Cilengitide (Cilengitide) is a synthetic new class of anticancer drugs. Merkel's research found that cilengitide combined with chemoradiotherapy (combined with and adjuvant temozolomide plus radiotherapy) may prolong survival. At the same time, as the first integrin inhibitor anti-tumor drug, it has entered Phase III clinical trials. Its important mechanism is to target tumors and supply blood structures that provide nutrition for tumors and promote the growth of cancer cells by hindering blood vessel growth.
Basic information
chinese name: Xilengitide
english name: Cilengitide
company No.: GT-F053
CAS No.: 188968-51-6
sequence: cyclo(Arg-Gly-Asp-D-Phe-N-Me-Val)
molecular formula: C27H40N8O7
molecular weight: 588.66
Cilengitide preparation method
at present, the preparation methods of cilengitide mainly include liquid phase synthesis process, solid phase synthesis precursor peptide cyclization process in liquid phase and solid phase synthesis process. The first two synthesis processes are cyclization of synthetic precursor peptide in liquid phase. This method requires reactants to react in extremely dilute solvent (10~10 · mol/L), and it is easy to react between molecules to form linear or cyclic polymers, the cyclization yield is greatly reduced, which brings trouble to the subsequent purification, and a large amount of waste liquid is produced in the large-scale production, which is not conducive to industrial production. Combined with the structure of cilengitide and the principle of solid phase pseudodilution, an efficient cyclization technology was developed. The cyclization time was shortened to 20% ~ 30% of the liquid phase cyclization, and the reaction solvent was 2%-8% of the liquid phase.
1. Fmoc-L-Asp(OtBu)-Wang Resin was prepared by Wang Resin and Fmoc-L-Asp-OtBu reaction with substitution degree of 0.4~0.9mmol/g.
2. The remaining 4 Fmoc-containing amino acids were sequentially coupled by solid-phase stepwise synthesis to obtain Cilengitide precursor peptide A- Wang Resin.
3. In the cilengitide precursor peptide A- Wang Resin, Fmoc and OtBu reagents were added respectively to obtain cilengitide precursor peptide B- Wang Resin.
4. Add cilengitide precursor peptide B- Wang Resin and cyclization reagent in DMF or DCM to obtain cilengitide-Wang Resin after reaction.
5. Cleavage, purification, freeze-drying to obtain pure cilengitide.
The solid-phase cyclization synthesis process of cilengitide, wherein the Fmoc-L-Asp(OtBu)-Wang Resin described in step 1) is generated by Fmoc-L-Asp-OtBu and Wang Resin in DCM or DMF under the action of DIC + HOBT + DMAP.
In step 2), solvent DMF or DCM is used, and coupling reagent C + D + E is used, wherein C is HOAt or HOBt, D is HBTU or HATU or TBTU, and E is DIEA; The Fmoc protected amino acids are Fmoc-Gly-OH, Fmoc-L-Arg(Mtr)-OH, Fmoc-N-Me-L-Val and Fmoc-D-Phe-OH respectively; The deprotecting agent of Fmoc protecting group is a 25% piperidine-DMF solution by volume.
Step 3) The added deprotecting group reagents are respectively: the reaction time of removing OtBu from the piperidine-DMF solution and the PhOH-DCM solution with a volume ratio of 25% is 5-8h.
Step 4) The cyclization reagent is DPPA + DIEA or DPPA + NMM or DIC + HOBT or C + D + E, where C is HOAr or HOBt,D is HBTU or HATU or TBTU, and E is DIEA.
Step 5) The lysis reagent is: TFA/H₂ O/T1S.
Compared with the existing traditional liquid phase cyclization technology, the process of the present invention has the advantages of simple operation, high yield, simple post-treatment, short reaction time, less waste liquid, low cost, etc., and has a wide range of application value in the field of cyclic peptide drug design and synthesis process.Cilengitide chemical structural formulaCilengitide Process Flow Diagram
Post time: 2026-09-03