Preparation of 8-(Arylsulfanyl)adenines
with Diazonium Salts under Mild,
Aerobic Conditions
proved in phase I/II clinical trials using the semisynthetic
inhibitor 17-allyl-17-desmethoxygeldanamycin.
As derivatives of the structurally complex natural
product geldanamycin are expensive, often difficult to
formulate, and limited to parenteral use, we are develop-
ing orally active, small-molecule inhibitors of Hsp90.
Recently, we and others have identified 8-arylsulfanyl
Marco A. Biamonte,* Jiandong Shi, David Hurst,
Kevin Hong, Marcus F. Boehm, and
Srinivas R. Kasibhatla
2
2,3
purines and 8-benzyl purines as new classes of potent
4
Conforma Therapeutics Corporation, 9393 Towne Centre
Drive, Suite 240, San Diego, California 92121
and specific Hsp90 inhibitors. For our investigations, the
need arose to produce 8-(arylsulfanyl)adenines having the
generic structure 5, which we initially obtained by
reacting 8-bromoadenine (1) with thiophenolates in DMF
at 70-120 °C (Scheme 1, eq 1).
Received August 23, 2004
This method had several limitations: (i) some thiophe-
nols did not withstand the reaction temperatures, (ii) the
preparation of 8-bromoadenine 1 by bromination of
5
adenine was in our hands capricious and often incom-
plete, and (iii) the range of commercial thiophenols did
not have the substitution pattern relevant to us.
We therefore evaluated an alternative route by react-
ing 6-amino-7,9-dihydropurine-8-thione (3) with diazo-
nium salts (Scheme 1, eq 2). The sulfur atom is present
on the adenine ring rather than on the benzene ring. This
formally reverses the polarity of the reaction, and the
adenine becomes the nucleophile.
8
-(Arylsulfanyl)adenines 11 were prepared in up to 75%
At the outset of our work, little was known about the
reaction of diazonium salts with heterocyclic sulfur nu-
yield by reacting the 8-thionoadenine 6 (acetic acid 3-(6-
amino-8-thioxo-7,8-dihydropurin-9-yl)propyl ester) with ben-
zenediazonium tetrafluoroborates in DMSO. Benzenedi-
azonium ions carrying an electron-withdrawing substituent
gave the highest yields. The reaction proceeded smoothly
at room temperature without any base and could be per-
formed under air atmosphere. The extremely mild conditions
are compatible with a wide range of functional groups.
6
cleophiles. In fact, only one example was reported: 2,4,6-
trimethylbenzenediazonium chloride was reacted with
the KOH salt of 3-mercapto-1H-1,2,4-triazole to yield the
corresponding sulfide (MeOH, 0-9 °C, 69%).
In contrast, the reaction of diazonium salts with
-
structurally simpler sulfur nucleophiles, such as HS ,
-
-
7
RS , or ArS , is well precedented. When the sulfur
-
nucleophile is HS or an equivalent thereof, the reaction
is a standard route to thiophenols. The diazonium salts
are then typically reacted with ROCS
thesis),
Heat Shock Protein 90 (Hsp90) is a molecular chap-
erone that maintains the proper conformation of “client”
proteins. Hsp90 client proteins include three clinically
8,9
-
2
(Leuckart syn-
1
10
2- 8
- 8
2- 8
11
S
n
,
NCS ,
S
2
O
3
, or thiourea to give,
validated cancer targets, Her-2/neu (Herceptin), Bcr-Abl
respectively, xanthates, thiophenolates, isothiocyanates,
(Gleevec), and the androgen receptor (Casodex), as well
as several oncogenes, such as EGFR, MET, IGF-1R, Akt,
Raf-1, and p53. Mutant client proteins, as found in cancer
cells, are particularly dependent on Hsp90 to preserve
their conformation and function. Inhibition of Hsp90
causes these client proteins to adopt aberrant conforma-
tions, which is followed by their rapid degradation by the
proteasome, resulting in cell-cycle arrest and ultimately
cell death. Hence, Hsp90 inhibitors can prevent tumor
growth by damaging multiple proliferative pathways.
Moreover, Hsp90 occurs in an activated form in cancer
cells and in a latent form in normal cells. This provides
a rare opportunity for medicinal chemists to specifically
target cancer cells with inhibitors selective for the
(
2) Kasibhatla, S. R.; Zhang, L.; Boehm, M. F.; Fan, J.; Hong, K.;
Shi, J.; Biamonte, M. A. Purine Analogs Having Hsp90 Inhibiting
Activity. WO 3037860, 2003.
(
3) Chiosis, G.; Lucas, B.; Shtil, A.; Huezo, H.; Rosen, N. Bioorg.
Med. Chem. 2002, 10, 3555.
4) The other classes of inhibitors are 3,4-diarylpyrazoles (Drysdale,
(
M. J.; Dymock, B. W.; Barril-Alonso, X.; Workman, P. 3,4-Diarylpyra-
zoles and their use in the therapy of cancer. WO 03/055860 A1, 2003),
the natural product radicicol and its derivatives (Ikuina, Y.; Amishiro,
N.; Miyata, M.; Narumi, H.; Ogawa, H.; Akiyama, T.; Shiotsu, Y.;
Akinara S.; Murakata, C. J. Med. Chem. 2003, 46, 2534), and
cycloproparadicol, obtained by total synthesis: Yang, Z. Q.; Geng, X.;
Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem.
Soc. 2004, 126, 7881.
(5) Janeba, Z.; Holy, A.; Masojidkova, M. Collect. Czech. Chem.
Commun. 2000, 65, 1126.
(
6) Horikawa, Y. et al. Production of sulfide compound. JP7053531,
1
c
activated form. This concept has been demonstrated in
murine models (tumor xenografts) and is currently being
1
995.
(7) Wulfman, D. S. Synthetic applications of diazonium ions. In The
chemistry of diazonium and diazo groups, Part 1; Patai, S., Ed.; John
Wiley and Sons: London, 1978; p 247.
(
1) (a) Kamal, A.; Boehm, M. F.; Burrows, F. J. Trends Mol. Med.
(8) For a fine review: Wardell, J. L. Preparation of thiols. In The
chemistry of the thiol group, Part 1; Patai, S., Ed.; John Wiley and
Sons: London, 1974; pp 163-263.
2
004, 10, 283. (b) Dymock, B. W.; Drysdale, M. J.; McDonald, E.;
Workman, P. Expert Opin. Ther. Pat. 2004, 14, 837. (c) Kamal, A.;
Thao, L.; Sensintaffar, J.; Zhang. L.; Boehm, M. F.; Fritz, L. C.;
Burrows, F. J. Nature, 2003, 425, 407. (d) Isaacs, J. S.; Wanping, X.;
Neckers, L. Cancer Cell 2003, 3, 213.
(9) Stadler, O. Chem. Ber. 1884, 17, 2075.
(10) Clifford, A. M.; Lichty, J. G. J. Am. Chem. Soc. 1932, 54, 1163.
(11) Busch, M.; Schultz, K. J. Prakt. Chem. 1938, 150, 173.
1
0.1021/jo048522a CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/21/2004
J. Org. Chem. 2005, 70, 717-720
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