Triptolide derivatives and preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-9809822-B2
Application number	US-201315100092-A
Country	US
Kind code	B2
Filing date	Dec 11, 2013
Priority date	Dec 11, 2013
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

Tripyolide-nucleic acid aptamer derivatives, a preparation method and use thereof are shown. The structure of the triptolide-nucleic acid aptamer derivatives is as shown by formula I, wherein the definitions of R 1 -R 7 , G, A, B, M, Z and X are described. The present invention uses a nucleic acid aptamer and triptolide or modified compounds thereof as the starting materials, and introduces a linking group A at the C-14 hydroxyl group, epoxy groups and five-membered ring lactones in triptolide, then connects it to a nucleic acid aptamer B, and obtains the triptolide-nucleic acid aptamer derivatives. The triptolide-nucleic acid aptamer derivatives of the present invention have the characteristics of good targeting, a high anti-cancer activity, low toxicity and side effects, good water solubility and high bioavailability, and the preparation method of the present invention is scientific and reasonable and has a controllable quality and good repeatability, and is thereby suitable for production.

First claim

The invention claimed is:

1. A triptolide derivative, being a compound of the Formula (I):

R 1 =H or OH;
R 2 =H or OH;
R 3 =H or OH;
R 4 =H or OH;
R 5 =H or OH;
R 6 =H or OH;
R 7 =H or OH;
G is O or NH;
A is —CO—, —CO—(CH 2 ) n— CO—, —CH═CH—CO—, —CH═CH—(CH 2 ) n —CO—, —CH(OH)-Ph-CO—, CH(OH)-Ph-(CH 2 ) n —CO—, —CH 2 -Ph-(CH 2 ) n— CO—, —CO—NH—CO—, —CO—NH—(CH 2 ) n —CO—, —CH 2 —CH═CH—CO—, —CH 2 —CH═CH—(CH 2 ) n— CO—, —CO—CH 2 —, —CO—O—(CH 2 ) n —CO—, —SO 2 -Ph-CO—, or —SO 2 -Ph-(CH 2 ) n —CO—; wherein 1≦n≦14; (CH 2 ) n further comprises a substituent selected from straight or branched alkyl, alkenyl, aralkyl, or alkyl aryalkyl, aryl, halogen, group with a heteroatom, heterocycle substituting one or more H in the (CH 2 ) n , the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl; the alkenyl is selected from vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, or the E, Z isomers thereof; the aralkyl and the alkyl aralkyl is selected from benzyl, diphenylmethyl, tolyl methyl, triphenylmethyl, cinnamyl, phenethyl, styryl, phenylbutyl and neophenyl; the aryl is selected from phenyl, diphenyl, tolyl, methylbenzyl, 4,2,6-trimethylphenyl, cumenyl, di(tert-butyl) phenyl, anthryl, indenyl, naphthyl, haloaryl, haloaryl alkylphenoxy, tolyloxy, xylyl alkoxy, 2,4,6-tris tolyloxy and cumene oxy, diphenyl, anilino, toluidino, tosyl, allyl benzyl or phenyl, furanyl, pyridyl, 2-pyridyl (pyridin-2-yl), indol-1-yl, chloromethylbenzyl or phenyl, trifluoromethylbenzyl or phenyl, hydroxybenzyl or phenyl, methoxybenzyl or phenyl, ethoxybenzyl or phenyl, ethoxymethoxybenzyl or phenyl, allyloxybenzyl or phenyl, phenoxybenzyl or phenyl, acetoxybenzyl or phenyl, benzoyloxy benzyl or phenyl, methylthiobenzyl or phenyl, phenylthio benzyl or phenyl, tolylthio benzyl or phenyl, methylaminobenzyl or phenyl, dimethylaminobenzyl or phenyl, ethylaminobenzyl or phenyl, diethylaminobenzyl or phenyl, acetamidobenzyl or phenyl, carboxybenzyl or phenyl, methoxycarbonyl benzyl or phenyl, ethoxycarbonyl benzyl or phenyl, phenoxycarbonyl benzyl or phenyl, chlorophenoxycarbonyl benzyl or phenyl, N-cyclohexylcarbamoyloxy benzyl or phenyl, allyloxycarbonyl benzyl or phenyl, carbamoyl benzyl or phenyl, N-methylcarbamoyl benzyl or phenyl, N,N-dipropyl carbamoyl benzyl or phenyl, N-phenyl-carbamoyl-benzyl or phenyl, nitrobenzyl or phenyl, cyanobenzyl or phenyl, S-benzyl or phenyl, sulfate benzyl or phenyl, phosphonyl benzyl or phenyl, phosphate benzyl or phenyl and morpholino benzyl or phenyl; the halogen comprises fluorine, chlorine, bromine or iodine; the group with the heteroatom is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, isobutylthio, tert-butylthio, methylsulfinyl, ethylsulfinyl, isopropyl sulfinyl, methylsulfonyl, ethylsulfonyl, isopropyl sulfonyl; the heterocycle is selected from pyridine, quinolone, thiophene, furan, oxazole, tetrazole, thiazole, imidazole, pyrazole, or indole;
B is an aptamer, and the aptamer is AS1411 or Sgc8c;
M is O or OH;
Z is O;
X is O;
wherein A is connected with M, Z or X.

2. The derivative according to claim 1 , wherein A is —CO—;
—CO—CH 2 —CO—, —CO—CH 2 —CH 2 —CO—, —CO—CH 2 —CH 2 —CH 2 —CO—,
—CO—CH 2 —CH 2 —CH 2 —CH 2 —CO—;
—CH═CH—CO—;
—CH(OH)-Ph-CO—, —CH(OH)-Ph-CH 2 —CO—,
—CH(OH)-Ph-CH 2 —CH 2 —CO—, —CH(OH)-Ph-CH 2 —CH 2 —CH 2 —CO—,
—CH(OH)-Ph-CH 2 —CH 2 —CH 2 —CH 2 —CO—;
—CH 2 -Ph-CH 2 —CO—, —CH 2 -Ph-CH 2 —CH 2 —CO—,
—CH 2 -Ph-CH 2 —CH 2 —CH 2 —CO—, —CH 2 -Ph-CH 2 —CH 2 —CH 2 —CH 2 —CO—;
—CO—NH—CO—, —CO—NH—CH 2 —CO—, —CO—NH—CH 2 —CH 2 —CO—,
—CO—NH—CH 2 —CH 2 —CH 2 —CO—, —CO—NH—CH 2 —CH 2 —CH 2 —CH 2 —CO—;
—CH 2 —CH═CH—CO—, —CH 2 —CH═CH—CH 2 —CO—,
—CH 2 —CH═CH—CH 2 —CH 2 —CO—, —CH 2 —CH═CH—CH 2 —CH 2 —CH 2 —CO—,
—CH 2 —CH═CH—CH 2 —CH 2 —CH 2 —CH 2 —CO;
—CO—CH 2 —;
—CO—O—CO—, —CO—O—CH 2 —CO—, —CO—O—CH 2 —CH 2 —CO—,
—CO—O—CH 2 —CH 2 —CH 2 —CO—, —CO—O—CH 2 —CH 2 —CH 2 —CH 2 —CO—;
—SO 2 -Ph-CO—, —SO 2 -Ph-CH 2 —CO—, —SO 2 -Ph-CH 2 —CH 2 —CO—,
—SO 2 -Ph-CH 2 —CH 2 —CH 2 —CO—, or —SO 2 -Ph-CH 2 —CH 2 —CH 2 —CH 2 —CO—.

3. The derivative according to claim 1 , wherein the compound has the following structure:

wherein, R 1 =H or OH;
R 2 =H or OH;
R 3 =H or OH;
R 4 =H or OH;
R 5 =H or OH;
R 6 =H or OH;
R 7 =H or OH;
G is O or NH;
M is O;
Z is O;
X is O;
A is selected from —CO—, —CO—(CH 2 ) n —CO—, —CH═CH—CO—, —CH═CH—(CH 2 ) n —CO—, —CH(OH)—Ph-CO—,CH(OH)-Ph-(CH 2 ) n —CO—, —CH 2 -Ph-(CH 2 ) n —CO—, —CO—NH—CO—, —CO—NH—(CH 2 ) n —CO—, —CH 2 —CH═CH—CO—, —CH 2 —CH═CH—(CH 2 ) n CO—, —CO—CH 2 —, —CO—O—(CH 2 ) n —CO—,—SO 2 -Ph-CO— or —SO 2 -Ph-(CH 2 ) n —CO—; wherein 1≦n≦14; (CH 2 ) n further comprises a substituent selected from straight or branched alkyl, alkenyl, aralkyl, alkyl aryalkyl, aryl, halogen, group with a heteroatom, heterocycle substituting one or more H in the (CH 2 ) n , the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl; the alkenyl is selected from vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, or the E, Z isomers thereof; the aralkyl and the alkyl aralkyl is selected from benzyl, diphenylmethyl, tolyl methyl, triphenylmethyl, cinnamyl, phenethyl, styryl, phenylbutyl or neophenyl; the aryl is selected from phenyl, diphenyl, tolyl, methylbenzyl, 4,2,6-trimethylphenyl, cumenyl, di(tert-butyl) phenyl, anthryl, indenyl, naphthyl, haloaryl, haloaryl alkylphenoxy, tolyloxy, xylyl alkoxy, 2,4,6-tris tolyloxy and cumene oxy, diphenyl, anilino, toluidino, tosyl, allyl benzyl or phenyl, furanyl, pyridyl, 2-pyridyl (pyridin-2-yl), indol-1-yl, chloromethylbenzyl or phenyl, trifluoromethylbenzyl or phenyl, hydroxybenzyl or phenyl, methoxybenzyl or phenyl, ethoxybenzyl or phenyl, ethoxymethoxybenzyl or phenyl, allyloxybenzyl or phenyl, phenoxybenzyl or phenyl, acetoxybenzyl or phenyl, benzoyloxy benzyl or phenyl, methylthiobenzyl or phenyl, phenylthio benzyl or phenyl, tolylthio benzyl or phenyl, methylaminobenzyl or phenyl, dimethylaminobenzyl or phenyl, ethylaminobenzyl or phenyl, diethylaminobenzyl or phenyl, acetamidobenzyl or phenyl, carboxybenzyl or phenyl, methoxycarbonyl benzyl or phenyl, ethoxycarbonyl benzyl or phenyl, phenoxycarbonyl benzyl or phenyl, chlorophenoxycarbonyl benzyl or phenyl, N-cyclohexylcarbamoyloxy benzyl or phenyl, allyloxycarbonyl benzyl or phenyl, carbamoyl benzyl or phenyl, N-methylcarbamoyl benzyl or phenyl, N,N-dipropyl carbamoyl benzyl or phenyl, N-phenyl-carbamoyl-benzyl or phenyl, nitrobenzyl or phenyl, cyanobenzyl or phenyl, S-benzyl or phenyl, sulfate benzyl or phenyl, phosphonyl benzyl or phenyl, phosphate benzyl or phenyl and morpholino benzyl or phenyl; the halogen comprises fluorine, chlorine, bromine and iodine; the group with the heteroatom is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, isobutylthio, tert-butylthio, methylsulfinyl, ethylsulfinyl, isopropyl sulfinyl, methylsulfonyl, ethylsulfonyl, isopropyl sulfonyl; the heterocycle is selected from pyridine, quinolone, thiophene, furan, oxazole, tetrazole, thiazole, imidazole, pyrazole or indole;
B is an aptamer, and the aptamer is AS1411 or Sgc8c.

4. The derivative according to claim 3 , wherein A is selected from —CO—;
—CO—CH 2 —CO—, —CO—CH 2 —CH 2 —

Assignees

• Univ Hong Kong Baptist Univ

Inventors

• Zhang Ge
• Lu Aiping
• Wang Cheng
• Lu Cheng
• Lu Jun
• Liu Biao

Classifications

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C07J73/003

  by oxygen as hetero atom · CPC title

• C12N2310/16

  Aptamers · CPC title

• C12N15/115 Primary

  Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers} · CPC title

• C12N2310/351

  Conjugate · CPC title