Evidence supporting the activity of 2′-C-cyano-2′-deoxy-1-β-d-arabino-pentafuranosylcytosine as a terminator in enzymatic DNA-chain elongation

doi:10.1016/S0960-894X(98)00459-4

Bioorganic & Medicinal Chemistry Letters

Volume 8, Issue 18, 22 September 1998, Pages 2559-2562

https://doi.org/10.1016/S0960-894X(98)00459-4 Get rights and content

Abstract

To investigate the stability of 2′-C-cyano-2′-deoxy-1-β-d-arabino-pentafuranosylcytosine 3′-phosphoric acid, its thymidine ester was prepared via the phosphoramidite method using allyl protection for the phosphate function. This ester is stable under acidic conditions but extremely labile under basic conditions, decomposing with a cleavage of the internucleotide bond even at pH 7.3.

The synthesis and the stability of an ester of 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentafuranosylcytosine (CNDAC) 3′-phosphoric acid are reported.

References (14)

Y. Hayakawa et al.
Tetrahedron Lett.
(1985)
S.L. Beaucage et al.
Tetrahedron
(1992)
Y. Hayakawa et al.
Tetrahedron Lett.
(1986)
P.G. Cookson et al.
J. Organometal. Chem.
(1975)
T. Ukai et al.
J. Orgmetal. Chem.
(1974)
A. Matsuda et al.
J. Med. Chem.
(1991)
A. Azuma et al.
J. Med. Chem.
(1993)

There are more references available in the full text version of this article.

Cited by (15)

Homologous recombination as a resistance mechanism to replication-induced double-strand breaks caused by the antileukemia agent CNDAC
2010, Blood
Citation Excerpt :
TAS-109, a formulation of the parent nucleoside, is being studied in solid tumors.2 Investigations of CNDAC have demonstrated a novel action mechanism of causing a single-strand nick after its incorporation into DNA.3-6 Ligation of the 3′-hydroxyl of the analog by incorporation of subsequent deoxynucleotides initiates β-elimination.
The nucleoside analog 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosyl-cytosine (CNDAC), currently in clinical trials for hematologic malignancies, has a novel action mechanism of causing a single-strand break after its incorporation into DNA. Double-strand breaks (DSBs) are generated thereafter in vivo and, if not repaired, pose lethal impact on cell survival. This study sought to define the mechanisms by which CNDAC-induced DSBs are formed and repaired. We demonstrated that single-strand breaks induced by CNDAC incorporation into DNA were converted to DSBs when cells progressed into the subsequent S-phase. CNDAC-induced DSBs were products of replication, rather than a consequence of apoptosis. ATM, the activator of homologous recombination (HR), was essential for cell survival after CNDAC treatment in cell lines and in primary acute myeloid leukemia samples, as were the HR components, Rad51, Xrcc3, and Brca2. Furthermore, formation of sister chromatid exchanges, a hallmark of HR, increased significantly after CNDAC-treated cells had progressed into a second replication cycle. In contrast, neither the replication stress sensor ATR nor DNA-PK, the initiator of nonhomologous end-joining of DSB, was involved in repair of CNDAC-induced damage. Together, these results indicate that HR, but not nonhomologous end-joining, is the major repair or survival mechanism for DNA damage caused by CNDAC.
Targeting and anti-tumor efficacy of liposomal 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine in mice lung bearing B16BL6 melanoma
2001, Cancer Letters
2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is a potent anti-cancer agent, and we previously observed that liposomal formulation of 5′-O-dipalmitoylphosphatidyl derivative of CNDAC (DPP-CNDAC) is desirable for targeting. For targeting to pulmonary cancer, we investigated the in vivo behavior of liposomes containing DPP-CNDAC by a non-invasive method using positron emission tomography. Liposomes composed of DPP-CNDAC and cholesterol (DPP-CNDAC/CH liposomes) were markedly accumulated in mice lung bearing B16BL6 melanoma. In metastatic pulmonary cancer model, DPP-CNDAC/CH liposomes significantly reduced the lung colonization in a dose-dependent manner. The activity was significantly superior to conventional liposomal formulation or soluble CNDAC. These results suggest that DPP-CNDAC/CH liposomes are useful for metastatic pulmonary cancer.
Analysis of the prolonged infusion of DFP-10917, a deoxycytidine analog, as a therapeutic strategy for the treatment of human tumor xenografts in vivo
2018, International Journal of Oncology
Permeation of aldopentoses and nucleosides through fatty acid and phospholipid membranes: Implications to the origins of life
2013, Astrobiology
Sapacitabine for cancer
2012, Expert Opinion on Investigational Drugs
Permeation of nucleosides through lipid bilayers
2011, Journal of Physical Chemistry B

View all citing articles on Scopus

View full text

Evidence supporting the activity of 2′-C-cyano-2′-deoxy-1-β-d-arabino-pentafuranosylcytosine as a terminator in enzymatic DNA-chain elongation

Abstract

Tetrahedron Lett.

Tetrahedron

Tetrahedron Lett.

J. Organometal. Chem.

J. Orgmetal. Chem.

J. Med. Chem.

J. Med. Chem.