phosphonylmethoxyalkyl derivatives of purines and pyrimides: a new class of antiviral agents active...
TRANSCRIPT
S38
18. PHOSPHONYLWZTSOXYALKYL DERIVATIVES OF F’URINER AND PYRINIDES:
A NEW CLASS OF ANTIVIRAL AGENTS ACTIVE AGAINST SOTS
SERPESVIRUSES AND RETROVIRUSES
De Clercq E*, Sakuma T*, Raba M*, Pauwele R*, Balzarini J*,
Rosenberg I**, Holy A**
* Rega Institute for Hedical Research, Katholieke
Universiteit Leuven, B-3000 Leuven, Belgium
** Institute of Organic Chemistry and Biochemistry,
Czechoslovak Academy of Sciences, 16610 Prague,
Czechoslovakia.
AIDS patients are predisposed to 4 number of opportunistic infections,
in particular hcrpesvirus infections due to herpes simplex virus (HSV), va-
ricalla-zoster virus (VZV), cytomcgalovirus (CMV) or Epstein-Barr virus
(EBV), and, vice a, such herpesvirue infections may stimulate the ex-
pression of the human immunodeficieocy virus (HIV) genome', and, possibly,
precipitate the manifesrations of the AIDS disease. Chemotherapeutic approa-
ches have been directed towards rhe development of antiviral drugs for the
treatment of both herpesvirus or retrovirus groups: 2 i.e. (A> acyclovir 19-
(Z-hydroxyethoxymethyl)guenine], @)-5-(Z-bromovinyl)-2'-deoxyuridine (BVDU)
and l-C-D-(2-deoxy-2-fluoroarabinofuranosyl)-5-iodocy~osine (FIAC) for the
treatment of HSV infections; (ii) acyclovir, - BVDU. FIAC and (E)-5-(Z-bromo-
vinyl)-I-S-D-arabinofuraaosyluracil (BVaraU) for the treatment of VZV infec-
tions; (l&) 9-(1,3-dihydroxy-2-propoxymethy1)guanine (DHPG) and. foscarnet
(phosphonoformste) for the treatment of CMV infections; (iv) BVDU, and some
of the above, as potential therapeutic modalities for EBV infections; and
($ retrovir (3'-azido-2'.3'-dideoxythymidine), 2',3'-dideoxycylidine and
other 2' ,3'-dideoxynucleoside derivatives for the treetment of HIV infec-
tions.
We have recently developed a new class of compounds, namely phosphonyl-
methoxyalkylpurine and -pyrimidine derivatives, which are effective against
herpesviruses as well as retroviruees. This class of compounds, of which
(~)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine t(S)-HPMPA13 could be
considered as the prototype. is effective against a broad variety of DNA vi-
ru6es, including, in eddition to the herpesviruses HSV, VZV, CMV and EBV,
also adenoviruses. iridoviruses (i.e. African swine fever virus) and poxvi-
ruses (i.e. vsccinia virus). Active congenere have beea found among both the
purine (adeoine, guanine, 2,6-diaminopurine) and pyrimidine (cytosine) deri-
vativcs; and the side chain attached fo the N-9 of the purioe or N-l of the pyrimidioe ring may be either 2-phosphooylmethoxyethyl or (S)-3-hydroxy-2-
phosphooylmethoxypropyl, as shown in the accompanying Scheme :
R, = OH , NH2
R2 = H , NH2
R3
NH2
0 0
R3 = CH2 - CH2- 0 - CHz- L - OH or (HI-CH-0-CH2-b-OH
bH i H~OH bH
Supported by grants from the Belgian Fonds voor Ctottekundig Weten-
echapptlijk Ondtrzoek (project 3.0040.83) and the Belgian Ctconcertterde Oo-
dtrzoeksacties (project 85190-79).
Rtftrtoctt
1. Hotct, J-D., Bednarik. D.P.. Raj. N.B.K., Rosen, C.A.. Sodroski, J.G.9
Haeeltinc. U.A. and Pitha, P.M. 1987. Herpes simplex virus type-l can
reactivate transcription of latent human i~uoodeflcieocy virus. Nature
325, b7-70.
2. De Cltrcq, E.D.A. 1987. Antiviral oucltosidt analogs. ISI Atlas of
Science (Pharmacology) 1, 20-24.
3. De Clercq, E., Holy, A., Rosenberg, I., Sakuma, T., Balzarini, J. aud
Maudgtl, P.C. 1986. A novel selective broad-spectrum anti-DNA virue
agent. Naturt 323, 464-467.