Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

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Title:Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds
Creators:
Holý, Antonín
Votruba, Ivan
Tloušťová, Eva
Masojídková, Milena
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 66, 10, pp. 1545-1592
Uncontrolled Keywords:Nucleotide analogs, Purines, ANP, Acyclic nucleoside phosphonates, Phosphonates, Cytostatic activity, Antineoplastic, Anticancer

Abstract

<i>N</i><sup>6</sup>-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)- ethyl] (PME), 9-[(<i>R</i>)-2-(phosphonomethoxy)propyl] [(<i>R</i>)-PMP] and enantiomeric (<i>S</i>)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (<strong>26</strong>-<strong>28</strong>) or 2-amino-6-chloro-9-{[2-(diisopropoxy- phosphoryl)methoxy]alkyl}purines (<strong>29</strong>-<strong>31</strong>) followed by treatment of the diester intermediates <strong>32</strong> with bromo(trimethyl)silane and hydrolysis. Diesters <strong>32</strong> were also obtained by reaction of <i>N</i><sup>6</sup>-substituted purines with synthons <strong>23</strong>-<strong>25</strong> bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (<strong>9</strong>) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (<strong>148</strong>) gave the diester <strong>149</strong> which was analogously converted to <i>N</i><sup>6</sup>-substituted 2,6-diamino- 9-[2-(2-phosphonoethoxy)ethyl]purines <strong>151</strong>-<strong>153</strong>. Alkylation of <i>N</i><sup>6</sup>-substituted 2,6-diaminopurines with (<i>R</i>)-[(trityloxy)methyl]oxirane (<strong>155</strong>) followed by reaction of thus-obtained intermediates <strong>156</strong> with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (<strong>158</strong>) followed by deprotection of the intermediates <strong>159</strong> gave <i>N</i><sup>6</sup>-substituted 2,6-diamino-9-[(<i>S</i>)-3-hydroxy-2-(phosphonomethoxy)propyl]purines <strong>160</strong>-<strong>163</strong>. The highest cytostatic activity <i>in vitro</i> was exhibited by the following <i>N</i><sup>6</sup>-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (<strong>53</strong>), allyl (<strong>54</strong>), [(2-dimethylamino)ethyl] (<strong>68</strong>), cyclopropyl (<strong>75</strong>) and dimethyl (<strong>91</strong>). In CCRF-CEM cells, the cyclopropyl derivative <strong>75</strong> is deaminated to the guanine derivative PMEG (<strong>3</strong>) which is then converted to its diphosphate. <p>

Title:Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds
Creators:
Holý, Antonín
Votruba, Ivan
Tloušťová, Eva
Masojídková, Milena
Uncontrolled Keywords:Nucleotide analogs, Purines, ANP, Acyclic nucleoside phosphonates, Phosphonates, Cytostatic activity, Antineoplastic, Anticancer
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:66
Number:10
Page Range:pp. 1545-1592
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc20011545UNSPECIFIED
ID Code:1877
Item Type:Article
Deposited On:06 Feb 2009 17:13
Last Modified:06 Feb 2009 16:13

Citation

Holý, Antonín; Votruba, Ivan; Tloušťová, Eva; Masojídková, Milena (2001) Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds. Collection of Czechoslovak Chemical Communications, 66 (10). pp. 1545-1592. ISSN 0010-0765

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