title: Bombesin analogs containing alpha-amino-isobutyric acid with potent anticancer activity.
abstract: Six octapeptide bombesin (BN) analogs were synthesized by substituting alpha-aminoisobutyric acid (Aib), in place of Ala9 or Gly11, or both, in the [D-Phe6, desMet14]-BN (6-14) sequence: D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-NH2 (P0). Additionally, Leu13 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 microM. 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)/alpha-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.
authors.affiliation: Dabur Research Foundation, 22, Site IV, Sahibabad, Ghaziabad 201010, India. sprasad@dabur.com
authors.forename: Sudhanand
authors.initials: S
authors.lastname: Prasad
authors.forename: Archna
authors.initials: A
authors.lastname: Mathur
authors.forename: Neena
authors.initials: N
authors.lastname: Gupta
authors.forename: Manu
authors.initials: M
authors.lastname: Jaggi
authors.forename: Anu T
authors.initials: AT
authors.lastname: Singh
authors.forename: Praveen
authors.initials: P
authors.lastname: Rajendran
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Sanna
authors.forename: Kakali
authors.initials: K
authors.lastname: Datta
authors.forename: Rama
authors.initials: R
authors.lastname: Mukherjee
mesh_terms: D000595:Amino Acid Sequence; D000621:Aminoisobutyric Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000621:Aminoisobutyric Acids; D000970:Antineoplastic Agents; C100049:2-aminoisobutyric acid; D001839:Bombesin