6′,7′-Dihydrokeramamine C and analogues: Synthesis and biological evaluation

Article abstract of DOI:10.1016/S0040-4039(01)01774-9

6′,7′-Dihydrokeramamine C 7d and analogues have been synthesised and evaluated for their cytotoxicity. Compound 7f in which the azacycloundecane ring has been substituted by a dihexylamino unit showed increasing biological activity.

Full text of DOI:10.1016/S0040-4039(01)01774-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8297–8299
6%,7%-Dihydrokeramamine C and analogues: synthesis and
biological evaluation
Annie Pouilhe`s,a Monica Duval-Lungulescu,a Ste´phanie Lambel,b Ste´phane Le´onceb and
Yves Langloisa,*
aLaboratoire de Synthe`se des Substances Naturelles, associe´ au CNRS, Baˆtiment 410, Universite´ de Paris-Sud,
91405 Orsay, France
bI.d.R Servier, 11 rue des Moulineaux, 92150 Suresnes, France
Received 20 September 2001
Abstract—6%,7%-Dihydrokeramamine C 7d and analogues have been synthesised and evaluated for their cytotoxicity. Compound
7f in which the azacycloundecane ring has been substituted by a dihexylamino unit showed increasing biological activity. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
manzamine alkaloids,6 in this report we describe a new
straightforward synthetic route to dihydrokeramamine
C 3 and congeners and the biological evaluation of
these compounds.
Manzamine alkaloids1 are a new family of cytotoxic
natural products isolated from several Okinawan
marine sponges. Manzamine A 12 has the highest bio-
logical activity but manzamine C 2,3 which possesses
the simplest structure among these alkaloids, still
retains a significant cytotoxicity. Keramamine C 3, a
possible biogenetic precursor of manzamine C 2, has
been later isolated4 (Scheme 1). Structure–activity rela-
tionship of manzamine C 2 has been also examined.5
The role of the b-carboline unit and its possible interac-
tion with DNA through GC intercalation has been
emphasised. As far as we know, the biological activity
of tetrahydro-b-carboline analogues of manzamine C 2,
like keramamine C 3, has never been reported. As part
of a program oriented towards the total syntheses of
2. Synthesis of dihydrokeramamine C 7d and analogues
A straightforward two step strategy has been developed
for the synthesis of these tetrahydrocarboline deriva-
tives. Accordingly, acrylonitrile was added dropwise to
secondary amines 4a–4d (1 equiv.). After 48 h at room
temperature, the reaction mixture was distilled in
vacuo, affording aminonitriles 5a–5d in moderate to
good yields. Aminonitriles 5a–5d and 5e, 5f, which are
commercially available, were then condensed with
tryptamine derivatives 6a–6d7 in acetic acid under an
NH
N
N
N
N
H
H
N
H
N
H
OH
N
N
3
2
1
N
Scheme 1.
* Corresponding author. E-mail: langlois@icmo.u-psud.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01774-9

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A. Pouilhe`s et al. / Tetrahedron Letters 42 (2001) 8297–8299
R
N
R
N
R
N
R
N
R
N
R
N
( )5
( )5
O
4a
5a (60%)
4b
5b (82%)
4 : R=H
5 : R = (CH2)2CN
4c
5c (54%)
4d
5d
5e
5f
NH2
NH2
NH2
Br
NH2
MeO
N
H
N
H
N
H
N
H
MeO
6a
6b
6c
6d
3
4
5
NH
2
NH
1
NH
NH
N
NH
N
6
7
9
N
H
N
N
H
N
H
N
H
8
H
N
N
N
7d (16%
7b (76%)
7c(47%)
7a (40%)
IC50 : 33,5
7e (31%)
for 2 steps)
IC50 : 13,8
IC50 : 20,5
IC50 : 30,9
IC50 : 51,8
O
NH
NH
NH
N
NH
N
MeO
N
H
N
N
H
N
H
Br
MeO
H
7h (34%)
>IC50 : 10
N
N
7f (45%)
IC50 : 2,4
7i (48%)
>IC50 : 10
7g (63%)
>IC50 : 10
( )5 ( )5
Scheme 2. (IC50 mM).
hydrogen atmosphere in the presence of palladium on
References
charcoal,8 according to the method of Le´vy and
colleagues.9 After 20 h at room temperature, tetra-
hydrocarbolines 7a–7i10 were isolated after chromato-
graphic purification in modest to good yields (Scheme
2).
1. For reviews, see: (a) Tsuda, M.; Kobayashi, J. Heterocy-
cles, 1997, 46, 765; (b) Matzanke, N.; Gregg, R.; Wein-
reb, S. Org. Prep. Proc. Intl. 1998, 30, 1; (c) Magnier, E.;
Langlois, Y. Tetrahedron, 1998, 54, 6201.
2. (a) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G.
J. Am. Chem. Soc. 1986, 108, 6404; (b) Nakamura, H.;
Deng, S.; Kobayashi, J.; Ohizumi, Y. Tetrahedron Lett.
1987, 28, 621.
3. Sakai, R.; Kohmoto, S.; Higa, T.; Jefford, C. W.; Bernar-
dinelli, G. Tetrahedron Lett. 1987, 28, 5493.
4. Tsuda, M.; Kawazaki, N.; Kobayashi, J. Tetrahedron
Lett. 1994, 35, 4387.
5. Torisawa, Y.; Hashimoto, A.; Okouchi, M.; Iimori, T.;
Nagasawa, M.; Hino, T.; Nakagawa, M. Bioorg. Med.
Chem. Lett. 1996, 6, 2565.
6. (a) Sageot, O.; Monteux, D.; Langlois, Y.; Riche, C.;
Chiaroni, A. Tetrahedron Lett. 1996, 37, 7019; (b) Mag-
nier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837; (c)
Vidal, T.; Magnier, E.; Langlois, Y. Tetrahedron 1998,
54, 5959–5966.
3. Biological evaluation
Compounds 7a–7i were evaluated for their antiproliter-
ative activity using the murine L1210 leukaemia cell
line.11 The results expressed as IC50 values (concentra-
tion reducing by 50% cell proliferation) are reported in
Scheme 2. It appears that the presence of a fully
aromatised b-carboline unit is not essential to the activ-
ity.12 The azacycloundecane ring in 7d can be advanta-
geously replaced by aliphatic hydrophobic side chains
as in compound 7f. Otherwise, substitution on the
indole ring in compounds 7g–7i seems to have little
influence on cytotoxicity.
7. 5-Methoxy tryptamine 6d has been prepared according
to: Taniguchi, M.; Anjiki, T.; Nakagawa, M. Chem.
Pharm. Bull. 1984, 32, 2544.
8. With 6-bromo tryptamine 6c, Rh-Al2O3 was used instead
of Pd-C which induced an undesired hydrogenolysis of
bromine.
4. Conclusion
This study describes a direct access to keramamine C 3
congeners and demonstrates that some of these struc-
turally
cytotoxicity.
simple
compounds
display
significant

A. Pouilhe`s et al. / Tetrahedron Letters 42 (2001) 8297–8299
9. (a) Diker, K.; Do¨e´ de Maindreville, M.; Le´vy, J. Tetra-
8299
CH2×3; 2.14–1.86, 1H, m, and 1.74–1.22, 7H, CH2×4. 13
C
NMR (62.5 MHz, CDCl3): 155.7, C7; 136.4, C8a; 135.0,
C9a; 122.2, C4b; 118.4, C5; 107.7, C6; 106.9, C4a; 95.5, C8;
57.8, C3; 55.9, C1; 54.6, NCH2×2; 43.6, NCH2; 32.0, CH2;
26.1, C4; 24.2, CH2; 22. 4, CH2×2. Compound 7h 1H
NMR: 8.48, 1H, N9H; 7.43, 1H, s, 7.29, 1H, d, 7.11, 1H,
d, C8-H, C6-H and C5-H; 4.16–3.88, 1H, m, C1-H; 3.53–
3.28, 1H, m and 3.12–2.82, 1H, m, C3H2; 2.73–2.12, 9H,
m, N2-H, C4-H2, NCH2×3; 2.05–1.84, 1H, m, and 1.80–
1.38, 7H, m, CH2×4. 13C NMR (62.5 MHz, CDCl3):
137.4, C8a; 136.4, C4b; 126.6, C9a; 121.7, C5; 119.2, C6;
114.0, C7; 113.7, C8; 58.0, C3; 56.0, C1; 54.7, NCH2×2;
43.9, NCH2; 32.7, CH2; 26.1, C4; 24.2, CH2; 22.4, CH2×
2.
hedron Lett. 1995, 36, 2497; (b) Le´tinois, S.; Dumur,
J.-C.; He´nin, F.; Muzart, J. Tetrahedron Lett. 1998, 39,
2327.
10. Selected data: 1H NMR (200 MHz, l ppm, TMS=0,
CDCl3): compound 7b 1H NMR: 12, 1H, N9-H; 7.48, 1H,
d, 7.34, 1H, d, 6.98–7.18, 2H, m, C5-H, C8-H, C6-H and
C7-H; 4.13–3.98, 1H, m, C1-H; 3.58–3.30, 1H, m, C3-H;
3.11–2.92, 1H, m, C3-H; 2.88–2.21, 9H, m, C4-H2,
NCH2×3, N2-H; 2.08–1.91, 1H, m, and 1.88–1.46, 7H, m,
CH2×4. 13C NMR (50 MHz, CDCl3): 136.6, C8a; 135.6,
C4b; 127.6, C9a; 120.8, C6; 118.6, C5; 118.0, C7; 111.0, C8;
107.2, C4a; 58, C3; 55.9, C1; 54.2, NCH2×2; 44.0, NCH2;
32.5, CH2; 25.9, C4; 24.1, CH2; 22.6, CH2×2. Compound
7e 1H NMR: 10.90, 1H, N9-H; 7.51, 1H, dd, 7.29, 1H,
dd, 7.12, 2H, dt, C5-H, C8-H, C6-H and C7-H; 4.10, 1H,
t, C1-H; 3.37 and 3.01, 2H, m, C3-H2; 2.92–2.68, 3H, m,
N2-H and C4-H2; 2.61, 1H, m, and 2.42, 1H, m, CH2;
2.26, 6H, s, N(CH3)2; 1.91, 2H, m, CH2. 13C NMR (50
MHz, CDCl3): 135.9 and 135.7, C4b and C8a; 127.5, C9a;
121.0, 118.7, 118.0 and 111.1, C5, C6, C7 and C8; 107.6,
C4a; 58.0, C4; 54.6, C1, 45.2, N(CH3)2; 43.3, C3; 32.8,
CH2; 22.4, CH2. Compound 7g 1H NMR: 8.71, 1H, s,
N9-H; 7.34, 1H, d, 6.83, 1H, s and 6.71, 1H, s, C6-H,
C8-H, C5-H; 4.12–3.95, 1H, m, C1-H; 3.79, 3H, s, OCH3;
3.42–2.72, 2H, m, C3-H2; 2.72–2.10, 9H, m, N2-H, C4-H2,
11. L1210 murine leukaemia cells were grown in RPMI 1640
medium supplemented with 10% foetal calf serum, 2 mM
L
-glutamine, 100 units/mL penicillin, 100 mg/mL strepto-
mycin and 10 mM HEPES buffer. Cells were exposed to
graduated concentrations of the compounds. After incu-
bation for 48 h at 37°C, cell proliferation was measured
by MTT essay (Alley, M. C; Scudiero, A.; Monks, M. L.;
Cserwinski, M. J.; Fine, D. L.; Abott, B. J.; Mayo, J. G.;
Shoemaker, R. H.; Boyd, M. R. Cancer Res., 1988, 48,
589.). Results are expressed as IC50.
12. Other manzamine type alkaloids devoided of b-carboline
unit also showed significant cytotoxicity, see Ref. 1c.