Cytotoxic 4-Phenylcoumarins from Marila
Journal of Natural Products, 2005, Vol. 68, No. 3 373
References and Notes
(9), 152(7), 139(7), 128(5), 115(14), 105(7), 91(5), 77(10), 69(15),
55(5); HRFABMS found m/z 322.1205 (calcd for C20H18O4,
322.1203).
(1) Woodson, R. E.; Shery, R. W. Ann. Mo. Bot. Gard. 1980, 67, 969-
1043.
5-O-Methylmammeisin (4a). A cooled ethereal diazo-
methane solution (3 mL) was added dropwise to a cooled
solution of mammeisin (10 mg) in ether (2 mL), and the
reaction mixture was maintained at 0 °C for 3 h, then
concentrated in vacuo to give 4a (11 mg): white amorphous
(2) D’Arcy, W. G. Flora of Panama, Checklist and Index. Part II. Ann.
Mo. Bot. Gard. 1987, pp 1-670.
(3) Correa, M. D.; Foster, R.; Galdames; Stapf, M. S, C. Cata´logo de
Plantas Vasculares de Panama´, 1st ed.; Universidad de Panama´,
Instituto Smithsonian de Investigaciones Tropicales, Novo Art:
Bogota, Colombia. 2004; pp 1-600.
(4) Jorgensen, P.; Leo´n, Y. Catalogue of the Vascular Plants of Ecuador.
Monographs in Systematic Botany. Ann. Mo. Bot. Gard. 1999, 75,
1-1182.
(5) Schultes, R. Bot. Mus. Leafl. Univ. Harv. 1983, 29, 49-56.
(6) Rahalison, L.; Hamburguer, M.; Hostettmann, K.; Monod, M.; Frenk,
E.; Gupta, M. P.; Santana, A. I.; Correa, A.; Gonzalez. Int. J.
Pharmacog. 1993, 31, 68-76.
(7) Ioset, J.-R.; Marston, A.; Gupta, M. P.; Hostettmann, K. Pharm. Biol.
1988, 36, 103-106.
(8) Bokesch, H.; Groweis, A.; McKee, T.; Boyd, M. J. Nat. Prod. 1999,
62, 1197-1199.
(9) Finnegan, R. A.; Morris, M. P.; Djerassi, C. J. Org. Chem. 1961, 26,
1180-1184.
(10) Crombie, L.; Jones, R. C. F.; Palmer, C. J. J. Chem. Soc., Perkin Trans.
1 1987, 317-331.
(11) Govindachari, T. R.; Pai, B. R.; Subramaniam, U. R.; Ramdas Rao,
R. U.; Muthukumaraswamy, N. Tetrahedron 1967, 23, 4161-4165.
(12) Cao, S.-G.; Sim, K.-Y.; Pereira, J.; Goh, S. H. Phytochemistry 1998,
47, 1051-1055.
(13) Bordoloi, M.; Mohan, S.; Barua, N. C.; Dutta, S. C.; Mathur, R. K.;
Ghosh, A. C. Phytochemistry 1997, 44, 939-942.
(14) Crombie, L.; Games, D. E.; McCormick, A. J. Chem. Soc. C 1967,
2553-2559.
(15) Morel, C.; Guilet, D.; Oger, J.-M.; Seraphin, D.; Se´venet, T.; Wiart,
C.; Hadi, A. H. A.; Richomme, P.; Bruneton, J. Phytochemistry 1999,
50, 1243-1247.
solid (CHCl3); mp 130-132 °C; 1H NMR data, see Table 1; 13
C
NMR data, see Table 2; EIMS m/z 420 [M]+ (50), 406(24), 405-
(91), 377(17), 366(13), 365(55), 363(38), 349(21), 347(12), 308-
(22), 307(100), 293(9), 253(16), 205(7), 178(6), 165(13), 152(11),
139(13), 115(13), 105(22), 91(14), 77(16), 69(15), 57(17).
Mammeisin diacetate (4b). Acetic anhydride (0.2 mL) was
added to a solution of 4 (15 mg) in dry pyridine (0.5 mL), and
the reaction mixture was allowed to stand for 3 h at room
temperature, diluted with H2O (15 mL), extracted with CH2-
Cl2, and washed with diluted HCl and H2O four times. Workup
led to the isolation of 4b (17 mg): colorless oil; IR (CHCl3) νmax
2959, 2931, 2871, 1738, 1623, 1581, 1446,1407 1374, 1162,
1
1123, 1112 cm-1; H NMR data, see Table 1; 13C NMR data,
see Table 2.
Cytotoxicity Bioassay. The cytotoxicity bioassay was
performed against breast (MCF-7), lung (H-460), and CNS (SF-
268) human cancer cell lines according to the method of Monks
et al.29 During the isolation process, the activity of all fractions
and compounds was monitored using all three cell lines.
Molecular Modeling. Calculations were performed on a
Silicon Graphics Indigo computer. Compounds were built using
Macromodel v.4.30 Conformational analysis was performed by
a Monte Carlo random search. All freely rotating bonds were
searched with MM231 minimization to a gradient of less than
0.001 kcal/mol. Full geometry optimization of the two main
conformers of each compound was performed using Stewart’s
AM1 and PM3 Hamiltonian in MOPAC 6.0.
(16) Cruz, F. G.; Silva-Neto, J. T. da; Guedes, M. L. S. J. Braz. Chem.
Soc. 2001, 12, 117-122.
(17) Gramacho, R. da S.; Nagem, T. J.; Oliveira, T. T. de; Queiroz, M. E.
L. R. de; Neves, A. A.; Saddi, N. Phytochemistry 1999, 51, 579-581.
(18) Reutrakul, V.; Leewanich, P.; Tuchinda, P.; Pohmakotr, M.; Jaipetch,
T.; Sophasan, S.; Santisuk, T. Planta Med. 2003, 69, 1048-1051.
(19) Crombie, L.; Games, D. E.; Haskins, N. J.; Reed, G. F. J. Chem. Soc.,
Perkin Trans. 1 1972, 2249-2253.
(20) Bandaranayake, W. M.; Selliah, S. S.; Sultanbawa, M.; Uvais, S.
Phytochemistry 1975, 14, 265-269.
(21) Guilet, D.; Morel, C.; Noyer, N.; Cornec, M.; Seraphin, D.; Wiart, C.;
Hadi, A. H. A.; Se´venet, T.; Richomme, P.; Bruneton, J. J. Heterocycles
1999, 51, 67-76.
(22) Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. H. K.; Vittal, J. J.; Pereira,
J. T.; Goh, S.-H. Helv. Chim. Acta 1998, 81, 1404-1416.
(23) Stewart, J. J. P. MOPAC: A General Molecular Orbital Package
(Version 6.0); Quantum Chemistry Program Exchange Catalogue
(QCPE), 1992.
(24) (a) Ito, A.; Chai, H. B.; Shin, Y. G.; Garcia, R.; Mejia, M.; Gao, Q.;
Fairchild, C. R.; Lane, K. E.; Menendez, A. T.; Farnsworth, N. R.;
Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D. Tetrahedron 2000, 56,
6401-6405. (b) Guilet, D.; Helesbeux, J.-J.; Seraphin, D.; Se´venet,
T.; Richomme, P.; Bruneton, J. J. Nat. Prod. 2001, 64, 563-568. (c)
Chaturvedula, V. S. P.; Schilling, J., K.; Kingston, D. G. I. J. Nat.
Prod. 2002, 65, 965-972. (d) Jenett-Siems, K.; Kohler, I.; Kraft, C.;
Beyer, G.; Melzig, M. F.; Eich, E. Pharmazie 2002, 57, 351-352. (e)
Scio, E.; Ribeiro, A.; Alves, T. M.; Romanha, A. J.; Shin, Y. G.; Cordell,
G. A.; Zani, C. L. J. Nat. Prod. 2003, 66, 634-637.
(25) Ishikawa, T. Heterocycles 2000, 53, 453-474.
(26) Spino, C.; Dodier, M.; Sotheeswaran, S. Bioorg. Med. Chem. Lett.
1998, 8, 3475-3478.
(27) Itoigawa, M.; Ito, C.; Tan, H. T. W.; Kuchide, M.; Tokuda, H.; Nishino,
H.; Furukawa, H. Cancer Lett. 2001, 169, 15-19.
(28) Ito, C.; Itoigawa, M.; Mishina, Y.; Filho, V. C.; Enjo, F.; Tokuda, H.;
Nishino, H.; Furukawa, H. J. Nat. Prod. 2003, 66, 368-371.
(29) Monks, A.; Scudiero, D. A.; Johnson, G. S.; Paull, K. D.; Sausville, E.
A. Anticancer Drug Des. 1997, 12, 533-41.
(30) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440-467.
(31) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127-8134.
(32) Mart´ınez-Ripoll, M.; Cano, F. H. An Interactive Program for Operating
Rich, Seifert Single-Crystal Four-Circle Diffractometers; Institute of
Physical Chemistry, Rocasolano, C.S.I.C., Serrano, 19: Madrid, Spain,
1996.
X-ray Analysis of Compound 4. Compound 4, C25H26O5,
crystallizes in orthorhombic space group P212121, with Z ) 4,
and unit cell parameters a ) 13.675(3) Å, b ) 14.243(2) Å, c
) 15.810(3) Å, R ) 116.46(1)°, â ) 69.46(2)°, γ ) 85.22(1)°.
X-ray diffraction data were collected on a four-circle Seifert
XRD 3003 SC diffractometer (Cu FR, λ ) 1.5418 Å), graphite
monochromator, room temperature, ω-2æ scan. The unit cell
parameters were determined by least-squares refinement on
the 2æ values of 25 strong well-centered reflections in the
range 16° < 2æ < 40°. Scattering factors for neutral atoms
and anomalous dispersion corrections for C and O were taken
from ‘International Tables for X-Ray Crystallography (1995,
Vol. C, Kluwer Academic Publishers: Dordrecht). The struc-
ture of C25H26O5 was resolved by direct methods and refined
in the space group P212121. Full matrix least-squares refine-
ment with anisotropic thermal parameters for non-H atoms
was carried out by minimizing w(Fo - Fc2)2. Refinement on
2
F2 for all reflections, weighted R factors (Rw), and all goodness
of fit S are based on F2, while conventional R factors (R) are
based on F; R factors based on F2 are statistically about twice
as large as those based on F, and R factors based on all data
will be even larger. Resulting absolute structure parameter:
0.36 (155).
All calculations were performed using CRYSOM,32 software
for data collection, XRAY80,33 and for data reduction, SHELX-
TLTM (Siemens SHELXTLTM version 5.0, Siemens Analytical
X-ray instruments Inc., Madison, WI, 1995) to resolve and
refine the structure and to prepare material for publication.
Full crystallographic details have been deposited at the
Cambridge Crystallographic Data Centre (CCDC No. 2506931).
Acknowledgment. Thanks are due to European Commis-
sion ALFA grant EC-1233, for a fellowship to D.A.O., Orga-
nization of American States for financial support to the Project
AE-106/3, Spanish grants MCyT SAF2001-0037 and FIS RIS-
G03-173, and the University of Panama for granting a study
leave to D.A.O.
(33) Stewart, J. M.; Kundell, F. A.; Baldwin, J. C. The X-RAY80 System;
Computer Science Centre, University of Maryland: College Park, MD,
1990.
NP049642G