Journal of Medicinal Chemistry
Article
cytotoxicity of arabinosyl nucleosides. Cancer Res. 1990, 50, 3675−
3680.
action of masked alaninyl d4T-MP derivatives. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 7295−7299.
(9) (a) Beumer, J. H.; Eiseman, J. L.; Parise, R. A.; Joseph, E.; Covey,
J. M.; Egorin, M. J. Modulation of gemcitabine (2′,2′-difluoro-2′-
deoxycytidine) pharmacokinetics, metabolism, and bioavailability in
mice by 3,4,5,6-tetrahydrouridine. Clin. Cancer Res. 2008, 14, 3529−
3535. (b) Mini, E.; Nobili, S.; Caciagli, B.; Landini, I.; Mazzei, T.
Cellular pharmacology of gemcitabine. Ann Oncol. 2006, 17 (Suppl 5),
v 7−12.
(10) (a) Mackey, J. R.; Mani, R. S.; Selner, M.; Mowles, D.; Young, J.
D.; Belt, J. A.; Crawford, C. R.; Cass, C. E. Functional nucleoside
transporters are required for gemcitabine influx and manifestation of
toxicity in cancer cell lines. Cancer Res. 1998, 58, 4349−4357.
(b) Gourdeau, H.; Clarke, M. L.; Ouellet, F.; Mowles, D.; Selner, M.;
(21) McGuigan, C.; Harris, S. A.; Daluge, S. M.; Gudmundsson, K.
S.; McLean, E. W.; Burnette, T. C.; Marr, H.; Hazen, R.; Condreay, L.
D.; Johnson, L.; De Clercq, E.; Balzarini, J. Application of
phosphoramidate pronucleotide technology to abacavir leads to a
significant enhancement of antiviral potency. J. Med. Chem. 2005, 48,
3504−3515.
(22) Vernachio, J. H.; Bleiman, B.; Bryant, K. D.; Chamberlain, S.;
Hunley, D.; Hutchins, J.; Ames, B.; Gorovits, E.; Ganguly, B.; Hall, A.;
Kolykhalov, A.; Liu, Y.; Muhammad, J.; Raja, N.; Walters, C. R.; Wang,
J.; Williams, K.; Patti, J. M.; Henson, G.; Madela, K.; Aljarah, M.;
Gilles, A.; McGuigan, C. INX-08189, a phosphoramidate prodrug of 6-
O-methyl-2′-C-methyl guanosine, is a potent inhibitor of hepatitis C
virus replication with excellent pharmacokinetic and pharmacodynamic
properties. Antimicrob. Agents Chemother. 2011, 55, 1843−1851.
(23) Walsby, E.; Congiatu, C.; Schwappach, A.; Walsh, V.; Burnett,
A. K.; McGuigan, C.; Mills, K. I. Nucleoside analogues of cladribine
produce enhanced responses in cell lines. Blood 2005, 106, 941A−
942A (Abstract 3369)..
̀
Richard, A.; Lee, N.; Mackey, J. R.; Young, J. D.; Jolivet, J.; Lafreniere,
R. G.; Cass, C. E. Mechanisms of uptake and resistance to
troxacitabine, a novel deoxycytidine nucleoside analogue, in human
leukemic and solid tumor cell lines. Cancer Res. 2001, 61, 7217−7224.
pancreatic cancer. (b) Liau, S.-S.; Whang, E. HMGA1 is a molecular
determinant of chemoresistance to gemcitabine in pancreatic
adenocarcinoma. Clin. Cancer Res. 2008, 14, 1470−1477.
(24) McGuigan, C.; Congiatu, C.; Mills, K. Phosphoramidate
derivatives of nucleoside compounds for use in the treatment of
cancer. EP1866324A1, WO 2006100439 A1.
(12) Moysan, E.; Bastiat, G.; Benoit, J. P. Gemcitabine versus
modified gemcitabine: a review of several promising chemical
modifications. Mol. Pharmaceutics 2013, 10, 430−444.
(13) Bender, D. M.; Bao, J.; Dantzig, A. H.; Diseroad, W. D.; Law, K.
L.; Magnus, N. A.; Peterson, J. A.; Perkins, E. J.; Pu, Y. J.; Reutzel-
Edens, S. M.; Remick, D. M.; Starling, J. J.; Stephenson, G. A.; Vaid, R.
K.; Zhang, D.; McCarthy, J. R. Synthesis, crystallization, and biological
evaluation of an orally active prodrug of gemcitabine. J. Med. Chem.
2009, 52, 6958−6961.
(14) Koolen, S. L. W.; Witteveen, P. O.; Jansen, R. S.; Langenberg,
M. H. G.; Kronemeijer, R. H.; Nol, A.; Garcia-Ribas, I.; Callies, S.;
Benhadji, K. A.; Slapak, C. A.; Beijnen, J. H.; Voest, E. E.; Schellens, J.
H. M. Phase I study of oral gemcitabine prodrug (LY2334737) alone
and in combination with erlotinib in patients with advanced solid
tumors. Clin. Cancer Res. 2011, 17, 6071−6082.
(15) (a) Bergman, A. M.; Adema, A. D.; Balzarini, J.; Bruheim, S.;
Fichtner, I.; Noordhuis, P.; Fodstad, O.; Myhren, F.; Sandvold, M. L.;
Hendriks, H. R.; Peters, G. J. Antiproliferative activity, mechanism of
action and oral antitumor activity of CP-4126, a fatty acid derivative of
gemcitabine, in in vitro and in vivo tumor models. Invest. New Drugs
2011, 29, 456−466. (b) Adema, A. D.; Smid, K.; Losekoot, N.;
Honeywell, R. J.; Verheul, H. M.; Myhren, F.; Sandvold, M. L.; Peters,
G. J. Metabolism and accumulation of the lipophilic deoxynucleoside
analogs elacytarabine and CP-4126. Invest. New Drugs 2012, 30, 1908−
1916.
(25) (a) Vande Voorde, J.; Liekens, S.; McGuigan, C.; Murziani, P.
G. S; Slusarczyk, M.; Balzarini, J. The cytostatic activity of NUC-3073,
a phosphoramidate prodrug of 5-fluoro-2′-deoxyuridine, is independ-
ent of activation by thymidine kinase and insensitive to degradation by
phosphorolytic enzymes. Biochem. Pharmacol. 2011, 82, 441−452.
(b) McGuigan, C.; Murziani, P. G. S.; Slusarczyk, M.; Gonczy, B.;
Vande Voorde, J.; Liekens, S.; Balzarini, J. Phosphoramidate ProTides
of the anticancer agent FUDR successfully deliver the preformed
bioactive monophosphate in cells and confer advantage over the
parent nucleoside. J. Med. Chem. 2011, 54, 7247−7258.
(26) (a) McGuigan, C. Preparation of amino acid-containing
nucleotide phosphoramidates as antitumor agents. PCT. Int. Appl.
2005 WO 2005012327 A2 20050210. (b) McGuigan, C. Nucleotide
phosphoramidates as anticancer agents. US 7951787 B2, 2005.
(27) Ghazaly E. A; Simon J.; Gribben, J. G.; Mohammad, T.;
Oluwadunni E.; Stavraka, Ch.; Hopkins, T.; Gabra, H.; Harpreet, W.;
Habib, N. A.; Leonard, R. C. F.; McGuigan, C.; Slusarczyk, M.;
Blagden, S. P. ProGem1: Phase 1 first-in-human study of the novel
nucleotide analogue NUC-1031 in adult patients with advanced solid
tumors. 2013 ASCO Annual Meeting J. Clin. Oncol. 2013, 31 (suppl;
Abstract 2576).
(28) Guo, Z.; Gallo, J. M. Selective protection of 2′,2′-
difluorodeoxycytidine (Gemcitabine). J. Org. Chem. 1999, 64, 8319−
8322.
(16) Ahmed, T. Clavis and Clovis collaborate on anticancer drug CP-
4126. Pharma Deals Review 2009, 12, 122. In 2012, Clavis Pharma and
Clovis Oncology suspended further development of CP-4126 after
demonstrating no difference in overall survival between CP-4126 and
gemcitabine in hENT1-low patients.
(29) McGuigan, C.; Pathirana, R. N.; Balzarini, J.; De Clercq, E.
Intracellular delivery of bioactive AZT nucleotides by aryl phosphate
derivatives of AZT. J. Med. Chem. 1993, 36, 1048−1052.
(30) Greene, T. W.; Wuts, P. G. M. Protective groups, in Organic
Chemistry, 2nd ed.; Wiley: New York, 1991.
(17) (a) Bazzanini, R.; Manfredini, S.; Durini, E.; Groschel, B.;
Cinatl, J.; Balzarini, J.; De Clercq, E.; Imbach, J. L.; Peirgaud, C.;
́
(31) Curley, D.; McGuigan, C.; Devine, K. G.; O′Connor, T. J.;
Jeffries, D. J.; Kinchington, D. Synthesis and anti-HIV evaluation of
some phosphoramidate derivatives of AZT: studies on the effect of
chain elongation on biological activity. Antiviral Res. 1990, 14, 345−
356.
(32) McGuigan, C.; Devine, K. G.; O′Connor, T. J.; Kinchington, D.
Synthesis and anti-HIV activity of some haloalkyl phosphoramidate
derivatives of 3′-azido-3′-deoxythymidine (AZT): potent activity of
the trichloroethyl methoxyalaninyl compound. Antiviral Res. 1991, 15,
255−263.
(33) Saboulard, D.; Naesens, L.; Cahard, D.; Salgado, A.; Pathirana,
R.; Velazquez, S.; McGuigan, C.; De Clercq, E.; Balzarini, J.
Characterization of the activation pathway of phosphoramidate triester
prodrugs of stavudine and zidovudine. Mol. Pharmacol. 1999, 56, 693−
704.
̈
Gosselin, G. Prodrugs of Ara-CMP and Ara-AMP with a S-acyl-2-
thioethyl (SATE) biolabile phosphate protecting group: synthesis and
biological evaluation. Nucleoside Nucleotides 1999, 18, 971−972.
(b) Galmarini, C. M.; Warren, G.; Senanayake, M. T.; Vinogradov,
S. V. Efficient overcoming of drug resistance to anticancer nucleoside
analogs by nanodelivery of active phosphorylated drugs. Int. J. Pharm.
2010, 395, 281−289.
(18) Cahard, D.; McGuigan, C.; Balzarini, J. Aryloxy phosphor-
amidate triesters as protides. Mini-Rev. Med. Chem. 2004, 4, 371−381.
(19) McGuigan, C.; Shackleton, J. M.; Tollerfield, S. M.; Riley, P. A.
Synthesis and evaluation of some novel phosphate and phosphinate
derivatives of araA. Studies on the mechanism of action of phosphate
triesters. Nucleic Acids Res. 1989, 17, 10171−10177.
(20) Balzarini, J.; Karlsson, A.; Aquaro, S.; Perno, C. F.; Cahard, D.;
Naesens, L.; De Clercq, E.; McGuigan, C. Mechanism of anti-HIV
(34) Birkus, G.; Wang, R.; Liu, X.; Kutty, N.; MacArthur, H.; Cihlar,
T.; Gibbs, C.; Swaminathan, S.; Lee, W.; McDermott, M. Cathepsin A
1541
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