-amino-1-[(2r,5s)-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2-one

28. Smr000058253

29. Ccris 692

30. Hivid(tm)

31. Hivid (tn)

32. Hsdb 7156

33. Interferon Ad + Ddc

34. Ddc & Gm-csf

35. Ddc & Scd4

36. Pc-sod & Ddc

37. Ddc (ddc)

38. Unii-6l3xt8cb3i

39. Brn 0654956

40. Zalcitabine (jan/usp/inn)

41. Ds-4152 & Ddc

42. 1-(2,3-dideoxy-beta-d-ribofuranosyl)cytosine

43. Ddc & Np (from Phca Or Hsa)

44. Sri-7707

45. Zalcitabine [usan:usp:inn:ban]

46. Cas-7481-89-2

47. Zalcitabine- Bio-x

48. Mfcd00012188

49. Ks-1130

50. Ddc & Ifn.alpha.

51. .beta.-d-ddc

52. Dideoxycytidine (ddc)

53. Zalcitabine [mi]

54. 4-amino-1-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one

55. Prestwick0_001037

56. Prestwick1_001037

57. Prestwick2_001037

58. Prestwick3_001037

59. Ddc & Interferon.alpha.

60. Zalcitabine [inn]

61. Zalcitabine [jan]

62. 2', 3'-dideoxycytidine

63. Zalcitabine [hsdb]

64. Zalcitabine [iarc]

65. Zalcitabine [usan]

66. Bmse000712

67. Upcmld-dp115

68. D 5782

69. Zalcitabine [vandf]

70. Schembl3598

71. Timtec1_004969

72. Zalcitabine [mart.]

73. Lopac0_000360

74. Bspbio_001253

75. Zalcitabine [usp-rs]

76. Zalcitabine [who-dd]

77. 3'-azido-3'-deoxythymidine/2',3'-dideoxycytidine

78. 5-25-14-00313 (beilstein Handbook Reference)

79. Mls000069636

80. Mls000759540

81. Mls001055363

82. Mls001424210

83. Mls006011951

84. Spbio_003104

85. Bpbio1_001378

86. Gtpl4828

87. Dtxsid0023747

88. Upcmld-dp115:001

89. Zinc39906

90. 2',3'-dideoxycytidine & Scd4(soluble Recombinant Protein)

91. Zalcitabine [orange Book]

92. Hms1548b19

93. Hms1571o15

94. Hms2051h18

95. Hms2090c12

96. Hms2098o15

97. Hms2236n08

98. Hms3261g21

99. Hms3715o15

100. Pharmakon1600-01502360

101. Zalcitabine [usp Impurity]

102. .beta.-d-2',3'-dideoxycytidine

103. Zalcitabine, 2'3'-dideoxycytidine

104. Bcp13878

105. Tox21_113491

106. Tox21_201655

107. Tox21_303169

108. Tox21_500360

109. Ac-824

110. Bdbm50145605

111. Lecithinized Superoxide Dismutase & .beta.-d-2',3'-dideoxycytidine

112. Nsc759655

113. S1719

114. Sulfated Polysaccharide-peptidoglycan Ds-4152 & 2',3'-dideoxycytidine

115. Akos015854844

116. Akos015894505

117. Tox21_113491_1

118. Ccg-101050

119. Cs-1110

120. Db00943

121. Lp00360

122. Nc00300

123. Nsc-759655

124. Sdccgsbi-0050348.p002

125. 2',3'-dideoxycytidine & Nanoparticles (from Human Serum Albumin Or Polyhexylcyanoacrylate)

126. Sri-7707-13

127. Sri-7707-14

128. Sri-7707_15

129. Sri-7707_17

130. Ncgc00090705-01

131. Ncgc00090705-02

132. Ncgc00090705-03

133. Ncgc00090705-05

134. Ncgc00090705-06

135. Ncgc00090705-07

136. Ncgc00090705-09

137. Ncgc00090705-10

138. Ncgc00090705-11

139. Ncgc00090705-13

140. Ncgc00090705-15

141. Ncgc00090705-24

142. Ncgc00090705-25

143. Ncgc00179242-01

144. Ncgc00257202-01

145. Ncgc00259204-01

146. Ncgc00261045-01

147. Bd164564

148. Hy-17392

149. Ddc;dideoxycytidine;2',3'-dideoxycytidine

150. 2',3'-dideoxycytidine & Interferon.alpha.

151. 2',3'-dideoxycytidine, >=98% (hplc)

152. Db-019728

153. D3581

154. Eu-0100360

155. Sw197364-4

156. 2',3'-dideoxycytidine, >=99.0% (hplc)

157. C07207

158. C76390

159. D00412

160. Cytidine, 2',3'-dideoxy- & Interferon.alpha.

161. 481d892

162. A838234

163. Sr-01000075822

164. Sr-01000736919

165. Zalcitabine (dideoxycytidine,ddc) [vandf]

166. J-700276

167. Q-201941

168. Q2344582

169. Sr-01000075822-1

170. Sr-01000736919-5

171. Cytidine, 2',3'-dideoxy- & Colony-stimulating Factor

172. Ro-242027000/ro-24-2027-000

173. Z1550648753

174. Zalcitabine, United States Pharmacopeia (usp) Reference Standard

175. 4-amino-1-(5-hydroxymethyl-tetrahydro-furan-2-yl)-1h-pyrimidin-2-one

176. .beta.-d-2',3'-dideoxycytidine & Granulocyte-macrophage Colony-stimulating Factor

2.4 Create Date
2005-06-24
3 Chemical and Physical Properties
Molecular Weight 211.22 g/mol
Molecular Formula C9H13N3O3
XLogP3-1.3
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count3
Rotatable Bond Count2
Exact Mass211.09569129 g/mol
Monoisotopic Mass211.09569129 g/mol
Topological Polar Surface Area88.2 Ų
Heavy Atom Count15
Formal Charge0
Complexity327
Isotope Atom Count0
Defined Atom Stereocenter Count2
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

Zalcitabine is indicated in combination with zidovudine, for the treatment of HIV infection in patients with limited prior exposure (< 3 months) to zidovudine. Zalcitabine is also indicated, in combination with antiretroviral protease inhibitors, for the treatment of HIV infection. /Included in US product labeling/

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2780


Zalcitabine is indicated as a monotherapy for the treatment of advanced HIV infection in patients who are intolerant of, or who have disease progression while receiving, alternative antiretroviral therapy. /Included in US product labeling/

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2780


4.2 Drug Warning

Peripheral neuropathy occurring during zalcitabine therapy generally is a sensorimotor neuropathy characterized initially as numbness and burning dysesthesia involving the distal extremities. When manifestations of peripheral neuropathy occur, they often become evident during the first 7-24 weeks of therapy and involve pain and discomfort in the feet, followed several weeks later by a burning dysesthesia in the same area. Clinically, patients may have diminished light touch, pin prick, temperature, and vibration sensations in the area of the feet and up to the midcalf; ankle deep-tendon reflexes may be decreased or absent. If the drug is not discontinued when these initial manifestations appear, sharp shooting pains or severe continuous burning pain may occur and can progress to severe pain requiring opiate analgesics and is potentially irreversible. Discomfort may be severe enough to cause gait disturbances. In some patients, manifestations of peripheral neuropathy progress to include the hands and are sometimes described as occurring in a stocking-and-glove pattern. Nerve biopsy and electrophysical studies indicate that axonal degeneration may occur.

McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 716


Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) have been reported rarely in patients receiving zalcitabine and also have been reported in patients receiving other nucleoside reverse transcriptase agents. Most reported cases have involved women; obesity and long-term therapy with a nucleoside antiretroviral also may be risk factors.

McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 716


Moderate to severe peripheral neuropathy has been reported in 3-35% of patients receiving oral zalcitabine at usual dosage (0.75 mg every 8 hours) either alone or in conjunction with zidovudine. Peripheral neuropathy occurs more frequently in patients with advanced HIV infection than in those with less advanced disease.

McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 716


The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in antiretroviral therapy should be considered if disease progression occurs during treatment with zalcitabine.

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2780


For more Drug Warnings (Complete) data for ZALCITABINE (33 total), please visit the HSDB record page.


4.3 Drug Indication

For the treatment of Human immunovirus (HIV) infections in conjunction with other antivirals.


FDA Label


5 Pharmacology and Biochemistry
5.1 Pharmacology

Zalcitabine is an analog of 2'-deoxycytidine that is pharmacologically related to but structurally different from other nucleotide reverse transcriptase inhibitors (NRTIs). Zalcitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.


5.2 MeSH Pharmacological Classification

Anti-HIV Agents

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)


Antimetabolites

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Antimetabolites.)


Reverse Transcriptase Inhibitors

Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)


5.3 ATC Code

J - Antiinfectives for systemic use

J05 - Antivirals for systemic use

J05A - Direct acting antivirals

J05AF - Nucleoside and nucleotide reverse transcriptase inhibitors

J05AF03 - Zalcitabine


5.4 Absorption, Distribution and Excretion

Absorption

Bioavailability is over 80% following oral administration.


Route of Elimination

Renal excretion of unchanged drug appears to be the primary route of elimination, accounting for approximately 80% of an intravenous dose and 60% of an orally administered dose within 24 hours after dosing (n=19). Renal clearance exceeds glomerular filtration rate suggesting renal tubular secretion contributes to the elimination of zalcitabine by the kidneys.


Volume of Distribution

0.304 to 0.734 L/kg


Clearance

285 mL/min [HIV-infected patients receiving 1.5 mg IV infusion for 1 hour]


Zalcitabine is eliminated principally in urine. Approximately 60-70% of an oral dose or 75-80% of an IV dose of the drug is eliminated unchanged in urine within 24 hours; approximately 10% of an orally administered dose is eliminated in feces as unchanged drug and ddU.

McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 722


Only limited information is available on the pharmacokinetics of zalcitabine in children; however, oral bioavailability of the drug appears to be lower in children than in adults. In a study in children 6 months to 13 years of age with symptomatic HIV infection, oral bioavailability of zalcitabine averaged 54% (range: 29-100%). Following oral administration of 0.03- or 0.04-mg/kg doses of zalcitabine every 6 hours in these children, peak plasma concentrations were 23.1-52.5 or 31.5-63 ng/mL, respectively. Following IV administration over 1 hour of 0.03- or 0.04-mg/kg doses of zalcitabine every 6 hours in these children, peak plasma concentrations were 39.9-44.1 or 79.8-165.9 ng/mL, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 721


Pregnant rhesus monkeys (Macaca mulatta) that were near term (146 days) received radiolabelled zalcitabine as a bolus dose of 0.6 mg/kg body weight via the radial vein. During a 3 hour sampling of both the mother and the fetus, the fetal:maternal ratio of the integrated area under the curve of plasma concentration-time was 0.32 +/- 0.02, and the fetal tissues were found to contain zalcitabine (0.05-0.8 umol/l equivalents) and zalcitabine monophosphate (0.008-0.09 nmol/g).

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V76 135 (2000)


About 10% of the drug appears in the feces and approximately 75% is excreted unchanged in the urine, suggesting that renal integrity is important for clearance.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V76 134 (2000)


For more Absorption, Distribution and Excretion (Complete) data for ZALCITABINE (9 total), please visit the HSDB record page.


5.5 Metabolism/Metabolites

Zalcitabine is not reported to undergo significant hepatic metabolism; it is mainly phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. The concentration of zalcitabine triphosphate remains low for quantitative detection and measurement in the plasma following administration of therapeutic doses.


The metabolic fate of zalcitabine has not been fully evaluated in humans. Dideoxyuridine (ddU) is the principal metabolite that has been identified for zalcitabine. In both urine and feces, ddU accounts for less than 15% of an oral dose of zalcitabine. Zalcitabine is not metabolized substantially in the liver and is relatively resistant to human cytidine deaminase, a catabolic enzyme that degrades many cytidine derivatives. Because zalcitabine is relatively resistant to degradation by cytidine deaminase, the drug is stable in plasma and resistant to first-pass metabolism in the liver.

McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 722


Hepatic metabolites have not been observed. The antiviral action of zalcitabine, like that of zidovudine and didanosine, is dependent on phosphorylation and incorporation into DNA. The first step is the formation of zalcitabine monophosphate by the enzyme 2'-deoxycytidine kinase, which is followed by formation of the diphosphate and triphosphate metabolites through the action of the cytosine monophosphate kinase and nucleotide diphosphate kinase enzymes, respectively.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V76 134 (2000)


5.6 Biological Half-Life

2 hours


Mean elimination half-life was 1.4 hr (range, 1.0-3.5) /in 23 mildly symptomatic human immunodeficiency virus-infected children (mean age, 4.2 years)/.

PMID:7594705 Chadwick EG et al; J Infect Dis 172 (6): 1475-9 (1995)


... The plasma half-time is reported to be 1-2.7 hours.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V76 134 (2000)


5.7 Mechanism of Action

Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Within cells, zalcitabine is converted to its active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the sequential action of cellular enzymes. ddCTP interferes with viral RNA-directed DNA polymerase (reverse transcriptase) by competing for utilization of the natural substrate deoxycytidine 5'-triphosphate (dCTP), as well as incorpating into viral DNA. Due to it's lack of a 3'-OH group, the formation of a 5' to 3' phosphodiester linkage that is necessary for DNA chain elongation is inhibited, thus leading to the termination of viral DNA growth.


Zalcitabine enters the cell through carrier-mediated and non-carrier-mediated mechanisms. It is first phosphorylated by deoxycytidine kinase and further by cellular kinases to its active metabolite, dideoxycytidine 5'-triphosphate. Unlike other nucleoside analogs, zalcitabine is most efficiently triphosphorylated in resting peripheral blood mononuclear cells. The triphosphate terminates viral DNA elongation. Zalcitabine decrease the intracellular pool of deoxycytidine triphosphate and binds somewhat to host beta and gamma DNA polymerases.

Goldfrank, L.R., Flomenbaum, N.E., Lewin, N.A., Weisman, R.S., Howland, M.A., Hoffman, R.S., Goldfrank's Toxicologic Emergencies 6th Ed. (1998)., McGraw-Hill, New York, N.Y., p. 1358


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