Synthesis of Novel Cyclopeptide Candidates: I-Cyclo-[Nα-isophthaloyl-bis-(Glycine-Amino Acid)-L-Lysine] Derivatives with Expected Anticancer Activity

Abstract

 
THE SEARCH for potent cytotoxic agents, namely anticancers, ……...presents and updated area of the organo-biochemical literature.
Herein, N
α-isophthaloyl bridged cyclo-pentapeptides, having the structure: Cyclo-[Nα- isophthaloyl-bis - (Glycine - Amino Acid)-L-Lys] -Y, 11 - 19, whereas, “Amino Acid” stands for “Glycine” or “L-Phenylalanine” or “Sarcosine” and Y represents: methyl ester or carboxylic or hydrazide group were, newly, synthesized.
Synthetically, hydrolysis of the starting linear tetra peptide bis-esters 5, 6 and 7 afforded the corresponding free acids, 8, 9 and 10, respectively, whilst upon their cyclization with L-lysine methyl ester, the cyclopeptide esters 11, 12 and 13 were, respectively, obtained. Hydrolysis or hdyrazinolysis of these cyclopeptide esters resulted in the cyclopeptide acids 14, 15 and 16 or hydrazides 17, 18 and 19.
Thus, Cyclo-[N
α-isophthaloyl-bis-(Gly-Gly)-L–Lys]-OMe, 11, Cyclo-[Nα-iso-phthaloyl-bis-(Gly-L-Phe)-L–Lys]-OMe, 12, Cyclo-(Nα-isophthaloyl- bis- (Gly-Sar)- L–Lys]-OMe, 13, Cyclo- [Nα-isophthaloyl- bis- (Gly-Gly)-L– Lys]- OH, 14, Cyclo-[Nα—iso-phthaloyl- bis- (Gly-L-Phe)-L–Lys]-OH, 15, Cyclo-[Nα-isophthaloyl-bis-(Gly-Sar)-L–Lys]-OH, 16, Cyclo- [Nα-isophthaloyl- bis (Gly-Gly)-L–Lys]-NHNH2 , 17, Cyclo-[Nα-isophthaloyl-bis-(Gly-L-Phe)-L–Lys]-NHNH2 , 18, Cyclo-[Nα-iso-phthaloyl-bis- (Gly-Sar)- L–Lys]-NHNH2 19, were rendered available, via conventional peptide synthesis, in solution.
A preliminary cytotoxicity evaluation (National Cancer Institute, Cairo, EGYPT), for a representative example, namely, candidate 12, against eight human cancer cell lines, seemed interesting. The detailed comparative results with those of five common anticancer drugs and their complementary biological and biochemical assays, for all the candidates, are envisioned, and will be published elsewhere.

Keywords


Volume 56, Issue 5 - Serial Number 5
December 2013
Pages 473-494
  • Receive Date: 03 December 2013
  • Revise Date: 04 January 2014
  • Accept Date: 05 January 2014
  • First Publish Date: 05 January 2014