Structure-activity of Sansalvamide A Derivatives and their Apoptotic Activity in the Pancreatic Cancer Cell Line PL-45
DOI:
https://doi.org/10.29356/jmcs.v52i3.1068Keywords:
structure activity relationship, Sansalvamide A, human pancreatic adenicarcinoma, molecular modeling, apoptosisAbstract
We report the structure-activity relationship (SAR) of forty Sansalvamide A (San A) derivatives against human pancreatic ductal adenicarcinoma cell line PL-45. Our comprehensive evaluation of these compounds utilizes: cytotoxicity based SAR, molecular modeling, and ApoAlert Annexin V apoptosis detection to evaluate these potent compounds. Compared to current pancreatic cancer drugs, these San A analogs are structurally unique, and are potentially cytotoxic. Our comprehensive studies including molecular modeling show that a single N-methyl, a single D-amino acid (D-aa) or a single N - methyl D-aa appears to be critical for presenting the active conformation of San A peptide derivates to its biological target, and show that the San A peptide derivative 8 has the ability to selectively induce apoptosis. Thus, showing that this class of compounds are promising chemotherapeutic agents that will eliminate cells in an orderly manner without eliciting an undesired immune response.
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References
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13 The ClogP values were calculated using an algorithm. The logP value of a compound, which is the logarithm of its partition coefficient between n-octanol and water log(coctanol/cwater), is a well established measure of the compound’s hydrophilicity. Low hydrophilicities and therefore high logP values cause poor absorption or permeation. It has been shown for compounds to have a
reasonable probability of being well absorbt their logP value must not be greater than 5.0. The distribution of calculated logP values
of more than 3000 drugs on the market underlines this fact.
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16. Styers, T. J.; Rodriguez, R. A.; Pan, P.-S.; McAlpine, S. R. Tetrahedron Lett. 2006, 47, 515-517.
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1H NMR. (Note: 1H NMR were taken for cyclized peptides, but due to their complexity, they were not seen as the primary confirmation for cyclized compounds). See supplementary data for spectra.
18. Unpublished results from the Guy lab at Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital,
Memphis, TN 38103, and published results from our lab show that the use of several coupling reagents facilitates formation of the peptide bond in high-yields.
19. (a) Bolla, M. L.; Azevedo, E. V.; Smith, J. M.; Taylor, R. E.; Ranjit, D. K.; Segall, A. M.; McAlpine, S. R. Org. Lett. 2003, 5, 109-112. (b) Liotta, L. A.; Medina, I.; Robinson, J. L.; Carroll, C. L.; Pan, P.-S.; Corral, R.; Johnston, J. V. C.; Cook, K. M.; Curtis, F. A.; Sharples, G. J.; McAlpine, S. R. Tetrahedron Lett. 2004, 45, 8447-8450.
20. Zhang, X.; Nikiforovich, G. V.; Marshall, G. R. J. Med. Chem. 2007, 50, 2921-2925.
2. (a) Cueto, M.; Jensen, P. R.; Fenical, W. Phytochemistry 2000, 55, 223-226. (b) Hwang, Y.; Rowley, D.; Rhodes, D.; Gertsch, J.; Fenical, W.; Bushman, F. Mol. Pharmacol. 1999, 55, 1049-1053.
3. Belofsky, G. N.; Jensen, P. R.; Fenical, W. Tetrahedron Lett. 1999, 40, 2913-2916.
4. Liu, S.; Gu, W.; D., L.; Ding, X.-Z.; Ujiki, M.; Adrian, T. E.; Soff, G. A.; Silverman, R. B. J. Med. Chem. 2005, 48, 3630-3638.
5. Ujiki, M.; Milam, B.; Ding, X.-Z.; Roginsky, A. B.; Salabat, M. R.; Talamonti, M. S.; Bell, R. H.; Gu, W.; Silverman, R. B.; Adrian, T. E. Biochem. Biophys. Res. Commun. 2006, 340, 1224-1228.
6. Pan, P. S.; McGuire, K.; McAlpine, S. R. Bioorg. Med. Chem. Lett. 2007, 17, 5072-5077.
7. Otrubova, K.; Styers, T. J.; Pan, P.-S.; Rodriguez, R.; McGuire, K. L.; McAlpine, S. R. Chem. Commun. 2006, 1033-1034.
8. Styers, T. J.; Kekec, A.; Rodriguez, R. A.; Brown, J. D.; Cajica, J.; Pan, P.-S.; Parry, E.; Carroll, C. L.; Medina, I.; Corral, R.; Lapera, S.; Otrubova, K.; Pan, C.-M.; McGuire, K. L.; McAlpine, S. R. Bioorg. Med. Chem. 2006, 14, 5625-5631.
9. Carroll, C. L.; Johnston, J. V. C.; Kekec, A.; Brown, J. D.; Parry, E.; Cajica, J.; Medina, I.; Cook, K. M.; Corral, R.; Pan, P.-S.; McAlpine, S. R. Org. Lett. 2005, 7, 3481-3484.
10. (a) Otrubova, K.; Lushington, G. H.; Vander Velde, D.; McGuire, K.; McAlpine, S. R. J. Med. Chem., in press. (b) Otrubova, K.; McGuire, K. L.; McAlpine, S. R. J. Med. Chem. 2007, 50, 1999-2002.
11. (a) Reed, J. C.; Pellecchia, M. Blood 2005, 106, 408-418. (b) Green, D. R.; Kroemer, G. Science 2004, 305, 626-629. (c) Guimaraes, C. A.; Linden, R. Eur. J. Biochem. 2004, 271, 1638-1650.
12. Hasan, N. M.; Adams, G. E.; Joiner, M. C. Int. J. Cancer 1999, 80, 400-405.
13 The ClogP values were calculated using an algorithm. The logP value of a compound, which is the logarithm of its partition coefficient between n-octanol and water log(coctanol/cwater), is a well established measure of the compound’s hydrophilicity. Low hydrophilicities and therefore high logP values cause poor absorption or permeation. It has been shown for compounds to have a
reasonable probability of being well absorbt their logP value must not be greater than 5.0. The distribution of calculated logP values
of more than 3000 drugs on the market underlines this fact.
14. Chatterjee, J.; Mierke, D. F.; Kessler, H. J. Am. Chem. Soc. 2006, 128, 15164-15172.
15. Heller, M.; Sukopp, M.; Tsomaia, N.; John, M.; Mierke, D. F.; Reif, B.; Kessler, H. J. Am. Chem. Soc. 2006, 128, 13806-13814.
16. Styers, T. J.; Rodriguez, R. A.; Pan, P.-S.; McAlpine, S. R. Tetrahedron Lett. 2006, 47, 515-517.
17. Dipeptide and tripeptide structures were confirmed using 1H NMR. All linear pentapeptides were confirmed using LCMS and
1H NMR. (Note: 1H NMR were taken for cyclized peptides, but due to their complexity, they were not seen as the primary confirmation for cyclized compounds). See supplementary data for spectra.
18. Unpublished results from the Guy lab at Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital,
Memphis, TN 38103, and published results from our lab show that the use of several coupling reagents facilitates formation of the peptide bond in high-yields.
19. (a) Bolla, M. L.; Azevedo, E. V.; Smith, J. M.; Taylor, R. E.; Ranjit, D. K.; Segall, A. M.; McAlpine, S. R. Org. Lett. 2003, 5, 109-112. (b) Liotta, L. A.; Medina, I.; Robinson, J. L.; Carroll, C. L.; Pan, P.-S.; Corral, R.; Johnston, J. V. C.; Cook, K. M.; Curtis, F. A.; Sharples, G. J.; McAlpine, S. R. Tetrahedron Lett. 2004, 45, 8447-8450.
20. Zhang, X.; Nikiforovich, G. V.; Marshall, G. R. J. Med. Chem. 2007, 50, 2921-2925.
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2019-07-31
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