Jasmonate derivatives and compositions thereof
The disclosure describes jasmonate conjugates and nanocarried and/or microcarried jasmonate conjugates and pharmaceutical compositions thereof, as well as use thereof for treating or preventing angiogenesis-related or NF-κB-related disorders. Also disclosed are methods of making the conjugates.
1. A conjugate
in which M 1 is a jasmonate compound, wherein the jasmonate compound is selected from the group consisting of jasmonic acid, 7-iso-jasmonic acid, 9,10-dihydrojasmonic acid, 9,10-dihydro-isojasmonic acid, 2,3-didehydrojasmonic acid, 3,4-didehydrojasmonic acid, 3,7-didehydrojasmonic acid, 4,5-didehydrojasmonic acid, 4,5-didehydro-7-isojasmonic acid, cucurbic acid, 6-epi-cucurbic acid, 6-epi-cucurbic acid-lactone, 12-hydroxy-jasmonic acid, 12-hydroxy-jasmonic acid-lactone, 11-hydroxy-jasmonic acid, 8-hydroxyjasmonic acid, homo-jasmonic acid, dihomo-jasmonic acid, 11-hydroxy-dihomo-jasmonic acid, 8-hydroxy-dihomo-jasmonic acid, tuberonic acid, tuberonic acid-O-β-glucopyranoside, cucurbic acid-O-β-glucopyranoside, 5,6-didehydro-jasmonic acid, 6,7-didehydro-jasmonic acid, 7,8-didehydro-jasmonic acid, cis-jasmone, dihydrojasmone, and a lower alkyl ester thereof,
M 2 is a compound different from M 1 and is covalently attached to M 1
and
between M 1 and M 2 denotes direct attachment of M 2 to M 1 ,wherein the conjugate is contained within a nanocarrier, wherein M 2 is selected from resveratrol, a gambogic acid, perillyl alcohol, curcumin, a flavonoid, 10-hydroxydecenoic acid, acetogenin, phosphatidylethanolamine, a chemical component of propolis selected from caffeic acid, cinnamic acid, 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C), and esters thereof, and caffeic acid, phenethyl ester (CAPE), a chemical component of Emu oil selected from stearic acid, oleic acid and linolenic acid, and esters thereof, a chemical component or an extract of bitter gourd (Momordica charantia) selected from momordin, saponin, charantin, momordicosides A, B, F1, F2, K, L, M, N, and S, charantosides I through VIII, karavilosides I, II, III, V, and XI, MAP30 and MCP30 proteins, kuguaglycoside A through H, goyaglycosides c and d, beta carotene, ascorbic acid, niacin, thiamin, and Coenzyme Q 10.
2. The conjugate of claim 1 , wherein the conjugate is of Formula (I):
wherein
n is 1, 2, 3, or 4;
X is O or S;
Y is O, or NH;
each occurrence of Z independently is CH or N;
R 1 is H, alkyl, alkenyl, or alkynyl;
each occurrence of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 independently is H, NH 2 , NHCOR 13 , —N═CHR 14 , —N═CH—R 13 , —NHCH 2 R 15 , —NHCH 2 R 13 , —NHSO 2 R 15 , —NHCONHR 15 , —N═CHR 16 , —COOR 16 , —CONR 16 R 16 , —CONR 16 R 15 , —CN, —COCH 2 Cl, —CONHNH 2 , R 17 , R 16 , —OR 16 , —SR 16 , —NO 2 , —COR 16 , —NO, —N 3 , —OCN, —NCS, —COOR 16 , —COCN, —NR 16 R 16 , —SOR 16 , —SO 2 R 16 , —SO 3 R 16 , —CH 2 OR 16 ,
alternatively, when valence permits, any two neighboring R 11 or neighboring R 11 and R 12 , together with the two carbon atoms to which they attach, form a carbon-carbon double bond or a cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, or heteroaryl group;
R 13 is R 14 , R 16 , —CH 2 OR 15 , —CH═CHR 15 , —CH 2 CHR 15 COR 16 , —C 2 H 4 OR 15 , —C 3 H 6 OR 15 , —C 2 H 4 SCOR 16 , —CH 2 SCOR 16 , —COOR 16 , —CH 2 S—R 18 , —CH 2 —R 18 , —CH═CH—R 18 , in which R 18 is cycloalkyl, 5- or 6-membered heteroaryl, or 5- to 12-memebered heterocycloalkyl and R 18 is optionally substituted with one or more of —COOR 16 , R 16 and R 17 ;
R 14 is phenyl optionally substituted with one or more R 16 ;
R 15 is phenyl optionally substituted with one or more substituents selected from R 13 and R 16 ;
R 16 is H, alkyl optionally substituted with halo or hydroxyl, alkenyl, phenyl, or —CH 2 R 14 ; and
R 17 is halo.
3. The conjugate of claim 2 , wherein the conjugate is of Formula (Ia) or (Ib):
4. A composition comprising a carrier and a conjugate of claim 1 .
5. The composition of claim 4 , being a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.
6. The composition of claim 4 , being a cosmetic composition and the carrier is a cosmetically acceptable carrier.
7. A method of treating disorder, comprising administering an effective amount of a conjugate of claim 1 in a subject in need thereof.
8. The method of claim 7 , wherein the disorder is cancer.
9. The method of claim 8 , wherein the cancer is leukemia, colon cancer, breast cancer, prostate cancer, pancreas cancer, liver cancer, skin cancer, ovary cancer, melanoma, or a sarcoma.
10. The method of claim 7 , wherein the disorder is an inflammatory disease.
11. The method of claim 10 , wherein the inflammatory disease is inflammatory bowel disease.
12. The method of claim 7 , wherein the disorder is caused by NF-κB-activation.
13. The method of claim 12 , wherein the disorder is a viral, bacterial, or fungal infection.
14. The conjugate of claim 1 , wherein the nanocarrier is comprised of cyclodextrin, a liposome, or synthetic nanoemulsion particles (LDEs) comprising a cholesteryl ester core surrounded by a phospholipid outer layer.
15. The conjugate of claim 14 , wherein the nanocarrier further comprises one or more of phosphoethanolamine, 3,7-dimethyl-2,6-octadienal, methyl salicylate, abscisic acid, natural amino acids, Ca 2+ , Zn 2+ .