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【结 构 式】 
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【药物名称】CHAP-31 【化学名称】Cyclo[L-isoleucyl-D-prolyl-2(S)-amino-8-(N-hydroxyamino)-8-oxooctanoyl-O-methyl-D-tyrosyl] 【CA登记号】221186-64-7 【 分 子 式 】C29H43N5O7 【 分 子 量 】573.69536 |
【开发单位】Japan Energy (Originator) 【药理作用】ONCOLYTIC DRUGS, Histone Deacetylase (HDAC) Inhibitors |
合成路线1
The linear peptide-bound resin (VIII) was prepared by solid-phase synthesis on a Kaiser’s oxime resin by sequential coupling-deprotection cycles with N-Boc-L-aminosuberic acid omega-benzyl ester (I), N-Boc-D-proline (III), N-Boc-L-isoleucine (V) and N-Boc-4-O-methyl-D-tyrosine (VII) to afford the peptide resins (II), (III), (IV) and (V), respectively. Cleavage of resin (VIII) with concomitant cyclization provided the cyclic tetrapeptide (IX). After hydrogenolysis of the side-chain benzyl ester, the resulting carboxylic acid was coupled to hydroxylamine in the presence of BOP and HOBt to obtain the title hydroxamic acid.
| 【1】 Tsukamoto, M.; et al.; Synthesis and activity of Cyl-1 analogs having hydroxamic acid at side chain. Pept Sci 1998, 185. |
| 【2】 Mimoto, T.; Komatsu, Y.; Horinouchi, S.; Nishino, N.; Yoshida, M. (Japan Energy Corp.); Novel cyclic tetrapeptide derivs. and medicinal use thereof. EP 1010705; WO 9911659 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 46469 | (2S)-8-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-8-oxooctanoic acid | C20H29NO6 | 详情 | 详情 | |
| (II) | 46470 | (2S)-2-amino-8-(benzyloxy)-8-oxooctanoic acid | C15H21NO4 | 详情 | 详情 | |
| (III) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (IV) | 46471 | (2S)-8-(benzyloxy)-8-oxo-2-[[(2R)pyrrolidinylcarbonyl]amino]octanoic acid | C20H28N2O5 | 详情 | 详情 | |
| (V) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (VI) | 46472 | (2S)-2-[([(2R)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-8-(benzyloxy)-8-oxooctanoic acid | C26H39N3O6 | 详情 | 详情 | |
| (VII) | 46475 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid | C15H21NO5 | 详情 | 详情 | |
| (VIII) | 46473 | (2S)-2-([[(2R)-1-((2S,3S)-2-[[(2R)-2-amino-3-(4-methoxyphenyl)propanoyl]amino]-3-methylpentanoyl)pyrrolidinyl]carbonyl]amino)-8-(benzyloxy)-8-oxooctanoic acid | C36H50N4O8 | 详情 | 详情 | |
| (IX) | 46474 | benzyl 6-[(3S,6R,9S,14aR)-6-(4-methoxybenzyl)-9-[(1S)-1-methylpropyl]-1,4,7,10-tetraoxotetradecahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl]hexanoate | C36H48N4O7 | 详情 | 详情 |