Synthesis of two new heteroaromatic β-carboline-fused pentacycles. Observation of a new intercalating agent

Article abstract of DOI:10.1016/S0960-894X(00)00339-5

Five-step synthetic routes of two new polyfused heterocycles: indazolo[3,2-a]-β-carboline (3) and benzo[4',5'][1,2,3]triazino[6,1-a]-β-carbolinium salt (10) applying Pd(0)-catalyzed cross-coupling reaction have been elaborated. (C) 2000 Elsevier Science L

Full text of DOI:10.1016/S0960-894X(00)00339-5

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1767±1769
Synthesis of Two New Heteroaromatic ꢀ-Carboline-Fused
Pentacycles. Observation of a New Intercalating Agent
Dorottya Csanyi,a Gyorgy Hajos,a,* Zsuzsanna Riedl,a
Geza Timari,a,y Zoltan Bajor,a Fabien Cochard,
b Janos Sapib and Jean-Yves Laronzeb
aInstitute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, PO Box 17, Hungary
b
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Laboratoire de Chimie Therapeutique, UPRES A CNRS 6013 Isolement, Structure, Transformations et Synthese de Produits Naturels,
IFR 53 Biomolecules, Faculte de Pharmacie, Universite de Reims Champagne-Ardenne, 51, rue Cognacq-Jay, F-51096 Reims, France
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Received 24 March 2000; accepted 8 June 2000
AbstractÐFive-step synthetic routes of two new polyfused heterocycles: indazolo[3,2-a]-û-carboline (3) and benzo[40,50][1,2,3]tria-
zino[6,1-a]-û-carbolinium salt (10) applying Pd(0)-catalyzed cross-coupling reaction have been elaborated. # 2000 Elsevier Science
Ltd. All rights reserved.
The 9H-pyrido[3,4-b]indole (b-carboline) core is the
main structural unit of many biologically active alka-
loids and synthetic molecules of therapeutic interest.
Besides the traditional methods (Pictet±Spengler and
Bischler±Napieralski cyclisations) imino- phosphor-
anes1 have emerged as versatile building blocks for the
preparation of such heterocycles. In continuation of our
program towards the synthesis of biologically active
1,2,3,4-tetrahydro-b-carboline derivatives2 we found
that the iminophosphorane of tryptamine (1) could
successfully be used for such purposes. Thus, treatment
of 1 with o-nitrobenzaldehyde at 120 ꢀC in a sealed tube
for 4 days a€orded two products simultaneously:
besides the expected tetrahydro-û-carboline 2 (31%),3 a
hitherto unknown pentacyclic ring system, indazolo[3,2-
a]-b-carboline 3 was also isolated in 15% yield.
As polycyclic N-heteroaromatics may exhibit inter-
calating properties4,5 and from this point of view com-
pounds of such type came more and more into focus of
interest, we decided to elaborate a more convenient and
easily reproducable straightforward synthetic pathway
to this ring system and to study its intercalating ability.
This synthesis has been accomplished by application of
a well established ring fusion strategy elaborated
recently by us for various related aza-heterocycles and
alkaloids.6,7 Thus, û-carboline-1(2H)-one (4) was trea-
ted with tri¯ic anhydride to give a tri¯ate8 which was
subjected to Suzuki-coupling9 with o-pivaloyl-amino-
phenylboronic acid to yield the 1-aryl substituted b-
carboline derivative 5 (mp >250 ꢀC; 52%). Removal of
the pivaloyl group by treatment of 5 with 40% sulfuric
*Corresponding author. Fax: +36-1-325-7863;
e-mail: ghajos@cric.chemres.hu
yPresent address: CHINOIN Pharmaceutical and Chemical Works Co.
Ltd, H-1325 Budapest, PO Box 110, Hungary.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00339-5

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D. Csanyi et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1767±1769
1768
acid at re¯ux temperature (i.e., preparation of the
amino compound 6 prepared earlier by Rocca et al.10 by
an independent route), and subsequent diazotation gave
the diazonium salt 7. Treatment with sodium azide
under weakly basic conditions (sodium acetate bu€er)
a€orded the azide 811 in 66% yield. Heat-treatment of 8
gave rise to formation (by generation of a nitrene) of the
desired pentacyclic compound 3 in 58% yield which
proved to be identical (NMR spectrum and mp)12 with
the sample obtained from 1. In order to obtain a deri-
vative of this new ring system suitable for biological
investigations 3 was methylated by trimethyloxonium
tetra¯uoroborate in dichloromethane to give the 5-
methyl substituted salt (9)13 in good yield.
several measurements signi®cantly revealed that the
methyl substituted compound 9 is highly active: a Tm
point increase of 20.6 ꢀC was found, while the triazi-
nium salt 10 proved to be inactive.
Extension of the synthesis for further related derivatives
as well as detailed biological investigation of the new
heterocyclic ring systems is in progress.
Acknowledgements
The funds OTKA 2211, 26476 and ®nancial support from
the French Ministry of Education and Research (these
co-tutelle for D.C.) are gratefully acknowledged.
References and Notes
1. Molina, P.; Vilaplana, M. J. Synthesis, 1994, 1197.
2. Nagy, T.; Jeannin, L.; Sapi, J.; Laronze, J.-Y.; Renard, P.;
Pfei€er, B.; Bizot-Espiard, J.-G. Eur. J. Med. Chem. 1995, 30, 575.
1
3. (2) H NMR (CDCl3 300 MHz) d ppm 8.25 (NH, s, 1H),
7.83 (H5, dd, 7 Hz, 1.8 Hz, 1H), 7.52 (H30, dd, 9 Hz, 2 Hz,
1H), 7.41 (H60, dd, 9 Hz, 1.7 Hz, 1H), 7.4±7.12 (m, 4H), 7.33
(H8, dd, 7.2 Hz, 1.6 Hz, 1H), 5.65 (H1, s, 1H), 3.15 (H3, m,
2H), 2.87 (H4, m, 2H); 13C NMR (CDCl3 75 MHz) d ppm
149.8, 136.4, 135.9, 132.9, 132.2, 131.2, 128.6, 126.9, 124.2,
122.0, 119.5,118.3, 111.1, 110.9, 52.0, 41.6, 22.1.
4. Julino, M.; Stevens, M.F.G. J. Chem. Soc. Perkin 1 1998,
1677.
5. Pastor, J.; Siro, J.; Garcia-Navio, J. L.; Rodrigo, M. M.;
Ballesteros, M.; Alvarez-Builla, J. Bioorg. Med. Chem. Lett.
1995, 5, 3043.
6. (a) Timari, G.; Soos, T.; Hajos, Gy.; Messmer, A.; Nacsa,
J.; Molnar, J. Bioorg. Med. Chem. Lett. 1996, 6, 2831. (b)
Timari, G. Soos, T.; Hajos, Gy. Synlett 1997, 1067.
7. Csanyi, D.; Timari, G.; Hajos, Gy. Synth. Commun. 1999,
29, 3959.
8. Formation of this compound in a mixture of O- and N-
tri¯ic isomers has been reported: Bracher, F.; Hildebrand, D.;
Ludger, E. Arch. Pharm. (Weinheim) 1994, 327, 121. We have
obtained the pure tri¯ate by treating 4 with tri¯ic anhydride in
pyridine at room temperature, mp 103±5 ꢀC; 71%.
9. Suzuki-coupling to 1-chloro-b-carboline has already been
published: Bracher, F.; Hildebrand, D.; Liebigs Ann. Chem.
1992. 1315.
An interesting extension of this synthetic work was pro-
vided by investigating the intermediate diazonium salt 7 in
more detail. In one of our early studies14 we described that
o-substituted a-pyridylphenyldiazonium salts can form a
valence bond isomeric equilibrium with a fused v-triazi-
nium salt, and these equilibria can be sensitively shifted
by changing the substituents. In order to check whether
or not such a ring closure of 7 takes place the product of
the diazotation reaction of 6 was also isolated in crys-
talline form (mp 130±2oC; 96%)15 and was investigated
by IR and NMR spectroscopy. These spectra unam-
biguously revealed that the isolated product is entirely
in the triazinium form 10, and neither the crystals nor its
solutions contain detectable amount of the diazonium
isomer 7. To the best of our knowledge, this ring closed
product: benzo[40,50][1,2,3]triazino[6,1-a]-b-carbolinium
salt (10) also represents a new ring system. It is inter-
esting to note that two fused quaternary ring systems
closely related to 10: pyrido[2,1-a]-b-carbolinium and
pyridazino[3,2-a]-b-carbolinium salts have been descri-
bed and proved to be potent antitumor compounds.16,17
10. Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner,
G. J. Heterocycl. Chem. 1997, 34, 1205.
11. (8) 1H NMR (CDCl3+C6H6-d6 400 MHz) d ppm 8.54
(H3, d, 5 Hz, 1H), 8.22 (NH, s, 1H), 8.04 (H5, m, 1H), 7.84
(H4, d, 5 Hz, 1H), 7.56 (H30, m, 1H), 7.42 (H7, td, 7 Hz, 1 Hz,
1H), 7.33 (H50, m, 1H), 7.25 (H8, dt, 8 Hz, 1 Hz, 1H), 7.21
(H6, td, 7 Hz, 1 Hz, 1H), 7.17 (H40, t, 6.5 Hz, 1H), 7.16 (H60,
d, 7.5 Hz, 1H); 13C NMR (CDCl3) d ppm 140.7, 140.6, 139.4,
138.1, 134.5, 132.3, 130.5, 130.3, 129.7, 128.8, 125.6, 122.0,
121.9, 120.4, 119.1, 114.5, 111.8;, IR (KBr) n cm 1 2126, 2095,
1626, 1497, 1321, 1298, 1238, 748.
The fact that an equilibrium between 7 and 10 exists is
also revealed by the ®nding that treatment of the ring-
closed 10 with sodium azide under the same conditions
as in the transformation of the open-chained 7, the same
product (i.e., 8) was obtained.
12. (3) mp >240 ꢀC; 1H NMR (CDCl3+DMSO-d6 400 MHz)
d ppm 12.1 (NH, s, 1H), 8.62 (H4, dd, 8 Hz, 1 Hz, 1H), 8.54
(H7, d, 7Hz, 1H), 8.00 (H9, d, 8 Hz, 1H), 7.79 (H8, d, 7 Hz,
1H), 7.70 (H1, d, 8 Hz, 1H), 7.62 (H12, dd, 8 Hz, 1 Hz, 1H),
7.43 (H2, td, 8Hz, 1Hz, 1H), 7.35 (H11, m, 1H), 7.20 (H10, td,
7 Hz, 1 Hz, 1H), 7.17 (H3, td, 8 Hz, 1 Hz, 1H); 13C NMR
(CDCl3) d ppm 147.4, 138.6, 128.3, 126.1, 123.9, 123.5, 121.0,
119.9, 119.1, 119.0, 118.4, 118.0, 113.7, 113.4, 112.8, 110.7,
108.4; IR (KBr) n cm 1 3307, 1542, 1456, 1377, 1367, 1212, 725.
The intercalating property of the two new water-soluble
polycycles (9 and 10) was investigated by determination
of the increase of Tm point.18 As a model DNS, T20±
dA20 duplex was used19 (Tm=45.7 ꢀC) The results of

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1
13. (9) H NMR (DMSO-d6 400 MHz) d ppm 13.0 (NH, s,
1H), 9.78 (H8, d, 6.5Hz, 1H), 9.18 (H1, d, 8 Hz, 1H), 9.09 (H9,
d, 6.5 Hz, 1H), 8.83 (H4, dd, 8 Hz, 1 Hz, 1H), 8.59 (H10, dt, 8
Hz, 1 Hz, 1H), 8.52 (H2, td, 8 Hz, 1 Hz, 1H), 8.36 (H3, td,
8Hz, 1Hz, 1H), 7.90 (H13, dt, 8 Hz, 1 Hz, 1H), 7.84 (H12, td,
8 Hz, 1 Hz, 1H), 7.52 (H11, td, 8 Hz, 1 Hz, 1H).
16. Diaz, A.; Matia, M. P.; Garcia-Navio, J. L.; Vaquero, J.
J.; Alvarez-Builla, J. J. Org. Chem. 1994, 59, 8294.
17. Yoshino, H.; Koike, K.; Nikaido, T. Heterocycles 1999,
51, 281.
1H), 9.19 (H7, d, 7Hz, 1H), 8.97 (H1, dd, 8 Hz, 1 Hz, 1H),
8.74 (H8, d, 7 Hz, 1H), 8.42 (H9, d, 8 Hz, 1H), 8.09 (H4, dd, 8
Hz, 1 Hz, 1H), 8.01 (H3, td, 7 Hz, 1 Hz, 1H), 7.80 (H12, dd,
8Hz, 1Hz, 1H), 7.72 (H2, td, 7 Hz, 1 Hz, 1H), 7.68 (H11, td, 8
Hz, 1 Hz, 1H), 7.44 (H10, m, 1H), 4.45 (CH3); 13C NMR
(DMSO-d6) d ppm 141.4, 139.0, 132.3, 128.7, 127.7, 124.3,
123.6, 122.3, 122.2, 121.8, 121.4, 120.4, 116.5, 113.8, 113.3,
112.6, 109.7, 34.0.
14. Messmer, A.; Hajos, Gy.; Giber, J.; Holly, S. J. Hetero-
cycl. Chem. 1987, 24, 1133.
15. (10) H NMR (DMSO-d6 400 MHz) d ppm 13.2 (NH, s,
18. Helene, C. Proc. Nat. Acad. Sci. USA 1994, 81, 3297.
19. Synthesized by a MilliGen/Biosearch 8700 DNA syntheti-
zer using standard phosphoramidite chemistry.
1