Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 7 1417
Gen er a l Syn th esis of DECA An a logu es. Synthesis of
unsaturated linkers for the compounds was carried out by
reduction (Lindlar catalyst and Birch reaction, respectively)
of the 1,10-alkynediol, which had been prepared by a previ-
ously described method.14 Saturated linkers were commercially
available as diols and were converted to diiodides.15 Alkylation
of each alkyl linker by 4-amino-2-methylquinoline (present in
3-fold stoichiometric excess) was carried out in 2-10 mL of
2-butanone at 95 °C for 48 h. The product, which precipitates
out of solution as a diiodide salt, was filtered and washed three
times with 5-10 mL of 2-butanone.
DMSO-d6) δ 0.85 (t, J ) 5.1 Hz, 3H), 1.24 (br, 12H), 1.43 (m,
2H), 1.70 (m, 2H), 2.73 (s, 3H), 4.45 (t, J ) 8.09 Hz, 2H), 6.73
(s, 1H), 7.72 (dd, 1H), 8.02 (dd, 1H), 8.15 (d, J ) 8.94 Hz, 1H),
8.43 (d, J ) 8.37 Hz), 8.81 (br, 2H). Anal. Calcd for C20H31N2I:
C, 56.33%; H, 7.33%; N, 6.57%. Found: C, 56.23%; H, 7.41%;
N, 6.42%. MS: [M - I-] ) 299 (m/z) (calcd 299.47 for
C20H31N2).
Ack n ow led gm en t. We thank Prof. J erome Schul-
man for valuable advice and discussion. Preliminary
syntheses were carried out by Mengxiao Shi, Yanzhong
Wu, and Tova Adlerstein. Mass spectrometry measure-
ments were carried out by Dr. Clifford Soll (Hunter
College) and Prof. David C. Locke (Queens College).
Assistance with NMR spectral analysis by Dr. Robert
J . Donovan is gratefully acknowledged. Funding was
provided by the Gustavus and Louise Pfeiffer Founda-
tion (to S.A.R.) and by NIH Grants CA60618 (to S.A.R.)
and HL16660 (to R.B.). The 400-MHz NMR spectrom-
eter was funded by a grant from NSF (CHE-9408535).
Ch a r a cter iza tion of DECA An a logu es.15 Product com-
pounds were analyzed for purity by HPLC on a Waters Delta-
Pak C18 reverse-phase column (2 × 150 mm, 300 Å), using an
acetonitrile gradient (0-60% acetonitrile) in water for 1 h. By
this analysis, each product was judged to be >90% pure. As
demonstrated by HPLC, the isomeric purity of the trans
compound 6 was nearly 100%. The cis isomer 5 however
contained 17% of 6 and was therefore composed of a 5:1 cis:
trans ratio. Compounds were analyzed by 1H NMR using a
Bruker NMR spectrometer at 400 MHz and by low-resolution
electrospray ionization-mass spectrometry.
Su p p or tin g In for m a tion Ava ila ble: Synthetic methods
are detailed along with a listing of NMR spectra and HPLC
chromatograms of key new compounds. This material is
1,1′-[(E)-5-Decen e-1,10-d iyl]bis[4-a m in o-2-m eth ylqu in -
olin iu m ], d iiod id e (5): 1H NMR (DMSO-d6) δ 1.52 (m, 4 H),
1.74 (m, 4 H), 2.10 (m, 4 H), 2.72 (br s, 6 H), 4.46 (m, 4 H),
5.45 (m, 2 H), 6.72 (br s, 2 H), 7.72 (m, 2 H), 8.00 (m, 2 H),
8.14 (m, 2 H), 8.45 (m, 2 H), 8.84 (br s, 4 H). Anal. Calcd for
Refer en ces
C
30H38N4I2: C, 50.86%; H, 5.41%; N, 7.91%. Found: C, 50.82%;
H, 5.30%; N, 6.97%. MS: [M - 2I-] ) 227.1 (m/z) (calcd 227.32
for C30H38N4).
(1) Rotenberg, S. A.; Sun, X.-g. Photoinduced inactivation of protein
kinase C by dequalinium identifies the RACK-1 binding domain
as a recognition site. J . Biol. Chem. 1998, 273, 2390-2395.
(2) Rotenberg, S. A.; Smiley, S.; Ueffing, M.; Krauss, R. S.; Chen,
L. B.; Weinstein, I. B. Inhibition of rodent protein kinase C by
the anticarcinoma agent dequalinium. Cancer Res. 1990, 50,
677-685.
(3) Rotenberg, S. A.; Weinstein, I. B. (review article) Protein kinase
C in neoplastic cells. Biochemical and Molecular Aspects of
Selected Cancers; Academic Press: Orlando, 1991; pp 25-73.
(4) Weiss, M. J .; Wong, J . R.; Ha, C. S.; Bleday, R.; Salem, R. R.;
Steele, G. D.; Chen, L. B. Dequalinium, a topical antimicrobial
agent, displays anticarcinoma activity based on selective mito-
chondrial accumulation. Proc. Natl. Acad. Sci. U.S.A. 1987, 84,
5444-5448.
(5) Chen, L. B. Mitochondrial membrane potential in living cells.
Annu. Rev. Cell Biol. 1989, 4, 155-181.
(6) Bernal, S. D.; Lampidis, T. J .; McIsaac, R. M.; Chen, L. B.
Anticarcinoma activity in vivo of rhodamine 123, a mitochon-
drial-specific dye. Science 1983, 222, 169-172.
(7) Rotenberg, S. A.; Zhu, J .; Hansen, H.; Li, X.-d.; Sun, X.-g.;
Michels, C. A.; Riedel, H. Deletion analysis of protein kinase
CR reveals a novel regulatory segment. J . Biochem. 1998, 124,
756-763.
(8) Zhuo, S.; Allison, W. S. Inhibition and photoinactivation of the
bovine heart mitochondrial F1-ATPase by the cytotoxic agent,
dequalinium. Biochem. Biophys. Res. Commun. 1988, 152, 968-
972.
1,1′-[(Z)-5-Decen e-1,10-d iyl]bis[4-a m in o-2-m eth ylqu in -
olin iu m ], d iiod id e (6): 1H NMR (DMSO-d6) δ 1.52 (m, 4 H),
1.74 (m, 4 H), 2.10 (m, 4 H), 2.72 (br s, 6 H), 4.46 (m, 4 H),
5.40 (m, 2 H), 6.72 (br s, 2 H), 7.72 (m, 2 H), 8.00 (m, 2 H),
8.14 (m, 2 H), 8.45 (m, 2 H), 8.84 (br s, 4 H). Anal. Calcd for
C
30H38N4I2: C, 50.86%; H, 5.41%; N, 7.91%. Found: C, 50.88%;
H, 5.28%; N, 7.76%. MS: [M - 2I-] ) 227.1 (m/z) (calcd 227.32
for C30H38N4).
1,1′-(1,12-Dod eca n ed iyl)b is[4-a m in o-2-m et h ylq u in o-
lin iu m ], d iiod id e (1d ): 1H NMR (DMSO-d6) δ 1.35 (br s, 8
H), 1.40 (m, 4 H), 1.48 (m, 4 H), 1.73 (m, 4 H), 2.75 (s, 6 H),
3.35 (br s, 4 H), 4.45 (t, J ) 7.7 Hz, 4 H), 6.75 (s, 2 H), 7.72 (t,
J ) 7.7 Hz, 2 H), 8.05 (t, J ) 7.7 Hz, 2 H), 8.15 (d, J ) 8.0 Hz,
2 H), 8.45 (d, J ) 8.0 Hz, 2 H), 8.85 (br s, 4 H). Anal. Calcd for
C
32H44N4I2: C, 52.09%; H, 6.01%; N, 7.59%. Found: C, 51.52%;
H, 6.08%; N, 7.13%. MS: [M - 2I-] ) 242.1 (m/z) (calcd 242.35
for C32H44N4).
1,1′-(1,14-Tetr a d eca n ed iyl)bis[4-a m in o-2-m eth ylqu in o-
lin iu m ], d iiod id e (1e): 1H NMR (DMSO-d6) δ 1.30 (br s, 8
H), 1.35 (m, 4 H), 1.45 (m, 4 H), 1.75 (m, 4 H), 2.75 (s, 6 H),
3.35 (m, 4 H), 4.47 (m, 4 H), 6.75 (s, 2 H), 7.72 (t, J ) 7.7 Hz,
2 H), 8.05 (t, J ) 7.7 Hz, 2 H), 8.15 (d, J ) 8.0 Hz, 2 H), 8.45
(d, J ) 8.0 Hz, 2 H), 8.85 (br s, 4 H); 13C NMR (DMSO-d6) δ
24.31, 28.57, 30.75, 31.53, 31.71, 31.75, 50.65, 106.61, 106.68,
119.25, 119.31, 121.14, 127.01, 128.61, 136.56, 141.72, 157.72,
159.37, 159.43. Anal. Calcd for C34H48N4I2: C, 53.27%; H,
6.31%; N, 7.31%. Found: C, 52.93%; H, 6.30%; N, 6.93%. MS:
[M - 2I-] ) 256.2 (m/z) (calcd 256.38 for C34H48N4).
(9) Bodden, W. L.; Palayoor, S. T.; Hait, W. N. Selective antimito-
chondrial agents inhibit calmodulin. Biochem. Biophys. Res.
Commun. 1986, 135, 574-582.
(10) Galanakis, D.; Ganellin, C. R.; Malik, S.; Dunn, P. M. Synthesis
and pharmacological testing of dequalinium analogues as block-
ers of the apamin-sensitive Ca2+-activated K+ channel: variation
of the length of the alkylene chain. J . Med. Chem. 1996, 39,
3592-3595.
1,1′-(1,16-Hexa d eca n ed iyl)bis[4-a m in o-2-m eth ylqu in o-
lin iu m ], d iiod id e (1f): 1H NMR (DMSO-d6) δ 1.30 (m, 16
H), 1.45 (br s, 4 H), 1.73 (br s, 4 H), 2.74 (s, 6 H), 3.34 (br s, 4
H), 4.46 (m, 4 H), 6.74 (s, 2 H), 7.73 (t, J ) 7.5 Hz, 2 H), 8.02
(t, J ) 8.2 Hz, 2 H), 8.16 (d, J ) 8.9 Hz, 2 H), 8.44 (d, J ) 8.2
Hz, 2 H), 8.83 (br s, 4 H); 13C NMR (DMSO-d6) δ 26.53, 30.80,
32.98, 33.57, 33.93, 34.00, 52.88, 108.85, 108.91, 121.49,
121.55, 123.37, 129.25, 130.84, 139.36, 143.96, 159.96, 161.68.
Anal. Calcd for C36H52N4I2: C, 54.41%; H, 6.59%; N, 7.05%.
Found: C, 53.94%; H, 6.68%; N, 6.65%. MS: [M - 2I-] ) 270.2
(m/z) (calcd 270.41 for C36H52N4).
N-Decyl-4-a m in oqu in a ld in iu m Iod id e (2). This com-
pound was prepared by mixing commercially available iodo-
decane and 4-aminoquinaldine in methyl ethyl ketone and
refluxing for 72 h. The solid product was collected by filtration
and recrystallized twice in absolute ethanol: 1H NMR (in
(11) This analysis was previously applied to a two-site binding model
by Shuker, S. B.; Hajduk, P. J .; Meadows, R. P.; Fesik, S. W.
Science 1996, 274, 1531-1535 (adapted from Proc. Natl. Acad.
Sci. U.S.A. 1981, 78, 4046). The IC50 value, which is identical
to the inhibitory binding constant (Ki) of C10-DECA with PKCR
(ref 1), provides a convenient concentration for comparing the
apparent Kd(AB) values of the monomeric and dimeric com-
pounds.
(12) W. S. Allison (University of California, San Diego), personal
communication.
(13) Sullivan, R. M.; Stone, M.; Marshall, J . F.; Uberall, F.; Roten-
berg, S. A. Manuscript submitted for publication.
(14) Qin, D.; Byun, H.-S.; Bittman, R. Palmitic and palmitoleic acids
from THF-d8. J . Org. Chem. 1996, 61, 8709-8711.
(15) See Supporting Information: synthetic methods along with a
listing of NMR spectra and HPLC chromatograms of key new
compounds.
J M990340Z