Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-03
2003-09-09
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S267000, C549S270000
Reexamination Certificate
active
06617348
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the organic synthesis of chemical compounds and anti-cancer pharmaceuticals, particularly macrocyclic lactones having anti-cancer activity and vacuolar ATPase inhibitory activity and methods of synthesis and use of these compounds.
BACKGROUND OF THE INVENTION
A number of biological metabolites isolated from natural sources such as sponges, tunicates, and bacteria have been found to have anti-cancer activity. These metabolites are macrocyclic lactones such as salicylihalamide and lobatamide, which appear to represent a new mechanistic class based on their cytotoxicity profiles when compared to other compounds in NCI's standard agents database. Apicularen has also been shown to be cytostatic against human cancer cell lines (Kunze et al. (1998)). Macrolides were previously known to have cytotoxic activity and some possess anti-fungal or anti-bacterial properties. The anti-cancer activity of a class of macrolides called salicylihalamide was discovered by Boyd et al., (1997) in a screen of the cytotoxic activity of extracts from a family of sponges (species Haliclona). Two novel macrolides, salicylihalamides A and B were purified from the extract and tested in the NCI 60-cell line human tumor screen. Upon screening, these compounds demonstrated a mean-graph profile that was unlike any of the known tumor profiles of known anti-tumor agents. Therefore, these compounds represent a new class of anti-tumor agents. These compounds were especially effective against human solid tumor cell lines. Solid tumors are usually the most resistant to drugs.
Various other macrocyclic lactones have been identified as having anti-tumor activity. Included are lobatamides (isolated from
Aplidium lobatum
), apicularens (isolated from Chondromyces), and oximidines (isolated from Pseudomonas). Lobatamides contain a similar enamide side chain and core structure to salicylihalamides. However, lobatamides contain an oxime methyl ether structure at the end of the enamide side chain. The NCI 60-cell line human tumor screen profile of the lobatamides correlated with the profile of salicylihalamide (McKee et al., (1998)).
Apicularen A causes a potent growth inhibition of human cancer cell lines, the induction of an apoptotic-like cell death, and the formation of mitotic spindles with multiple spindle poles and clusters of bundled actin from the cytoskeleton (Kunze et al., 1998; Jansen et al., 2000).
The NCI 60-cell line human tumor screen is a measure of the effectiveness of a compound for inhibiting or killing various human cancers. It is a set of 60 different cancer cell lines against which chemical compounds can be tested against to determine if the compound has anti-cancer activity. Each compound has an individual “fingerprint” based on effectiveness in killing each of the 60 cancer cell lines.
Füirstner et al. (U.S. Pat. No. 5,936,100) has used ring closing metathesis as a step in the synthesis of macrocyclic lactones containing one or more polar functional groups. Macrocycles of ring sizes 12 are challenging to synthesize because the precursors tend to oligomerize.
The naturally occurring structure of salicylihalamide is unstable under certain conditions. Salicylihalamides decompose in CDCl
3
, due to the unstable side chain (Snider and Song (2000)). The present invention provides macrocyclic lactones which exhibit improved stability over the natural compound. The present invention also includes a process for the synthesis of these compounds which is particularly flexible for making various compounds. The natural compound has not previously been synthesized and its structure was misidentified when it was purified from marine sponges of the genus Haliclona. Boyd et al., in PCT/US98/15011 disclosed the structure of natural salicylihalamide with a negative rotation and assigned the absolute configuration as 12R, 13S, 15R. This assignment was incorrect because the isomer with the 12R, 13S, 15R absolute configuration has a positive rotation and does not have anti-cancer activity, as proven by the inventor in the present application. Only the isomer with the 12S, 13R, 15S absolute configuration has a negative rotation and anti-cancer activity.
The present invention describes the first synthesis of (+)-and (−)-salicylihalamide A and assigns the absolute configuration of the natural product with negative rotation as 12S, 13R, 15S. It a highly efficient, trans-selective ring-closing olefin metathesis for the assembly of the benzolactone skeleton and has been readily adapted to obtain a variety of analogs.
SUMMARY OF THE INVENTION
The invention includes a method of synthesis of a broad class of cyclic benzolactones with chemotherapeutic activity which exhibit increased stability over natural benzolactones. Included in the invention are the compounds, compositions containing the compounds, methods of synthesis, and methods of treatment.
An embodiment of the invention is a composition comprising a compound of the formula:
wherein E is
X═O, S, NR
2
; Y═CH
2
, O, S, NR
2
;
Q═O, NH;
F=ortho, meta, para substituents such as halogen, CN, OR
2
, OC(O)R
3
, NO
2
, OSO
2
R
3
, NR
2
R
2
, NR
2
C(O)R
3
, NR
2
SO
2
R
3
, R
3
;
R
1
═H, Me;
R
2
═R
1
, straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH
2
aryl, CH
2
heteroaryl, CH
2
heterocycle, CHR
1
CHR
1
, CHR
1
CHR
1
heteroaryl, CHR
1
CHR
1
heterocycle;
R
3
═R
2
or CR
1
═CR
1
aryl, CR
1
═CR
1
heteroaryl, CR
1
═CR
1
heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and Z is a contiguous linker whose presence completes an 11 to 15 membered ring. The linker can contain heteroatoms and substituents.
A further embodiment of the invention are compositions comprising compounds of the formulas:
wherein E is
X═O, NR
2
Y═CH
2
, O, S, NR
2
Q═O, NH
F=ortho, meta, para substituents such as halogen, CN, OR
2
, OC(O)R
3
, NO
2
, OSO
2
R
3
, NR
2
R
2
, NR
2
C(O)R
3
, NR
2
SO
2
R
3
, R
3
R
1
═H, Me
R
2
═R
1
, straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH
2
aryl, CH
2
heteroaryl, CH
2
heterocycle, CHR
1
CHR
1
aryl, CHR
1
CHR
1
heteroaryl, CHR
1
CHR
1
heterocycle
R
3
═R
2
or CR
1
═CR
1
aryl, CR
1
═CR
1
heteroaryl, CR
1
═CR
1
heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and R
4
═R
1
, C(O)R
3
, SO
2
R
3
, R
2
Another embodiment of the invention are compositions comprising compounds of the formulas:
where F=ortho, meta, para substituents such as halogen, CN, OR
2
, OC(O)R
3
, NO
2
, OSO
2
R
3
, NR
2
R
2
, NR
2
C(O)R
3
, NR
2
SO
2
R
3
, R
3
;
R
1
═H, Me;
R
2
═R
1
, straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH
2
aryl, CH
2
heteroaryl, CH
2
heterocycle, CHR
1
CHR
1
, CHR
1
CHR
1
heteroaryl, CHR
1
CHR
1
heterocycle;
R
3
═R
2
or CR
1
═CR
1
aryl, CR
1
═CR
1
heteroaryl, CR
1
═CR
1
heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
R
4
═R
1
, C(O)R
3
, SO
2
R
3
, R
2
An embodiment of the invention is a a composition wherein the compound is selected from the group consisting of
wherein R=straight chain saturated alkyl or straight chain unsaturated alkyl that is comprised of a chain of 5 to 8 carbons.
An embodiment of the invention is a composition wherein the compound is of the formula:
wherein R=straight chain saturated alkyl or straight chain unsaturated alkyl that is comprised of a chain of 5 to 8 carbons
An embodiment of the invention is a composition comprising a compound of the formula:
An embodiment of the invention is a composition comprising a compound of the formula:
An embodiment of the invention is a composition comprisin
De Brabander Jef Karel
Wu Yusheng
Owens Amelia A.
UT Southwestern Medical Center
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