M., Solid-phase synthesis of C-terminally modified peptides.

Synthesis was performed by Fmoc-solid-phase strategy and 99m Tc labeled by SnCl 2 .

The advantage of solid-phase peptide synthesis, ..

One major problem associated with unmodified linear peptides is their often short biological half-life due to rapid proteolysis in plasma. A short half-life in blood is a major obstacle for the successful in vivo application as radiopharmaceuticals since they may be degraded before reaching the intended target. Therefore, most peptides have to be modified synthetically to minimize rapid enzymatic degradation , . Great efforts have been focused on developing metabolically-stable peptides suitable for clinical use by carrying appropriate molecular modifications, such as the use of more stable D-amino acids for L-amino acids, the use of pseudo-peptide bonds, the inclusion of amino alcohols and the insertion of unnatural amino acids or amino acid residues with modified side-chains without compromising the receptor binding affinity and biological activity of the peptide . It is the specific amino acid sequence of a peptide and usually the nature and type of particular amino acid side-chains that determine resistance to enzymatic degradation. For example, native SST, has a plasma half-life of approximately 2-3 min, but its molecularly modified synthetic peptide derivative, octreotide has a half-life of 1.5-2 h, making it suitable for clinical application .

Quantitative monitoring of solid‐phase peptide synthesis by the ninhydrin reaction.

Solid phase peptide synthesis (SPPS) ..

The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 μM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.

L., Evaluation of Solution and Solid-Phase Approaches to the Synthesis of Libraries of α,α-Disubstituted-α-acylaminoketones.

AB - Despite the advances in molecular biology and biochemistry, the prognosis of patients suffering from tumor diseases remains poor. The limited therapeutic success can be explained by the insufficient performance of the common chemotherapeutic drugs that lack the ability to specifically target tumor tissues. Recently peptide radiopharmaceuticals have been developed that enable the concurrent imaging and therapy of tumors expressing a specific target. Here, with a special emphasis on the synthesis of the building blocks required for the complexation of metallic radioisotopes, the requirements to the design and synthesis of radiolabeled peptides for clinical applications are described.

D., Synthesis and reactivity of 6,7-dihydrogeranylazides: reagents for primary azide incorporation into peptides and subsequent Staudinger ligation.


90.11 standard solid phase peptide synthesis, ..

N2 - The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 μM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.

Solid-phase synthesis of a radiolabeled, biotinylated, …

The distinctive advantages of small radiopeptides over other biologically active molecules, such as proteins and antibodies, are summarized in Table . Receptors for peptides are often found in higher density on tumor cells than in normal tissues; hence specifically designed receptor-binding radiolabeled peptides could enable efficient visualization of tumors. Because of their small size, peptides usually exhibit rapid pharmacokinetics, and good tumor targeting characteristics, with the ability to penetrate into tumors efficiently -. Peptides can easily be synthesized using conventional peptide synthesizers and the desired pharmacokinetic characteristics can be molecularly engineered (by making appropriate changes in the peptide sequence) during synthesis and/or by adding a biomodifying molecule , . Automated peptide synthesizers are available for parallel synthesis procedures allowing the synthesis of peptide libraries in short time.