Synthesis and Biological Evaluation of 6-Substituted Purinylcarbanucleosides with a Cyclopenta[b]thiophene Pseudosugar

Abstract

The first members of a new family of heterocarbobicyclic nucleoside analogues have been synthesized from the cis/trans mixture of (4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)methanols (cis/trans -7). The separation of the cis and trans intermediates during the preparation of the 6-chloropurine derivatives allowed a separate preparation of the purine heterocarbanucleosides cis-10 and trans-11, from which cis-12-14 and trans-16-18 were obtained by replacement of the 6-chloro substituent with amino, hydroxy, and cyclopropylamino groups. Additionally, the 6-phenylpurinyl analogues cis-15 and trans- 19 were prepared from cis-10 and trans-11 using Suzuki-Miyaura methodology. In tests of antiviral and cytostatic activities, compound 11 showed cytostatic activity against Molt4/C8 human T lymphoblastic leukemia cells. Antiviral activity was shown by compounds 15 and 19 against Punta­ Toro virus and Coxackie virus B4 (compound 11).

heterobicyclic amino alcohol - cyclopenta[b]thiophene - Suzuki-Miyaura cross-coupling reaction - purinylcarbanucleoside - biological activity

References

<A NAME="RP06109SS-1A">1a</A> Vermeire K. Schols D. Bell TW. Curr. Med. Chem.  2006,  13:  731 

<A NAME="RP06109SS-1B">1b</A> De Clercq E. J. Med. Chem.  2005,  48:  1297 

<A NAME="RP06109SS-1C">1c</A> De Clercq E. Front. Med. Chem.  2004,  1:  543 

<A NAME="RP06109SS-1D">1d</A> Lazzarin A. Clotet B. Cooper D. Reynes J. Arastéh D. Nelson M. Katlama C. Stellbrink H.-J. Delfraissy J.-F. Lange J. Huson L. DeMasi R. Wat C. Delehanty J. Drobnes C. Salgo M. N. Engl. J. Med.  2003,  348:  2186 

<A NAME="RP06109SS-2">2</A> Mansour TS. Storer R. Curr. Pharm. Des.  1997,  3:  227 

<A NAME="RP06109SS-3A">3a</A> Nucleoside Analogs in Cancer Therapy   Cheson BD. Keating MJ. Plunkett W. Marcel Dekker; New York: 1997. 

<A NAME="RP06109SS-3B">3b</A> De Clercq E. Clin. Microb. Rev.  1997,  10:  674 

<A NAME="RP06109SS-3C">3c</A> De Clercq E. Curr. Med. Chem.  2001,  8:  1543 

<A NAME="RP06109SS-3D">3d</A> Ena J. Pasquau F. Clin. Infect. Dis.  2003,  36:  1186 

<A NAME="RP06109SS-3E">3e</A> Louie M. Hogan C. Di Mascio M. Hurley A. Simon V. Rooney J. Ruiz N. Brun S. Sun E. Perelson AS. Ho DD. Markowitz M. J. Infect. Dis.  2003,  187:  896 

<A NAME="RP06109SS-4">4</A> Balzarini J. Kang G.-J. Dala M. Herdewijn P. De Clercq E. Broker S. Johns DG. Mol. Pharmacol.  1987,  32:  162 

<A NAME="RP06109SS-5">5</A> Lea AP. Faulds D. Drugs  1996,  51:  846 

<A NAME="RP06109SS-6">6</A> Krayevsky AA. Watanabe KA. Modified Nucleosides as Anti-AIDS Drugs: Current Status and Perspectives   Bioinform; Moscow: 1993. 

<A NAME="RP06109SS-7">7</A> Thomas S. McDowall JE. Cheah V. Bye A. Segal MB. The Entry of Abacavir into the Guinea Pig Brain: Comparison with Other Reverse Transcriptase Inhibitors   Presented at the 12th World AIDS Conference, Geneva; Italy: 1998. 

For recent reviews of the biological properties of CNs, see:

<A NAME="RP06109SS-8A">8a</A> Cho JH. Bernard DL. Sidwell RW. Kern ER. Chu CK. J. Med. Chem.  2006,  49:  1140 

<A NAME="RP06109SS-8B">8b</A> Schneller SW. Curr. Top. Med. Chem.  2002,  2:  1087 

<A NAME="RP06109SS-8C">8c</A> Rodríguez JB. Comin MJ. Mini Rev. Med. Chem.  2003,  3:  95 

<A NAME="RP06109SS-8D">8d</A> Ichicawa E. Kato K. Curr. Med. Chem.  2001,  8:  385 

<A NAME="RP06109SS-8E">8e</A> Zhu X.-F. Nucleosides, Nucleotides Nucleic Acids  2000,  19:  651 

<A NAME="RP06109SS-8F">8f</A> Agrofoglio L. Challand SR. Acyclic, Carbocyclic and l -Nucleosides   Klewer Academic; Dordrecht: 1998. 

<A NAME="RP06109SS-9">9</A> Crimmins MT. King BW. J. Org. Chem.  1996,  61:  4192 

<A NAME="RP06109SS-10A">10a</A> Foster RH. Faulds D. Drugs  1998,  55:  729 

<A NAME="RP06109SS-10B">10b</A> Daluge SM. Martín MT. Sickles BR. Livingston DA. Nucleosides, Nucleotides Nucleic Acids  2000,  19:  297 

<A NAME="RP06109SS-10C">10c</A> Mahony WB. Domin BA. Daluge SM. Zimmerman TP. Biochem. Pharmacol.  2004,  68:  1797 

<A NAME="RP06109SS-10D">10d</A> Opravil M. Hirschel B. Lazzarin A. Furrer H. Chave J.-P. Yerly S. Bisset LR. Fischer M. Vernazza P. Benasconi E. Battegay M. Ledergerber B. Günthard H. Howe C. Weber R. Perrin L. J. Infect. Dis.  2002,  185:  1251 

<A NAME="RP06109SS-11">11</A> Bisacchi GS. Chao ST. Bachard C. Daris JP. Innaimo S. Jacobs GA. Kocy O. Lapointe P. Martel A. Merchant Z. Slusarchyk WA. Sundeen JE. Young MG. Colonno R. Zahler R. Bioorg. Med. Chem. Lett.  1997,  7:  127 

<A NAME="RP06109SS-12">12</A> Wyatt PG. Anslow AS. Coomber BA. Cousins RPC. Evans DN. Gilbert VS. Humber DC. Paternoster IL. Sollis SL. Tapolczay DJ. Weingarten GG. Nucleosides Nucleotides  1995,  14:  2039 

<A NAME="RP06109SS-13A">13a</A> Fernández F. García-Mera X. Morales M. Rodríguez-Borges JE. Synthesis  2001,  239 

<A NAME="RP06109SS-13B">13b</A> Fernández F. García-Mera X. Morales M. Vilariño L. Caamaño O. De Clercq E. Tetrahedron  2004,  60:  9245 

<A NAME="RP06109SS-13C">13c</A> Fernández F. García-Mera X. López C. Morales M. Rodríguez-Borges JE. Synthesis  2005,  3549 

<A NAME="RP06109SS-14A">14a</A> Fernández F. García-Mera X. Morales M. Rodríguez-Borges JE. De Clercq E. Synthesis  2002,  1084 

<A NAME="RP06109SS-14B">14b</A> Yao S.-W. Lopes VHC. Fernández F. García-Mera X. Morales M. Rodríguez-Borges JE. Cordeiro MNDS. Bioorg. Med. Chem.  2003,  11:  4999 

<A NAME="RP06109SS-15">15</A> Hocek M. Hol A. Votruba I. Dvoráková H. J. Med. Chem.  2000,  43:  1817 

<A NAME="RP06109SS-16A">16a</A> García MD. Caamaño O. Fernández F. Abeijón P. Blanco JM. Synthesis  2006,  73 

<A NAME="RP06109SS-16B">16b</A> Caamaño O. Gómez G. Fernández F. García MD. García-Mera X. De Clercq E. Synthesis  2004,  2855 

<A NAME="RP06109SS-16C">16c</A> Hergueta AR. López C. García-Mera X. Fernández F. Tetrahedron  2004,  60:  10343 

<A NAME="RP06109SS-16D">16d</A> García MD. Caamaño O. Fernández F. Figueira MJ. Gómez G. Synthesis  2003,  2138 

<A NAME="RP06109SS-16E">16e</A> López C. Caamaño O. Hergueta AR. García MD. Fernández F. Tetrahedron Lett.  2002,  43:  5311 

<A NAME="RP06109SS-17">17</A> García MD. Caamaño O. Fernández F. López C. De Clercq E. Synthesis  2005,  925 

<A NAME="RP06109SS-18">18</A> García MD. Caamaño O. Fernández F. García-Mera X. Pérez-Castro I. Synthesis  2006,  3967 

<A NAME="RP06109SS-19A">19a</A> Blanco JM. Caamaño O. Fernández F. Rodríguez-Borges JE. Balzarini J. De Clercq E. Chem. Pharm. Bull.  2003,  51:  1060 

<A NAME="RP06109SS-19B">19b</A> Guan H.-P. Ksebati MB. Cheng YC. Drach JC. Kern ER. Zemlicka J. J. Org. Chem.  2000,  65:  1280 

<A NAME="RP06109SS-20">20</A> Abeijón P. Blanco JM. Fernández F. García MD. López C. Eur. J. Org. Chem.  2006,  759 

<A NAME="RP06109SS-21">21</A> Yoon NM. Brown HC. J. Am. Chem. Soc.  1968,  90:  2927 

<A NAME="RP06109SS-22A">22a</A> Daluge S. Vince R. J. Org. Chem.  1978,  43:  2311 

<A NAME="RP06109SS-22B">22b</A> Patil SD. Schneller SW. Hosoya M. Snoeck R. Andrei G. Balzarini J. De Clercq E. J. Med. Chem.  1992,  35:  3372 

<A NAME="RP06109SS-23">23</A>

CCDC-636456 contains the supplementary crystallographic data for compound trans-18 reported in this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

<A NAME="RP06109SS-24">24</A> Cesnek M. Hocek M. Holy A. Collect. Czech. Chem. Commun.  2000,  65:  1357 

<A NAME="RP06109SS-25A">25a</A> Hocek M. Eur. J. Org. Chem.  2003,  245 

<A NAME="RP06109SS-25B">25b</A> Havelková M. Dvorak D. Hocek M. Synthesis  2001,  1704 

<A NAME="RP06109SS-25C">25c</A> Havelková M. Hoces M. Cesnek M. Dovorák D. Synlett  1999,  1145 

<A NAME="RP06109SS-26">26</A> Suzuki A. J. Organomet. Chem.  1999,  576:  147 ; and references cited therein

<A NAME="RP06109SS-27">27</A> Walker SD. Barder TE. Martinelli JR. Buchwald SL. Angew. Chem. Int. Ed.  2004,  43:  1871 

<A NAME="RP06109SS-28">28</A> De Clercq E. In Vitro and Ex Vivo Test Systems to Rationalize Drug Design and Delivery   Cromelin D. Couvreur P. Duchene D. Editions de Sante; Paris: 1994.  p.108