Triterpene saponins, methods of synthesis, and uses thereof
View Patent ↗The present invention relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, intermediates thereto, and uses thereof. QS-7 is a potent immuno-adjuvant that is significantly less toxic than QS-21, a related saponin that is currently the favored adjuvant in anticancer and antiviral vaccines. Tedious isolation and purification protocols have hindered the clinical development of QS-7. A novel semi-synthetic method is provided wherein a hydrolyzed prosapogenin mixture is used to synthesize QS-7, QS-21, and related analogs, greatly facilitating access to QS-7 and QS-21 analogs for preclinical and clinical evaluation.
1. A method comprising the steps of:
(a) providing a mixture of prosapogenins of formula IV-a:
wherein:
is a single or double bond;
Y′ is hydrogen, halogen, alkyl, aryl, OR, OR y , OH, NR 2 , NHR, NH 2 , SR, or NROR;
W is Me, —CHO,
—CH 2 OR x , or —C(O)R y ;
V is hydrogen or —OR x ;
R y is —OH, or a carboxyl protecting group, wherein the carboxyl protecting group, when taken with its attached carbonyl group, is an ester, amide, or hydrazide;
R s1 is
each occurrence of R x′ is independently an optionally substituted group selected from 6-10-membered aryl, C 1-6 aliphatic, or C 1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
or:
two R x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12 aliphatic, or C 1-12 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
each occurrence of R x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates;
(b) treating said mixture of prosapogenins of formula IV-a under suitable conditions to form a mixture of prosapogenins of formula IV:
wherein each of , R y ′ Y′, V, and W is as defined for compounds of formula IV-a, and each occurrence of R x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates;
R s is
with the proviso that at least one R x group is not hydrogen;
and
(c) obtaining a prosapogenin of formula IV by suitable physical means.
2. The method according to claim 1 , wherein the mixture of prosapogenins of formula IV-a comprises compounds A and B:
3. The method according to claim 1 , wherein the mixture of prosapogenins of formula IV-a comprises compound A.
4. The method according to claim 2 , wherein the prosapogenin of formula IV is:
5. The method according to claim 1 , wherein each R x is independently trialkylsilyl or arylalkyl.
6. The method according to claim 5 , wherein R x is —SiEt 3 or benzyl.
7. The method according to claim 1 , wherein W is CHO.
8. The method according to claim 1 , wherein V is OH for a prosapogenin of formula IV-a and OR x for a prosapogenin of formula IV.
9. The method according to claim 1 , wherein the suitable physical means is chromatography.
10. The method according to claim 1 further comprising:
(d) treating the prosapogenin of formula IV under suitable conditions with a compound of formula V:
LG-Z V
wherein:
Z is a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, and heteroaryl; or Z comprises a carbohydrate domain having the structure:
wherein:
each occurrence of R 1 is R x or a carbohydrate domain having the structure:
wherein:
each occurrence of a, b, and c is independently 0, 1, or 2;
d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or pyranose moiety, and the sum of b and c is 1 or 2;
R o is hydrogen, an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R a , R b , R c , and R d is independently hydrogen, halogen, OH, OR, OR x , NR 2 , NHCOR, or an optionally substituted group selected from acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 2 is hydrogen, halogen, OH, OR, OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 , OC(O)NRR 4 , OC(O)SR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , NHC(O)NHR 4 , NHC(O)NRR 4 , N(R 4 ) 2 , NHR 4 , NRR 4 , N 3 , or an optionally substituted group selected from C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is hydrogen, halogen, CH 2 OR 1 , or an optionally substituted group selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 4 is
wherein X is —O— or —NR—; or
T-R z , wherein:
T is a covalent bond or a bivalent C 1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and
R z is hydrogen, halogen, —OR, —OR x , —OR 1 , —SR, —NR 2 , —NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; or
two R 4 on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
LG is a suitable leaving group selected from the group consisting of halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl, and diazonium moieties; or a suitable glycoside donor leaving group;
to give a compound of formula I:
wherein Y is CH 2 , —O—, —NR—, or —NH—.
11. The method according to claim 10 , wherein the compound of formula V is a compound of formula VI:
wherein:
each occurrence of R 1 is R x or a carbohydrate domain having the structure:
wherein:
each occurrence of a, b, and c is independently 0, 1, or 2;
d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or pyranose moiety, and the sum of b and c is 1 or 2;
R o is hydrogen, an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R a , R b , R c , and R d is independently hydrogen, halogen, OH, OR, OR x , NR 2 , NHCOR, or an optionally substituted group selected from acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 2 is hydrogen, halogen, OH, OR, OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 , OC(O)NRR 4 , OC(O)SR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , NHC(O)NHR 4 , NHC(O)NRR 4 , N(R 4 ) 2 , NHR 4 , NRR 4 , N 3 , or an optionally substituted group selected from C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is hydrogen, halogen, CH 2 OR 1 , or an optionally substituted group selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 4 is
wherein X is —O— or —NR—; or
T-R z , wherein:
T is a covalent bond or a bivalent C 1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and
R z is hydrogen, halogen, —OR, —OR x , —OR 1 , —SR, —NR 2 , —NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; or
two R 4 on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-6 aliphatic, or C 1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
LG 1 is a glycoside donor leaving group.
12. The method according to claim 11 , wherein the compound of formula VI is of formula VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, or VI-8:
wherein:
R 2 is hydrogen, halogen, OH, OR, OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 , OC(O)NRR 4 , OC(O)SR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , NHC(O)NHR 4 , NHC(O)NRR 4 , N(R 4 ) 2 , NHR 4 , NRR 4 , N 3 , or an optionally substituted group selected from C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is hydrogen, halogen, CH 2 OR 1 , or an optionally substituted group selected from the group consisting of acyl, C 1-10 aliphatic, C 1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 4 is
wherein X is —O— or —NR—; or
T-R z , wherein:
T is a covalent bond or a bivalent C 1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and
R z is hydrogen, halogen, —OR, —OR x , —OR 1 , —SR, —NR 2 , —NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; or
two R 4 on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates;
R y is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides;
each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12 aliphatic, or C 1-12 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or:
two R on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
LG 1 is a glycoside donor leaving group.
13. The method according to claim 11 , wherein the compound of formula VI is selected from:
14. The method according to claim 10 , wherein the prosapogenin of formula IV is of formula IV-b:
15. The method according to claim 10 , wherein the prosapogenin of formula IV is:
16. The method according to claim 10 , wherein the compound of formula I is of formula I-a: