N. Kashihara et al. / Bioorg. Med. Chem. Lett. 10 (2000) 101±103
103
Table 1. Comparison of vincristine accumulation in the multidrug
resistant 2780AD cells, a subline of A 2780 ovarian carcinoma cells by
hapalosin (1) and its derivatives (5a±5e)a,b
6. The selective MDR-reversing activity was supported by the
low cytotoxicity of this molecule (IC =5ꢀ15 mg), see ref 1.
5
0
7. Dinh, T. Q.; Armstrong, R. W. J. Org. Chem. 1995, 60,
8
8
118±8119.
. Ghosh, A. K.; Liu, W.; Xu, L.; Chen, Z. Angew. Chem., Int.
Additives
Ed. Engl. 1996, 35, 74±76.
5
a
5b
5c
5d
5e
1
Verapamil
350
9
6
1
1
. Dinh, T. Q.; Du, X.; Armstrong, R. W. J. Org. Chem. 1996,
1, 6606±6616.
0. Wagner, B.; Beugelmans, R.; Zhu, J. Tetrahedron Lett.
996, 37, 6557±6560.
%
of control
4
41
288
308
269
254
267
a
11. Dinh, T. Q.; Smith, C. D.; Armstrong, R. W. J. Org.
Chem. 1997, 62, 790±791.
Concentration of the additives: 10 mg/mL.
Control: absence of the additives.
b
1
2. Dinh, T. Q.; Du, X.; Smith, C. D.; Armstrong, R. W. J.
Org. Chem. 1997, 62, 6773±6783.
3. Dinh, T. Q.; Smith, C. D.; Du, X.; Armstrong, R. W. J.
Med. Chem. 1998, 41, 981±987.
4. Wagner, B.; Gonzalez, G. I.; Dau, M. E. T. H.; Zhu, J.
Bioorg. Med. Chem. 1999, 7, 737±747.
5. O'Connell, C.; Salvato, K. A.; Meng, Z.; Little®eld, B. A.;
Schwartz, C. E. Bioorg. Med. Chem. Lett. 1999, 9, 1541±1546.
6. Pais, G. C. G.; Maier, M. E. J. Org. Chem. 1999, 64, 4551±
1
and 5e possessing only the cis-peptides. These observa-
tions suggested that exhibition of the signi®cant activity
requires additional factors, such as hydrophobic inter-
action of the C12-substituent with the receptor site. In
contrast to the MDR-reversing activities, hapalosin 1
and its derivatives (5a±5e) showed no induction of
apoptosis in human ®brosarcoma HT1080 cell line at
the 10 mg/mL concentration.
1
1
1
4554.
17. Haddad, M.; Botuha, C.; Larcheveque, M. SYNLETT
1
1
999, 703±704.
8. Ohmori, K.; Okuno, T.; Nishiyama, S.; Yamamura, S.
Further investigation related to this structure±activity
relationship is in progress.
Tetrahedron Lett. 1996, 37, 3467±3470.
9. Okuno, T.; Ohmori, K.; Nishiyama, S.; Yamamura, S.;
Nakamura, K.; Houk, K. N.; Okamoto, K. Tetrahedron 1996,
1
5
2
2, 14723±14734.
0. It was anticipated that alkyl groups such as ethyl or propyl,
Acknowledgements
introduced at the N-position would conduct the cis-peptide
geometry, according to computational calculations. However,
coupling of the corresponding alkylated amino group, or
insertion of alkyl groups to the peptide moiety were unsuccess-
ful, owing to low reactivities.
The authors wish to thank the Screening Committee of
New Anticancer Agents supported by Grant-in-Aid for
Science Research on Priority Area `Cancer' from the
Ministry of Education, Science, Sports and Culture,
Japan, for the evaluation of the MDR-reversing activities.
2
1. The hydroxyl acids (>99% ee) were obtained by the stereo-
retentive conversion of the corresponding amino acids, via the
diazonium intermediates.2
2±24
2
2
2
2. Scheibler, H.; Wheeler, A. S. Chem. Ber. 1911, 44, 2684±
690.
3. Abderhalden, E.; Weil, A. Z. Physiol. Chem. 1913, 84, 39±59.
References and Notes
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24. Mori, K. Tetrahedron 1976, 32, 1101±1106.
25. The cis/trans ratio should be determined by the relative
stability of the transition state of the cyclization rather than
that of the cyclized products calculated in the present study.
However, we assumed that the thermodynamic stability cal-
culated correlates with the above-mentioned stability, based
on the observation of a reversible change in the isomeric pro-
2
3
4
ꢁ
18,19
portion (ca. 3:1) to 1.7:1 at 100 C.
1988, 37, 2389±2393.
5. Simon, S. M.; Schinller, M. Proc. Natl. Acad. Sci. USA
1994, 91, 3497±3504.
26. Low cytotoxicities of 5a±5e were determined.
27. During preparation of this paper, this sample was reported:
see ref 15.