Synthesis, molecular docking and anticancer studies of peptides and iso-peptides Farukh Jabeen a,b , Siva S. Panda a,⇑ , Tamara P. Kondratyuk c , Eun-Jung Park c , John M. Pezzuto c , Ihsan-ul-haq d , C. Dennis Hall a , Alan R. Katritzky a,e,  a Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA b Department of Chemistry, Quaid-i-Azam University, Islamabad 44000, Pakistan c College of Pharmacy, University of Hawii at Hilo, Hilo, HI, USA d Department of Pharmacy, Quaid-i-Azam University, Islamabad 44000, Pakistan e Chemistry Department, King Abdulaziz University, Jeddah 21589, Saudi Arabia article info Article history: Received 12 April 2015 Revised 8 May 2015 Accepted 12 May 2015 Available online 16 May 2015 Keywords: Peptides iso-Peptides Anti-cancer Benzotriazole Molecular docking abstract Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimer- ization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski’s Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA- MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results. Ó 2015 Elsevier Ltd. All rights reserved. A diverse arsenal of peptide based drugs have been developed for the treatment of cancer, viral infections, pain management, and other diseases. 1,2 The ubiquity of biologically active peptides and peptide derivatives has attracted attention of the synthetic community. In this context the 1923 Nobel Prize was awarded to Banting and Macleod for the discovery and extraction of insulin. 2 du Vigneaud, a Nobel laureate in chemistry, presented the first total solution phase synthesis of a naturally occurring bioactive octapeptide, oxytocin. 3–5 Peptides are now routinely prepared by chemical synthesis in solution or solid phase and are being used as therapeutic agents such as leuprolide acetate (Lupron™), octre- odide acetate (Sandostatin™) and goserelin acetate (Zoladex™). 2,5 Peptides are intrinsically able to interact with biological sys- tems and are therefore potent therapeutics, 6–8 but their conforma- tional flexibility, low ability to cross physiological barriers and metabolic instability, represent major hurdles for the successful development of peptide-based drugs. 9 Advantages for purely synthetic peptides include, large scale preparation, incorporation of unnatural amino acid residues to improve their absorption–distribution–metabolism profile, limitless sequence variations and well-defined homogeneity. 10–12 New and improved strategies lead to more efficient synthesis of complex peptide targets, opening avenues to both new drug candi- dates and a deeper understanding of the intimate relation between sequence, conformation and properties. Despite recent progress and the arsenal of reagents available, peptide synthesis remains challenging. Benzotriazole emerged as a powerful synthetic tool in 1987. 13–16 Since then tremendous progress has been achieved in this field. 17 This solution phase benzotriazole mediated peptide coupling avoids both epimerization and hydrolysis due to fast coupling rate. Peptides containing iso-peptide bonds are called iso-peptides. iso-Peptides are useful for the synthesis of large peptides and pro- teins. The iso-peptide method led to the efficient preparation and purification of large peptides, which are known to aggregate in solution. Significantly, the combination of both techniques, peptide and iso-peptide synthesis has advanced the frontiers of synthetic peptide chemistry. ‘O-Acyl iso-peptides’ are more hydrophilic and easier to purify by HPLC than the corresponding native peptides. 18 This study reports the synthesis of chiral peptides and iso-pep- tides by benzotriazole chemistry and their anticancer activity. Molecular docking studies against kinases completes the study. N-(Pg-Aminoacyl)-benzotriazoles 3a–d were readily prepared from commercial N-protected-amino acids 1a–e following http://dx.doi.org/10.1016/j.bmcl.2015.05.020 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +1 352 392 0554; fax: +1 352 870 9288. E-mail address: sspanda12@gmail.com (S.S. Panda).   Deceased on February 10, 2014. Bioorganic & Medicinal Chemistry Letters 25 (2015) 2980–2984 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl