A kind of synthetic method of active cyclic octapeptide reniochalistatin E and its analogs
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A synthesis method and technology of cyclic octapeptide, which is applied in the field of synthesis of active cyclic octapeptide Reniochalistatin E and its analogues, can solve the problems of unsatisfactory practical application and small amount of cyclic peptide, and achieve reduction of racemization, reduction of synthesis time, The effect of simple synthesis process
Inactive Publication Date: 2020-05-08
JINAN UNIVERSITY
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[0002] Marine drugs have attracted more and more attention from scientists, especially the cyclic peptides, which have good anti-tumor, anti-inflammatory, antibacterial and enzyme-inhibiting activities in vivo (Tripathi A, Puddick J.J.Nat Prod, 2010, 73( 11) 1810-1814), because the amount of cyclic peptides isolated in nature is very small, which is far from satisfying practical applications, so artificial synthesis of peptides has become one of the hottest topics now
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Embodiment 1
[0045] Embodiment 1: the resin complex (Fmoc-Pro-resin) of fluorenyl methaneoxycarbonyl proline
[0046] Take 1.00 g of 2-chlorotrityl chloride resin (loading capacity 0.985 mmol / g) in a 100 mL peptide synthesis tube, add 20 mL of DCM to swell for 30 minutes. Drain the filtrate, add 0.84g (3mmol) of Fmoc-Pro-OH to it and dissolve it in 20mL of DCM, adjust the pH to 7-8 with nitrogen, react on a shaker for 4 hours, drain the filtrate, and use 10mL of DCM and DMF were washed alternately for 3 times, and the filtrate was drained to obtain Fmoc-Pro-resin.
Embodiment 2
[0047] Example 2: Residual site blocking on resin
[0048] Add 20 mL of DIEA / MeOH solution with a volume ratio of 10% to Example 1, react on a shaker for 1 hour, drain the filtrate, wash with 10 mL of DCM and DMF alternately for 3 times, and drain the filtrate.
Embodiment 3
[0049] Example 3: Protected linear dipeptide-resin complex (Fmoc-Ile-Pro-resin)
[0050] 1. Add 10 mL of 20% piperidine / DMF solution to Example 2, react for 10 to 15 minutes, wash with 10 mL of DCM and DMF alternately for 3 times, and drain the filtrate.
[0051] Repeat step I once.
[0052] Ⅱ. Weigh 1.06g (3mmol) of Fmoc-Ile-OH and 0.90g (3mmol) of DEPBT in a 50mL conical flask, add 15mL of DMF to dissolve, then add 0.52mL (3mmol) of DIEA, and keep at room temperature After activating for 3 to 5 minutes, add it to Example 2 treated in step I, pass nitrogen gas, react on a shaking table for 3 hours, drain the filtrate, wash it with 10 mL of DCM and DMF alternately for 3 times, and drain the filtrate to obtain Fmoc-Ile-Pro-resin.
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Abstract
The invention discloses a synthesis method of active cyclic octapeptide Reniochalistatin E and an analogue thereof. A complete synthesis method of the cyclic octapeptide disclosed by the invention adopts a polypeptide solid phase synthesis method, and the synthesis time and purification processes are greatly shortened; in order to prevent the condition that hydrogen on tryptophan indole nitrogen possibly causes decrease of a connection rate and increase of by-products, tryptophan with protection of carbonyl tert-butyl (Boc) on indole is adopted as a raw material, and finally, after cyclizationis finished, a TFA / DCM solution with a high volume ratio is adopted for removing Boc protection to obtain a final product. Compared with traditional condensation reagents and cyclization reagents, condensation reagents DEPBT and DIEA and a cyclization reagent PyBOP adopted by the invention have the advantages of greatly reducing racemization caused by reaction processes and reducing toxicity hazards to the body of a user. The product obtained by the synthesis method provided by the invention is simple in synthesis process, low in raw material cost, mild in reaction condition, high in purity and easy to industrialize, and has broad market prospects.
Description
technical field [0001] The present invention relates to a compound with extensive anti-tumor activity, in particular to a synthetic method of active cyclic octapeptide Reniochalistatin E and its analogues. Background technique [0002] Marine drugs have attracted more and more attention from scientists, especially the cyclic peptides, which have good anti-tumor, anti-inflammatory, antibacterial and enzyme-inhibiting activities in vivo (Tripathi A, Puddick J.J.Nat Prod, 2010, 73( 11) 1810-1814), because the amount of cyclic peptides isolated in nature is very small, which is far from satisfying practical applications, so the artificial synthesis of peptides has become one of the hottest topics now. [0003] Reniochalistatin E is a new type of cyclic octapeptide isolated from the sponge Reniochalinastalagmitis collected from Yongxing Island, Xisha, South my country Sea. It has very good activity on various cancer cell lines, such as human multiple myeloma cells RPMI- 8226 (IC ...
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