【结 构 式】 |
【药物名称】5[Kpsi(CH2N)PR]-TASP, HB-19 【化学名称】N2,N6-[H-L-Lys[psi(CH2N)]L-Pro-L-Arg]-L-Lys-L-Lys-N6-[H-L-Lys[psi(CH2N)]L-Pro-L-Arg]-L-Lys-Gly-L-Pro-N6-[H-L-Lys[psi(CH2N)]L-Pro-L-Arg]-L-Lys-L-Glu-N6-[H-L-Lys[psi(CH2N)]L-Pro-L-Arg]-L-Lys-Gly-L-Cys-OH 【CA登记号】175297-53-7 【 分 子 式 】C132H252N50O23S 【 分 子 量 】2939.86544 |
【开发单位】CNRS (Originator), Institut Pasteur (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY |
合成路线1
The title compound was obtained by solid-phase peptide synthesis starting from N-Boc-S-(4-methylbenzyl)cysteine linked to PAM resin (I). The protected peptide template (XVII) was synthesized by sequential coupling-deprotection cycles using the appropriate combination of either Boc- or Fmoc- N-alpha-protected amino acids. The following side-chain-protected amino acid residues were assembled: Gly (III), Lys(Boc) (V), Glu(cyclohexyl ester) (VII), Lys(Boc) (V), Pro (X), Gly (III), Lys(Boc) (V), Lys(chlorobenzyloxycarbonyl) (XIV) and Lys(Boc) (XVI) to produce the peptide resins (IV), (VI), (VIII), (IX), (XI), (XII), (XIII), (XV) and (XVII), respectively. Subsequent removal of the N-terminal and the four side-chain Boc protecting groups by means of trifluoroacetic acid yielded the peptide resin (XVIII).
【1】 Callebaut, C.; et al.; Inhibition of HIV infection by pseudopeptides blocking viral envelope glycoprotein-mediated membrane fusion and cell death. Virology 1996, 218, 1, 181. |
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) | 42129 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-[(4-methylbenzyl)sulfanyl]propionic acid | C16H23NO4S | 详情 | 详情 | |
(II) | 42130 | (2R)-2-amino-3-[(4-methylbenzyl)sulfanyl]propionic acid | 42294-52-0 | C11H15NO2S | 详情 | 详情 |
(III) | 42131 | 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid | 29022-11-5 | C17H15NO4 | 详情 | 详情 |
(IV) | 42132 | (2R)-2-[(2-aminoacetyl)amino]-3-[(4-methylbenzyl)sulfanyl]propionic acid | C13H18N2O3S | 详情 | 详情 | |
(V) | 18854 | (2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C26H32N2O6 | 详情 | 详情 | |
(VI) | 42133 | (10S,16R)-10-amino-2,2-dimethyl-16-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid | C24H38N4O6S | 详情 | 详情 | |
(VII) | 42134 | (2S)-5-(cyclohexyloxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 150047-85-1 | C26H29NO6 | 详情 | 详情 |
(VIII) | 42135 | (10R,16R)-10-[(3S)-3-amino-6-(cyclohexyloxy)-2,6-dioxohexyl]-2,2-dimethyl-16-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid | C36H56N4O9S | 详情 | 详情 | |
(IX) | 42136 | (10S,13S,16R,22R)-10-amino-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14,17,20-pentaoxo-3-oxa-5,12,18,21-tetraazatricosan-23-oic acid | C47H76N6O12S | 详情 | 详情 | |
(X) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
(XI) | 42137 | (10S,13S,16R,22R)-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14,17,20-pentaoxo-10-[[(2S)pyrrolidinylcarbonyl]amino]-3-oxa-5,12,18,21-tetraazatricosan-23-oic acid | C52H83N7O13S | 详情 | 详情 | |
(XII) | 42138 | (10S,13S,16R,22R)-10-([[(2S)-1-(2-aminoacetyl)pyrrolidinyl]carbonyl]amino)-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14,17,20-pentaoxo-3-oxa-5,12,18,21-tetraaz | C54H86N8O14S | 详情 | 详情 | |
(XIII) | 42139 | (10S,13S,16R,22R)-10-[([(2S)-1-[2-([(2S)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoyl]amino)acetyl]pyrrolidinyl]carbonyl)amino]-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl] | C65H106N10O17S | 详情 | 详情 | |
(XIV) | 42140 | (2S)-6-([[(4-chlorobenzyl)oxy]carbonyl]amino)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C29H29ClN2O6 | 详情 | 详情 | |
(XV) | 42141 | (10S,13S,16R,22R)-10-[([(2S)-1-[(5S,8S)-8-amino-5-[4-[(tert-butoxycarbonyl)amino]butyl]-16-(4-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl]pyrrolidinyl]carbonyl)amino]-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy) | C79H123ClN12O20S | 详情 | 详情 | |
(XVI) | 37991 | (2S)-2,6-bis[(tert-butoxycarbonyl)amino]hexanoic acid | 2483-46-7 | C16H30N2O6 | 详情 | 详情 |
(XVII) | 42142 | (10S,13S,16R,22R)-10-[[((2S)-1-[(5S,8S,11S)-11-[(tert-butoxycarbonyl)amino]-5-[4-[(tert-butoxycarbonyl)amino]butyl]-8-[4-([[(4-chlorobenzyl)oxy]carbonyl]amino)butyl]-19,19-dimethyl-4,7,10,17-tetraoxo-18-oxa-3,6,9,16-tetraazaicos-1-anoyl]pyrrolidinyl | C95H151ClN14O25S | 详情 | 详情 | |
(XVIII) | 42143 | (3S,6S,9R,15R)-3,9-bis(4-aminobutyl)-1-[(2S)-1-((5S,8S)-5-(4-aminobutyl)-16-(4-chlorophenyl)-8-[[(2S)-2,6-diaminohexanoyl]amino]-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl)pyrrolidinyl]-6-[3-(cyclohexyloxy)-3-oxopropyl]-15-[[(4-methylbenzyl)s | C70H111ClN14O15S | 详情 | 详情 |
合成路线2
Simultaneous coupling of five N-Boc-arginin (XIX) residues to the free amino groups of the peptide template (XVIII), followed by acid deprotection of the Boc groups, furnished (XX). To this were assembled five N-Boc-proline residues (XXI) to provide, after acid deprotection, resin (XXII). Then, reductive condensation with Boc-protected lysinal (XXIII) furnished the protected pseudopeptide adduct (XXIV). Finally, simultaneous cleavage from the resin and removal of protecting groups was effected by treatment with anhydrous hydrogen fluoride.
【1】 Callebaut, C.; et al.; Inhibition of HIV infection by pseudopeptides blocking viral envelope glycoprotein-mediated membrane fusion and cell death. Virology 1996, 218, 1, 181. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVIII) | 42143 | (3S,6S,9R,15R)-3,9-bis(4-aminobutyl)-1-[(2S)-1-((5S,8S)-5-(4-aminobutyl)-16-(4-chlorophenyl)-8-[[(2S)-2,6-diaminohexanoyl]amino]-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl)pyrrolidinyl]-6-[3-(cyclohexyloxy)-3-oxopropyl]-15-[[(4-methylbenzyl)s | C70H111ClN14O15S | 详情 | 详情 | |
(XIX) | 14073 | (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 13726-76-6 | C11H22N4O4 | 详情 | 详情 |
(XX) | 42144 | C100H171ClN34O24S | 详情 | 详情 | ||
(XXI) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
(XXII) | 42145 | C81H126ClN19O17SArg4Pro4 | 详情 | 详情 | ||
(XXIII) | 42146 | tert-butyl (1S)-5-[(tert-butoxycarbonyl)amino]-1-formylpentylcarbamate | C16H30N2O5 | 详情 | 详情 | |
(XXIV) | 42147 | C205H350ClN53O50S | 详情 | 详情 |