New macrocyclic analogs of the natural histone deacetylase inhibitor FK228; design, synthesis and preliminary biological evaluation.

Among the natural histone deacetylase inhibitors (HDACi), the bicyclic depsipeptide macrolactone FK228 stands out for its unique chemical structure and mechanism of action. In order to expand the chemical diversity, exploiting the FK228 peculiar structure, we have synthesized a collection of 24 simplified novel analogs. A first series consists of bicyclic macrolactones, where the carboxy terminus of the natural compound was substituted by peptidomimetic aminomethylphenylacetic acid derivatives.

Conjugates of a novel 7-substituted camptothecin with RGD-peptides as α(v)β₃ integrin ligands: An approach to tumor-targeted therapy.

Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide.

Novel tumor-targeted RGD peptide-camptothecin conjugates: synthesis and biological evaluation.

Five RGD peptide-camptothecin (CPT) conjugates were designed and synthesized with the purpose to improve the therapeutic index of this antitumoral drug family. New RGD cyclopeptides were selected on the basis of their high affinity to alpha(v) integrin receptors overexpressed by tumor cells and their metabolic stability. The conjugates can be divided in two groups: in the first the peptide was attached to the drug through an amide bond, in the second through a hydrazone bond.

Incorporation of the unusual C(alpha)-fluoroalkylamino acids into cyclopeptides: synthesis of arginine-glycine-aspartate (RGD) analogues and study of their conformational and biological behavior.

A series of six arginine-glycine-aspartate (RGD) cyclopeptide analogues containing a C(alpha)-di- or trifluoromethylamino acid (alpha-Dfm or alpha-TfmAaa) at different positions of the ring were synthesized. All peptides were obtained in two diastereomeric forms, which were separated by HPLC. In vitro biological tests of the new cyclopeptides P were carried out in comparison with their corresponding cyclopeptides R lacking the alpha-fluoromethyl group.

Amino acid bromides: their N-protection and use in the synthesis of peptides with extremely difficult sequences.

N(alpha)-Protected alpha-amino acid bromides were easily generated in situ with 1-bromo-N,N-2-trimethyl-1-propenylamine from the corresponding amino acids under very mild conditions. o-Nbs and the azido moieties proved to be compatible with these overactivated halides and were successfully applied in difficult peptide bond formations. N-Deprotection methods and the total step-by-step solution synthesis of a peptide containing up to seven consecutive L-(alphaMe)Valine residues are also reported.