Solid-phase synthesis and DNA binding studies of dichloroplatinum(ii) conjugates of dicarba analogues of octreotide as new anticancer drugs

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

“…With this idea in mind we have synthesized conjugates between a dichloridoplatinum(II) complex and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 octreotide derivatives in which the disulfide bond had been replaced by CH 2 -CH 2 or CH=CH linkages. 23 This chemical modification on the peptide does not substantially alter the binding affinity of the dicarbaoctreotide analogues for the sst 2 receptor but increases the stability of the carrier biomolecule in the reductive cellular environment. 24 In addition, we have recently described the synthesis and DNA ruthenation under visible light irradiation of a photoactivated ruthenium(II) arene complex conjugated to a dicarba analogue of octreotide.…”

“…23 Finally, 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (3 mol equiv) or γ-aminoisobutyric acid (3 mol equiv) were coupled onto the cyclic dicarba analogue of octreotide 2 bound to resin with DIPC (3 mol equiv) and HOAt (3 mol equiv) in anhydrous DMF for 1 h. After removal of the Fmoc group (20% piperidine in DMF) from the Fmoc-protected linker-derivatized dicarba analogue of octreotide bound to resin, coupling or assembly of the metal complexes on the free N-terminal end was carried out as indicated for each metal. The reactor was protected from light by covering it with aluminium foil.…”

“…All suitably-protected Fmoc-amino acids were incorporated with HATU in the presence of DIPEA in anhydrous DMF as a solvent. As previously described, 23,24 Fmocprotected threoninol functionalized as the p-carboxybenzaldehyde acetal was first anchored to the solid support. In addition, the two cysteine amino acids in octreotide were replaced by allyl glycine residues to perform the cyclization reaction.…”

“…The assembly of the dicarba analogue of octreotide was performed as previously described. 23,24 Briefly, Fmoc-L-threoninol p-carboxyacetal (1.8 mol equiv) was first coupled using DIPC (1.8 mol equiv) and HOBt (1.8 mol equiv) in anhydrous DMF for 1 h. The following Fmoc-protected amino acids (2.4 mol equiv) were incorporated with HATU (2.3 mol equiv) and DIPEA (4.8 mol equiv)…”

“…Then, hydrogenation of the double bond using Wilkinson's catalyst afforded the protected cyclic saturated dicarba analogue of octreotide (2) For the synthesis of conjugate 3, [PtCl 2 (dap)] (7) was coupled using DIPC and NHS in anhydrous DMF (15 h at rt, protected from light). 23 Cleavage from the resin and removal of the protecting groups were carried out by treatment with a TFA/phenol/H 2 O cocktail (95:2.5:2.5) for 1 h at rt. Reversed-phase HPLC analysis of the crude revealed a main double peak.…”