Bombesin analogs containing α-amino-isobutyric acid with potent anticancer activity

✍ Scribed by Sudhanand Prasad; Archna Mathur; Neena Gupta; Manu Jaggi; Anu T. Singh; Praveen Rajendran; Vinod K. Sanna; Kakali Datta; Rama Mukherjee

• Book ID: 105360623
• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 216 KB
• Volume: 13
• Category: Article
• ISSN: 1075-2617
• DOI: 10.1002/psc.799

✦ Synopsis

Abstract

Six octapeptide bombesin (BN) analogs were synthesized by substituting α‐aminoisobutyric acid (Aib), in place of Ala^9^ or Gly^11^, or both, in the [D‐Phe^6^, __des__Met^14^]‐BN (6–14) sequence: D‐Phe^6^‐Gln^7^‐Trp^8^‐Ala^9^‐Val^10^‐Gly^11^‐His^12^‐Leu^13^‐NH~2~ (P0). Additionally, Leu^13^ was replaced with isoleucine in two analogs and one of the analogs was butanoylated at the N‐terminus. The antiproliferative activity of the analogs was tested in vitro on human pancreatic (MiaPaCa‐2) and colon cancer (SW620, HT29 and PTC) cell lines using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The analogs demonstrated anticancer activity in the above cell lines at concentrations ranging from 0.01 nM to 1 µM. One of the analogs, P6, was evaluated for in vivo tumor regression in a xenograft model of human primary colon cancer in athymic nude mice and was found to cause significant reduction in tumor volume. NMR and molecular dynamics (MD) simulation studies for this analog revealed the presence of a mixed 3~10~/α‐helical structure. This study demonstrates that the designed BN analogs retain their anticancer activity after the incorporation of the constrained amino acid, Aib, and are potential molecules for future use in cancer therapy and drug targeting. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.