Ligand-drug-conjugate comprising single molecular weight polysarcosine
A technology of molecular weight and conjugates, which is applied in the field of conjugation technology, ligand-drug-conjugate of single molecular weight polysarcosine, to achieve the effects of improving drug loading capacity, easy large-scale production, and excellent yield
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Embodiment 1
[0256] Embodiment 1: the synthesis of polysarcosine compound (synthetic method 1 on the resin)
[0257] The reaction scheme is as follows.
[0258]
[0259] 1.1) General method
[0260] On-resin synthesis was performed in empty SPE plastic tubes filled with 20 μm polyethylene frit (Sigma-Aldrich). Agitation was performed using a Titramax 101 horizontal shaker (Heidolph). All synthesis yields reported are based on an initial theoretical resin loading of 0.63 mmol / g (labelled range indicated by the manufacturer). All reactions were performed at room temperature unless otherwise stated.
[0261] 1.2) Resin loading
[0262] Typically, 500mg NovaGEL TM Rink Amide beads (0.63 mmol / g, Novabiochem) were swelled in 5 mL DMF for 15 minutes. The first monomer was added by reacting 10 equivalents of bromoacetic acid with 13 equivalents of diisopropylcarbodiimide (Sigma-Aldrich) in 5 mL of DMF for 60 minutes at room temperature, followed by extensive washing with DMF (5 times 5...
Embodiment 2
[0276] Embodiment 2: the synthesis of polysarcosine compound (synthetic method 2 on the resin)
[0277] The reaction scheme is as follows.
[0278]
[0279] 2.1) General method
[0280] On-resin synthesis was performed in empty SPE plastic tubes filled with 20 μm polyethylene frit (Sigma-Aldrich). Agitation was performed using a Titramax 101 horizontal shaker (Heidolph). All synthesis yields reported are based on an initial resin loading of 1.1 mmol / g (labelled range indicated by the manufacturer). All reactions were performed at room temperature unless otherwise stated.
[0281] 2.2) Synthesis of Fmoc-Sar-Sar-OH
[0282]
[0283] 2.2.1) Synthesis of Fmoc-Sar-Sar-OtBu
[0284] In a round bottom flask, Fmoc-Sar-OH (2000 mg / 6.42 mmol) and HATU (2443 mg / 6.42 mmol) were dissolved in 28 mL of anhydrous DMF. DIPEA (2491 mg / 19.27 mmol) was added, and the mixture was stirred at room temperature for 3 minutes. Then, tert-butyl sarcosine hydrochloride (1167 mg / 6.42 mmol) wa...
Embodiment 3
[0304] Example 3: Synthesis of polysarcosine compounds with one or several azido-functionalized orthogonal linkers (tree Lipid Synthesis Method 3)
[0305] The reaction scheme is as follows.
[0306]
[0307] 3.1) General method
[0308] On-resin synthesis was performed in empty SPE plastic tubes filled with 20 μm polyethylene frit (Sigma-Aldrich). Agitation was performed using a Titramax 101 horizontal shaker (Heidolph). All synthesis yields reported are based on an initial resin loading of 1.1 mmol / g (labelled range indicated by the manufacturer). All reactions were performed at room temperature unless otherwise stated. The starting material was obtained as described in Example 2 above.
[0309] 3.2) Step (1)
[0310] A 3 molar solution of 2-azidoethan-l-amine in DMF was added (1 mL per 100 mg resin), the vessel was shaken for 45 minutes, drained and washed with DMF (4x) and DCM (4x).
[0311] 3.3) Step (2)
[0312] To the resin was added commercially available...
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