Synthesis of (+)-Lasonolide A: (-)-Lasonolide A is the biologically active enantiomer

Article abstract of DOI:10.1016/S0960-894X(02)00821-1

(+)-Lasonolide A was synthesized following the established procedure. (-)-Lasonolide A was found to be the biologically active enantiomer.

Full text of DOI:10.1016/S0960-894X(02)00821-1

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3519–3520
Synthesis of (+)-Lasonolide A: (À)-Lasonolide A is the Biologically
Active Enantiomer
Eun Lee,a,* Ho Young Song,a Jung Min Joo,a Jung Won Kang,a Dae Shik Kim,a
Cheol Kyu Jung,a Chang Yong Hong,b ShinWu Jeongb and Kiwan Jeonb
aSchool of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-747, Republic of Korea
bDrug Discovery Research Institute, LGCI Life Science R&D, PO Box 61, Yusung, Daejon 305-380, Republic of Korea
Received 1July 2002; revised 2 September 2002; accepted 3 October 2002
Abstract—(+)-Lasonolide A was synthesized following the established procedure. (À)-Lasonolide A was found to be the biologi-
cally active enantiomer.
# 2002 Elsevier Science Ltd. All rights reserved.
Lasonolide A is a novel macrolide isolated from the
shallow water Caribbean marine sponge, Forcepia sp. It
is a potent cytotoxin against the A-549 human lung
carcinoma and P388 murine leukemia cell lines, and
inhibits cell adhesion in the EL-4.IL-2 cell line.1 In the
previous communication,2 we reported synthesis of the
compounds 1 and 2 (the proposed structures), neither of
which corresponded with the structure of the natural
product. Compounds 3, 4, 5, and 6 were also prepared
(Fig. 1), and we were able to show that compound 6
exhibited identical spectroscopic data (except the optical
rotation) as reported for the natural product. Since the
naturally occurring (and presumably biologically active)
enantiomer was reported to be dextrorotatory ([a]D
+24.4 (c 0.045, CDCl3)),1 and compound 6 was found
to be levorotatory ([a]2D0 À24.1( c 0.055, CDCl3)), we
concluded that the natural product should be repre-
sented by the structure 7, which is the (+)-enantiomer
of 6. Compound 7 was duly synthesized following the
established synthetic procedure (Scheme 1), and the
samples were subjected to biological assay. Surprisingly,
it was found that the (À)-enantiomer 6 was the most
potent compound tested (Table 1). On the contrary, the
(+)-enantiomer 7 was found to possess much lower
activities.3 Accordingly, it was concluded that the
active (and natural) enantiomer of lasonolide A is the
(À)-enantiomer 6, and the original report1 on the
optical rotation data for natural lasonolide A is in error.
Inspection of the data on Table 1 reveals that the (R)-
configuration at C28 enhances the activity. The cis
double bond at C25-26 is important, and the trans
double bond at C17-18 is essential, for the compound 1
is almost devoid of activity. The correct structure of
*Corresponding author. Tel.: +82-2-880-6646; fax: +82-2-889-1568;
e-mail: eunlee@snu.ac.kr
Figure 1. (À)-Lasonolide A and related compounds.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00821-1

3520
E. Lee et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3519–3520
Korea 21graduate fellowship grants to H. Y. Song and
C. K. Jung are gratefully acknowledged.
References and Notes
1. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell,
O. J. J. Am. Chem. Soc. 1994, 116, 6015.
2. Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.;
Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384.
3. The IC50 value of the natural lasonolide A against the
A-549 human lung carcinoma cell line was reported to be 40
ng/mL (ꢀ0.06 mM).
4. Wu, L.; Smythe, A. M.; Stinson, S. F.; Mullendore, L. A.;
Monks, A.; Scudiero, D. A.; Paull, K. D.; Koutsoukos, A. D.;
Rubinstein, L. V.; Boyd, M. R.; Shoemaker, R. H. Cancer
Res. 1992, 52, 3029.
5. Cell Culture. All tumor cell lines including A549 and NCI-
H460, human small cell lung carcinoma cell lines, and HCT-
116, a human colon cancer cell line, were maintained in
RPMI1640 plus 5% (v/v) heat-inactivated fetal bovine serum
(FBS). All the media were supplemented with additional 100
units/mL penicillin G, 100 mg/mL streptomycin, 0.25 mg/mL
Scheme 1. Synthesis of (+)-lasonolide A (7).
Table 1. GI50 (mM) values of lasonolide A and related compounds4,5
Compd
A549
HCT-116
NCI-H460
amphotericin B and 2 mM l-glutamine. Cells were maintained
1
3
4
5
6
7
>1
3.2
2
0.05
0.02
6
0
5
5
at 37 ꢁC in a humidified incubator containing 5% CO2.
0.10.04
0.04
0.009
<0.003
3
Cell proliferation assay. Cellular response to drugs was
determined using sulforhodamine B (SRB) method described
in ref 3 with minor modifications. Briefly, cells were seeded at
3000 cells/100 mL/well in 96-well plates, and on the next day
treated with 100 mL of medium containing test compounds at
the serial concentrations for another 48 h incubation. To fix
the cells, 100 mL of 4% formaldehyde was added to each well
and kept at room temperature for at least 30 min. The wells
were washed with distilled water three times and air dried.
Subsequently, 100 mL of SRB at 0.4% (w/v) (Sigma Chemical
Co., St. Louis, MO) was added to each well for >10 min at
room temperature before washing five times with 1% acetic
acid. Bound stain in the dried wells was solubilized with 10
mM Tris buffer, and the absorbances were read at 530 nm on
an automated plate reader. Percentage growth inhibition (GI)
was calculated to be (Ti-Tz)/(C-Tz)Â100, where Ti is the
OD540 value at 48 h at the concentration i, Tz at 0 h, and C is
the OD540 value at 48 h at zero concentration.
0.02
<0.003
<0.003
2
lasonolide A is finally identified, and the search for
more useful analogues may now begin.
Acknowledgements
The authors thank the Ministry of Science and Tech-
nology, Republic of Korea, and Korea Institute of
Science and Technology Evaluation and Planning for a
National Research Laboratory grant (1999). Brain