Design and Synthesis of Novel Triazole-based Peptide Analogues as Anticancer Agents

Document Type : Research article


1 Department of Chemistry, Payame Noor University, Tehran, Iran.

2 Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.


Cancer disease is a great concern in the worldwide public health and current treatments do not give satisfactory results, so, developing novel therapeutic agents to combat cancer is highly demanded. Nowadays, anticancer peptides (ACPs) are becoming promising anticancer drug candidates. This is due to several advantages inherited in peptide molecules, such as being usually with small size, high activity, low immunogenicity, good biocompatibility, diversity of sequence, and more modification sites for functionalization. To get benefit of these merits, in this work, we synthesized a new series of triazole- based analogues with peptide scaffold by employing click chemistry and evaluated their anticancer activities against breast, colon cancer cell lines as well as fibroblast cells using MTT assay. Our results suggest that peptide scaffolds containing 1H-1, 2, 3-triazole ring group are toxic against colon and breast cancer cells viability, and this effect was more pronounced on MDA-MB-231 cells compared with MCF-7 breast cells. As a conclusion, these designed peptide analogues may be good and safe candidates as future anticancer agents.


Main Subjects

Chandrudu S, Simerska P and Toth I. Chemical
methods for peptide and protein Production. Molecules
(2013) 18: 4373-88.

(2) Vlieghe P, Lisowski V, Martinez J and Khrestchatisky
M. Synthetic therapeutic peptides: science and market.
Drug Discov. Today (2010) 15: 4056.

(3) Li H, Aneja R and Chaiken I. Click chemistry in
peptide-based drug design. Molecules (2013) 18: 9797-

(4) Merrifield RB. Solid phase peptide synthesis. I. The
synthesis of a tetrapeptide. J. Am. Chem. Soc. (1963)
85: 214954.

(5) Dawson PE, Muir TW, Clark-Lewis I and Kent SB.
Synthesis of proteins by native chemical ligation.
Science (1994) 266: 77679.

(6) Rosca EV, Koskimaki JE, Rivera CG, Pandey NB,
Tamiz AP and Popel AS. Anti-angiogenic peptides for
cancer therapeutics. Curr. Pharm. Biotechnol. (2011)
12: 110116.

(7) Karagiannis ED and Popel AS. Novel anti-angiogenic

peptides derived from ELR-containing CXC
chemokines. J. Cell. Biochem. (2008) 104: 135663.

(8) Kritzer JA, Stephens OM, Guarracino DA, Reznika SK
and Schepartza A. β-Peptides as inhibitors of
proteinprotein interactions. Bioorg. Med. Chem.
(2005) 13: 116.

(9) Mochly-Rosen D and Qvit N. Peptide inhibitors of
protein protein interactions: from rational design to the
clinic. Chim. Oggi. (2010) 28: 146.

(10) Eldar-Finkelman H and Eisenstein M. Peptide
inhibitors targeting protein kinases. Curr. Pharm. Des.
(2009) 15: 246370.

(11) Tonelli R, Purgato S, Camerin C, Fronza R, Bolongna
F, Alboresi S, Franzoni M, Corradini R, Sforza S,
Faccini A, Shohet JM, Marchelli R and Pession A.
Antigene peptide nucleic acid specifically inhibits
MYCN expression in human neuroblastoma cells
leading to cell growth inhibition and apoptosis. Mol.
Cancer Ther. (2005) 4: 77986.

(12) Kakde D, Jain D, Shrivastava V, Kakde R and Patil
AT. Cancer therapeutics-opportunities, challenges and
advances in drug delivery. J. Appl. Pharm. Sci. (2011)
1: 110.

(13) Zheng LH, Wang YJ, Sheng J, Wang F, Zheng Y, Lin
XK and Sun M. Antitumor peptides from marine
organisms. Mar. Drugs (2011) 9: 184059.

(14) Kolb HC, Finn MG and Sharpless KB. Click
chemistry: diverse chemical function from a few good
reactions. Angew. Chem. Int. Ed. (2001) 40: 200421.

(15) Kolb HC and Sharpless KB. The growing impact of
click chemistry on drug discovery. Drug Discov.
Today (2003) 8: 112837.

(16) Tilliet M, Lundgren S, Moberg C and Levacher V.
Polymer-bound pyridine-bis (oxazoline). Preparation
through click chemistry and evaluation in asymmetric
catalysis. Adv. Synth. Catal. (2007) 349: 207984.

(17) Lee JW, Kim JH, Kim BK, Kim JH, Shin WS and Jin SH.
Convergent synthesis of PAMAM dendrimers using click
chemistry of azide-functionalized PAMAM dendrons.
Tetrahedron (2006) 62: 9193200.

(18) Nandivada H, Jiang X and Lahann J. Click chemistry:
versatility and control in the hands of materials
scientists. Adv. Mater. (2007) 19: 2197208.

(19) Rozkiewicz DI, Gierlich J, Burley GA, Gutsmiedl K,
Carell T, Ravoo BJ and Reinhoudt DN. Transfer
printing of DNA by “click” chemistry. Chem. Bio.
Chem. (2007) 8: 19972002.

(20) Sharpless K B and Manetsch R. In situ click chemistry:
a powerful means for lead discovery. Exp. Opin. Drug
Discov. (2006) 1: 52538.

(21) Nwe K and Brechbiel MW. Growing applications of
“click chemistry” for bioconjugation in contemporary
biomedical research. Cancer Biother. Radiopharm.
(2009) 24: 289302.

(22) Gil MV, Arevalo MG and Lopez O. Click chemistry:
What’s in a name? Triazol synthesis and beyond.
Synthesis (2007) 11: 1589620.

(23) Gouault N, Gupif JF, Sauleau A and David M.

ɣ-Methyl-substituted- ɣ-butyrolactones: solid-phase

Triazole peptides as anticancer agents

synthesis employing a cyclisation-cleavage strategy.

Tetrahedron Lett. (2000) 41: 729397.

(24) Gnanaprakazam A, Senthi kumar U and Reddy G.
Process for the preparation of tazobactam in pure form.
United States patent 7417143 (2008).

(25) Sultana N and Arayne MS. In-vitro activity of
cefadroxil, cephalexin, cefatrizine and cefpirome in
presence of essential and trace elements. Pak. J.
Pharm. Sci. (2007) 20: 30510.

(26) Brik A, Muldoon J, Lin YC, Elder JH, Goodsell DS,
Olson AJ, Fokin VV, Sharpless KB and Wong CH.
Rapid diversity-oriented synthesis in microtiter plates
for in situ screening of HIV protease inhibitors. Chem.
Bio. Chem. (2003) 4: 1246-8.

(27) Soltis MJ, Yeh HJ, Cole KA, Whittaker N, Wersto RP
and Kohn EC. Identification and characterization of
human metabolites of CAI [5-amino-1-1(4′-
chlorobenzoyl-3, 5-dichlorobenzyl)-1, 2, 3-triazole-4-
carboxamide). Drug Metab. Dispos. (1996) 24: 799-

(28) Alvarez R, Velazquez S, San-Felix A, Aquaro S, De
Clercq E, Perno CFN, Karlsson A, Balzarini J and
Camarasa MJ. 1, 2, 3-Triazole-[2,5-Bis-O-(tert-
5′′-(4′′-amino-1′′,2′′-oxathiole 2′′,2′′-dioxide) (TSAO)
analogs: synthesis and anti-HIV-1 activity. J. Med.
Chem. (1994) 37: 4185-94.

(29) Hein CD, Liu XM and Wang D. Click chemistry, a
powerful tool for pharmaceutical sciences. Pharm.
Res. (2008) 25: 221630.

(30) Ahmaditaba MA, Houshdar Tehrani MH, Zarghi A,
Shahosseini S and Daraei B. Design, synthesis and
biological evaluation of novel peptide-like analogues
as selective COX-2 inhibitors. Iran. J. Pharm. Res.
(2018) 17: 87-92.

(31) Li Z, Yang J, Wang X, Li H, Liu C, Wang N, Huang
W and Qian H. Discovery of novel free fatty acid
receptor 1 agonists bearing triazole core via click
chemistry. Bioorg. Med. Chem. (2016) 24: 544954.

(32) Luna Vital DA, González de Mejía E, Dia VP and
Loarca-Piña G. Peptides in common bean fractions
inhibit human colorectal cancer cells. Food Chem.
(2014) 157: 34755.

(33) Rabzia A, Khazaei M, Rashidi Z and Khazaei MR.
Synergistic anticancer effect of paclitaxel and
noscapine on human prostate cancer cell lines. Iran. J.
Pharm. Res. (2017) 16: 1432-42.

(34) Mohammadpour F, Ostad SN, Aliebrahimi S and
Daman Z. Anti-invasion effects of cannabinoids
agonist and antagonist on human breast cancer stem
cells. Iran. J. Pharm. Res. (2017) 16: 1479-86.

(35) Mosmann T. Rapid colorimetric assay for cellular
growth and survival: application to proliferation and
cytotoxicity assays. J. Immunol. Methods (1983) 65:

(36) Dheer D, Singh V and Shankar R. Medicinal attributes
of 1, 2, 3-triazoles: current developments. Bioorg.
Chem. (2017) 71: 3054.

(37) Haider S, Sarwar Alam M and Hamid H. 1, 2,

Baharloui M et al. / IJPR (2019), 18 (3): 1299-1308
3-Triazoles: scaffold with medicinal significance.

Inflamm. Cell Signal. (2014) 1: e95.

(38) Huisgen R. 1, 3-dipolar cyloaddition chemistry. In:
Padwa A (ed.) 1st ed. John Wiley and Sons, New York
(1984) 1-176.

(39) Bock VD, Hiemstra H and van Maarseveen JH. CuI -
Catalyzed alkyneazide “Click” cycloadditions from a
mechanistic and synthetic perspective. Eur. J. Org.
Chem. (2006) 12: 51-68