Constrained derivatives of stylostatin 1. 1. Synthesis and biological evaluation as potential anticancer agents.

Abstract

Hydroxyaminolactams have been used as constrained surrogates of the Ser-Leu dipeptide in the synthesis of analogues of the cycloheptapeptide stylostatin 1 (2). The rate of cyclization through formation of the Ile-Pro amide bond allowed us to prove that the valerolactams used induced a turn in the linear precursor. Ring closure at the Pro-Phe amide bond was much quicker and provided access to larger amounts of the target structures, with high purity. The conformation of psi-stylostatin 4 was compared to that of native stylostatin 1 using NMR analysis. The ability of three psi-stylostatins and the native stylostatin 1 to inhibit growth of cancer cell lines was tested. None of the compounds showed activity below 1 microM. A possible relationship between the decrease in activity and the presence of the piperidone Ser-Leu surrogate is considered.

• Authors: Pilar Forns, Jordi Piró, Carmen Cuevas, Mònica García, Mario Rubiralta, Ernest Giralt, Anna Diez
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 26 Pg. 5825-33 (Dec 18 2003) ISSN: 0022-2623 [Print] United States
• PMID: 14667235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dipeptides
• Peptides, Cyclic
• Piperidones
• Solvents
• stylostatin 1
• Dimethyl Sulfoxide

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cyclization
• Dimethyl Sulfoxide (chemistry)
• Dipeptides (chemistry)
• Drug Screening Assays, Antitumor
• Hydrogen Bonding
• Kinetics
• Magnetic Resonance Spectroscopy
• Mice
• Peptides, Cyclic (chemical synthesis, chemistry, pharmacology)
• Piperidones (chemical synthesis, chemistry, pharmacology)
• Protein Conformation
• Solvents
• Structure-Activity Relationship
• Temperature