Synthesis, biological studies and molecular dynamics of new anticancer RGD-based peptide conjugates for targeted drug delivery

Y Gilad; E Noy; H Senderowitz; A Albeck; M A Firer; G Gellerman

doi:10.1016/j.bmc.2015.12.020

Synthesis, biological studies and molecular dynamics of new anticancer RGD-based peptide conjugates for targeted drug delivery

Bioorg Med Chem. 2016 Jan 15;24(2):294-303. doi: 10.1016/j.bmc.2015.12.020. Epub 2015 Dec 12.

Authors

Y Gilad¹, E Noy², H Senderowitz², A Albeck³, M A Firer⁴, G Gellerman⁵

Affiliations

¹ Department of Biological Chemistry, Ariel University, Ariel 40700, Israel; The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
² Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
³ The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
⁴ Department of Chemical Engineering, Ariel University, Ariel 40700, Israel.
⁵ Department of Biological Chemistry, Ariel University, Ariel 40700, Israel. Electronic address: garyg@ariel.ac.il.

PMID: 26719208
DOI: 10.1016/j.bmc.2015.12.020

Abstract

New cyclic RGD peptide-anticancer agent conjugates, with different chemical functionalities attached to the parent peptide were synthesized in order to evaluate their biological activities and to provide a comparative study of their drug release profiles. The Integrin binding c(RGDfK) penta-peptide was used for the synthesis of Camptothecin (CPT) carbamate and Chlorambucil (CLB) amide conjugates. Substitution of the amino acid Lys with Ser resulted in a modified c(RGDfS) with a new attachment site, which enabled the synthesis of an ester CLB conjugate. Functional versatility of the conjugates was reflected in the variability of their drug release profiles, while the conserved RGD sequence of a selective binding to the αv integrin family, likely preserved their recognition by the Integrin and consequently their favorable toxicity towards targeted cancer cells. This hypothesis was supported by a computational analysis suggesting that all conjugates occupy conformational spaces similar to that of the Integrin bound bio-active parent peptide.

Keywords: Bio-stability; Cancer; Chemo-stability; Conjugate; Drug release profiles; Molecular dynamics; RGD; Targeted drug delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Camptothecin / chemistry
Camptothecin / pharmacology*
Carbamates / chemistry
Carbamates / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Chlorambucil / chemistry
Chlorambucil / pharmacology*
Dose-Response Relationship, Drug
Drug Delivery Systems*
Drug Screening Assays, Antitumor
Humans
Liver / chemistry
Liver / metabolism
Mice
Molecular Dynamics Simulation*
Molecular Structure
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbamates
Peptides, Cyclic
cyclic arginine-glycine-aspartic acid peptide
Chlorambucil
Camptothecin