4
Tetrahedron
uptake of both 16 and 18 into MM.1R, relative to the
References
concentrations of 16 at the four hour evaluation point. Maximum
accumulation of both compounds was observed at four hours, and
over the next eight hours compounds 16 and 18 showed only a
49% and 62% reduction in intracellular concentration,
respectively. Whether the reduction is by intracellular
degradation or removal from the cell is currently being explored.
Given the C6 variability between 16 and 18, the rapid uptake by
both in MM.1R, and the length of accumulation it could be
envisioned that the C6 position could possibly be altered to allow
for compound appendage as a drug delivery system towards this
aggressive and difficult-to-treat form of cancer.
1. C. Portmann, S. Sieber, S. Wirthensohn, J. F. Blom, L. Da
Silva, E. Baudat, M. Kaiser, R. Brun and K. Gademann, J.
Nat. Prod., 2014, 77, 557-562.
2. S. Peña, L. Scarone, E. Manta and G. Serra, Tetrahedron
Lett., 2013, 54, 2806-2808.
3. S. Peña, L. Scarone, E. Manta, L. Stewart, V. Yardley, S.
Croft and G. Serra, Bioorg. Med. Chem. Lett., 2012, 22, 4994-
4997.
4. S. Pena, L. Scarone, A. Medeiros, E. Manta, M. Comini and
G. Serra, MedChemComm, 2012, 3, 1443-1448.
5. C. Portmann, J. F. Blom, K. Gademann and F. Jüttner, J. Nat.
Prod., 2008, 71, 1193-1196.
6. C. Portmann, J. F. Blom, M. Kaiser, R. Brun, F. Jüttner and
K. Gademann, J. Nat. Prod., 2008, 71, 1891-1896.
7. R. G. Linington, J. González, L.-D. Ureña, L. I. Romero, E.
Ortega-Barría and W. H. Gerwick, J. Nat. Prod., 2007, 70,
397-401.
3. Conclusion
The synthetic efforts towards balgacyclamide A have given
access to numerous oxazoline units, and while the synthesis of 1
has not yet been achieved, the oxazoline formed gave rise to four
new tri-oxazoline macrocycles, 16-19. Compounds 16 and 18
were shown to have marginal cytotoxicity against a panel of
cancerous cell lines screened, but upon further evaluation, these
two compounds were shown to have enhanced cellular uptake
and accumulation within MM.1R, a multiple myeloma (MM)
cancerous cell line. Given that MM is an incurable hematologic
malignancy, the limited FDA approved drugs for its treatment,
and the current limited therapeutic delivery to MM, these two
compounds provide a new avenue for possible drug delivery via
attachment about the C6 position (former α-carbon) of the E-
ring. These results illustrate that the heterocyclic triazol(in)e
systems are not directly required for biological activity, as
suggested by the isolation team. Through an unexpected detour
towards the total synthesis of balgacyclamide A, two new
oxazoline-based cyclic peptides have been constructed and found
to have selective penetration and accumulation characteristics
into multiple myeloma.
8. M. R. Davis, E. K. Singh, H. Wahyudi, L. D. Alexander, J. B.
Kunicki, L. A. Nazarova, K. A. Fairweather, A. M. Giltrap,
K. A. Jolliffe and S. R. McAlpine, Tetrahedron, 2012, 68,
1029-1051.
9. R. P. Sellers, L. D. Alexander, V. A. Johnson, C.-C. Lin, J.
Savage, R. Corral, J. Moss, T. S. Slugocki, E. K. Singh, M. R.
Davis, S. Ravula, J. E. Spicer, J. L. Oelrich, A. Thornquist,
C.-M. Pan and S. R. McAlpine, Bioorg. Med. Chem., 2010,
18, 6822-6856.
10. P. Wipf, C. P. Miller, S. Venkatraman and P. C. Fritch,
Tetrahedron Lett., 1995, 36, 6395-6398.
11. G. M. Atkins and E. M. Burgess, J. Am. Chem. Soc., 1968,
90, 4744-4745.
12. E. M. Burgess, H. R. Penton and E. A. Taylor, J. Am. Chem.
Soc., 1970, 92, 5224-5226.
13. E. M. Burgess, H. R. Penton and E. A. Taylor, J. Org. Chem.,
1973, 38, 26-31.
14. J. A. Duncan, R. T. Hendricks and K. S. Kwong, J Amer.
Chem. Soc., 1990, 112, 8433-8442.
15. P. Wipf and P. C. Fritch, J. Amer. Chem. Soc., 1996, 118,
12358-12367.
Acknowledgements
The authors would like to thank Kansas State University for
providing startup capital that was used to fund this work. A
special thanks to Dr. Leila Maurmann for extensive help in the
LC/MS work performed. All authors have read, edited, and
contributed to the writing of this paper.
A. Supplementary data
Supplementary data associated with this article can be found, in
069.