Constrained derivatives of stylostatin 1. 1. Synthesis and biological evaluation as potential anticancer agents.
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.
Forns
Pilar
P
Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, 08028-Barcelona, Spain.
Piró
Jordi
J
Cuevas
Carmen
C
García
Mònica
M
Rubiralta
Mario
M
Giralt
Ernest
E
Diez
Anna
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003500:Cyclization; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006860:Hydrogen Bonding; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012997:Solvents; D013329:Structure-Activity Relationship; D013696:Temperature
D000970:Antineoplastic Agents; D004151:Dipeptides; D010456:Peptides, Cyclic; D010881:Piperidones; D012997:Solvents; C480618:stylostatin 1; D004121:Dimethyl Sulfoxide