GFB-111
Chemical Name: 1,1',1'',1'''-[[25,26,27,28-Tetrabutoxypentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19,(26),21,23-dodecaene-5,11,17,23-tetrayl]tetrakis[carbonylimino[5-(aminomethyl)-3,1-phenylene]carbonyl]]tetrakis[glycyl-L-alpha-aspartyl-glycyl-L-tyrosine] (4-1),(4'-1'),(4''-1''),(4'''-1''')-tetralactam
CAS No. 220064-45-9
项目整合开发状态: Preclinical
项目研究机构: University of South Florida (Originator)
合成路线:The cyclic peptide precursor (XIV) was prepared by solid-phase synthesis on a preformed HMPB-MBHA resin.Attachment of N-Fmoc-glycine (I) to the resin by means of DCC and DMAP afforded resin (II).The Fmoc protecting group was then removed with piperidine in DMF,yielding the glycine-bound resin (III).Further couplings with the following protected amino acids: N-Fmoc-3-(aminomethyl)-5-nitrobenzoic acid (IV),N-Fmoc-L-tyrosine(O-t-butyl) (VI) and N-Fmoc-glycine (I),followed by Fmoc deprotection cycles,produced in turn the peptide resins (V),(VII) and (VIII).To peptide resin (VIII) was then coupled N-Fmoc-L-aspartic acid gamma-t-butyl ester (IX),yielding resin (X).Peptide (XI) was then liberated from the resin by means of 1% trifluoroacetic acid in CH2Cl2.The Fmoc group was subsequently removed by treatment with diethylamine in acetonitrile,giving (XII).
合成路线:Compound (XII) was cyclized to (XIII) employing BOP and HOBt.The nitro group was then reduced to the corresponding amino derivative (XIV) by catalytic hydrogenation over Pd/C.
合成路线:Calix[4]arene (XXI) was alkylated with n-butyl bromide (XXII) and NaH to produce the tetrabutyl ether (XXIII).Formylation of (XXIII) with dichloromethyl methyl ether and TiCl4 yielded the aldehyde (XXIV),which was further oxidized to the tetracarboxylic acid (XXV) using sodium chlorite.Then,treatment of (XXV) with oxalyl chloride and DMF gave the corresponding acid chloride (XXVI).
合成路线:Coupling of the cyclic peptide (XIV) with tetraacid chloride (XXVI) produced the corresponding tetraamide.The O-tert-butyl groups were then removed by treatment with trifluoroacetic acid to produce the title compound.
📌 参考资料/链接：
参考文献标题:Protein surface recognition by synthetic receptors: A route to novel submicromolar inhibitors for alpha-chymotrypsin
文献作者:Park,H.S.; et al.
参考来源:J Am Chem Soc 1999,121(1),8
📄 详细内容
合成路线:In an alternative method for the solution-phase synthesis of this intermediate,methyl 3-carbamoyl-5-nitrobenzoate (XV) was reduced with borane to amino ester (XVI),which was subsequently hydrolyzed to the corresponding amino acid (XVII).Coupling of amino acid (XVII) with N-Fmoc-L-tyrosine(O-t-butyl) (VI) using DCC and N-hydroxysuccinimide produced dipeptide (XVIII).This was then coupled with the tripeptide H-Gly-Asp(t-Bu)-Gly-OH (XIX) to yield the linear peptide (XX).After Fmoc deprotection,cyclization in the presence of TBTU and DMAP furnished the cyclic peptide (XIII),which was further reduced to the amino derivative (XIV) as above.
合成路线:Calix[4]arene (XXI) was alkylated with n-butyl bromide (XXII) and NaH to produce the tetrabutyl ether (XXIII).Formylation of (XXIII) with dichloromethyl methyl ether and TiCl4 yielded the aldehyde (XXIV),which was further oxidized to the tetracarboxylic acid (XXV) using sodium chlorite.Then,treatment of (XXV) with oxalyl chloride and DMF gave the corresponding acid chloride (XXVI).
合成路线:Coupling of the cyclic peptide (XIV) with tetraacid chloride (XXVI) produced the corresponding tetraamide.The O-tert-butyl groups were then removed by treatment with trifluoroacetic acid to produce the title compound.
参考文献标题:Protein surface recognition by synthetic receptors
文献作者:Lin,Q.; et al.
参考来源:NATO ASI Series.Series C: Mathematical and Physical Sciences 1999,527197